1. Healthcare

cancercontroljournal.org Vol. 22, No. 1, January 2015
H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE, AN NCI COMPREHENSIVE CANCER CENTER
Safety of the Blood Supply
German F. Leparc, MD
Adverse Effects of Transfusion
Radhika Dasararaju, MD, and Marisa B. Marques, MD
Clinical Effects of Red Blood Cell Storage
Lirong Qu, MD, PhD, and Darrell J. Triulzi, MD
Transfusion Indications for Patients With Cancer
Thomas Watkins, DO, PhD, Maria Katarzyna Surowiecka, MD,
and Jeffrey McCullough, MD
Platelet Transfusion for Patients With Cancer
Craig H. Fletcher, MD, Melkon G. DomBourian, MD,
and Peter A. Millward, MD
Transfusion Support Issues in Hematopoietic Stem Cell
Transplantation
Claudia S. Cohn, MD, PhD
Therapeutic Apheresis for Patients With Cancer
Laura S. Connelly-Smith, MBBCh, DM, and Michael L. Linenberger, MD
Using HLA Typing to Support Patients With Cancer
Mark K. Fung, MD, PhD, and Kaaron Benson, MD
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January 2015, Vol. 22, No. 1
Cancer Control 1
Editorial Board Members
Editor:
Lodovico Balducci, MD
Senior Member
Program Leader, Senior Adult Oncology Program
Moffitt Cancer Center
Deputy Editor:
Julio M. Pow-Sang, MD
Senior Member
Chair, Department of Genitourinary Oncology
Director of Moffitt Robotics Program
Moffitt Cancer Center
Editor Emeritus:
Rami Komrokji, MD
Associate Member
Malignant Hematology
Conor C. Lynch, PhD
Assistant Member
Tumor Biology
Amit Mahipal, MD
Assistant Member
Clinical Research Unit
Gastrointestinal Oncology
Kristen J. Otto, MD
Assistant Member
Head & Neck Oncology
John Horton, MB, ChB
Professor Emeritus of Medicine & Oncology
Michael A. Poch, MD
Assistant Member
Genitourinary Oncology
Moffitt Cancer Center
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Assistant Member
Endocrine Tumor Oncology
Aliyah Baluch, MD
Assistant Member
Infectious Diseases
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Assistant Member
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Associate Member
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All rights reserved.
Cancer Control: Journal of the Moffitt Cancer Center is a peer-reviewed journal that is published to enhance the knowledge needed by professionals in oncology to help them minimize the
impact of human malignancy. Each issue emphasizes a specific theme relating to the detection or management of cancer. The objectives of Cancer Control are to define the current state of
cancer care, to integrate recently generated information with historical practice patterns, and to enlighten readers through critical reviews, commentaries, and analyses of recent research studies.
DISCLAIMER: All articles published in this journal, including editorials and letters, represent the opinions of the author(s) and do not necessarily reflect the opinions of the editorial board, the H.
Lee Moffitt Cancer Center & Research Institute, Inc, or the institutions with which the authors are affiliated unless clearly specified. The reader is advised to independently verify the effectiveness
of all methods of treatment and the accuracy of all drug names, dosages, and schedules. Dosages and methods of administration of pharmaceutical products may not be those listed in the
package insert and solely reflect the experience of the author(s) and/or clinical investigator(s).
January 2015, Vol. 22, No. 1
Cancer Control 1
Table of Contents
Editorial
Transfusion Medicine Issues Pertaining to Patients With Cancer
4
Kaaron Benson, MD
Articles
Safety of the Blood Supply
7
German F. Leparc, MD
Adverse Effects of Transfusion
16
Radhika Dasararaju, MD, and Marisa B. Marques, MD
Clinical Effects of Red Blood Cell Storage 26
Lirong Qu, MD, PhD, and Darrell J. Triulzi, MD
Transfusion Indications for Patients With Cancer 38
Thomas Watkins, DO, PhD, Maria Katarzyna Surowiecka, MD, and Jeffrey McCullough, MD
Platelet Transfusion for Patients With Cancer
47
Craig H. Fletcher, MD, Melkon G. DomBourian, MD, and Peter A. Millward, MD
Transfusion Support Issues in Hematopoietic Stem Cell Transplantation 52
Claudia S. Cohn, MD, PhD
Therapeutic Apheresis for Patients With Cancer 60
Laura S. Connelly-Smith, MBBCh, DM, and Michael L. Linenberger, MD
2 Cancer Control
January 2015, Vol. 22, No. 1
Table of Contents
Using HLA Typing to Support Patients With Cancer 79
Mark K. Fung, MD, PhD, and Kaaron Benson, MD
Departments
Special Report: Mobilization and Transplantation Patterns of Autologous
Hematopoietic Stem Cells in Multiple Myeloma and Non-Hodgkin Lymphoma
87
Luciano J. Costa, MD, PhD, Shaji Kumar, MD, Stephanie A. Stowell, MPhil, and Shari J. Dermer, PhD
Special Report: Functional Health Literacy, Chemotherapy Decisions, and Outcomes Among a Colorectal Cancer Cohort
95
Evan L. Busch, MPH, Christopher Martin, MSPH, Darren A. DeWalt, MD, and Robert S. Sandler, MD
Pathology Report: Familial Gastrointestinal Stromal Tumor Syndrome: Report of 2 Cases With KIT Exon 11 Mutation
102
Derek H. Jones, MD, Jamie T. Caracciolo, MD, Pamela J. Hodul, MD, Jonathan R. Strosberg, MD,
Domenico Coppola, MD, and Marilyn M. Bui, MD, PhD
Tumor Biology: Current and Emerging Therapies for Bone Metastatic Castration-Resistant Prostate Cancer
109
Jeremy S. Frieling, David Basanta, PhD, and Conor C. Lynch, PhD
Ten Best Readings Relating to Transfusion Medicine
121
About the art in this issue:
Ray Paul began drawing and painting as a young boy, so art has always been part of his life. Animals and images from National Geographic
magazine were his early subjects. Growing up in Ohio, dreams of Florida and all things tropical helped him survive the dreary winters and
infused his palette with saturated hues. This and his fascination with science led him to Florida State University where he received a bachelor of
science in biology in 1986. Returning to his first love, art, Paul earned a master of fine arts in painting from the University of Cincinnati in 1991.
Paul currently resides in Tampa, Florida, where he maintains a studio. His work is a synthesis of life experiences and a desire to illuminate the
subconscious. Elements of abstract expressionism, surrealism, pop art, biology, and psychedelic music all combine and intertwine, creating a
unique style of abstract painting. Each work is an experiment as different paints mix and swirl, with meticulous layering providing the final touch.
Paul was diagnosed with high-grade myxofibrosarcoma and is currently a patient at the Moffitt Cancer Center in Tampa and has undergone
9 surgeries, 2 courses of radiation therapy, chemotherapy, and participated in a clinical trial. This experience has led Paul to a greater understanding and appreciation of his work. He envisions his art to be a prescient, visual manifestation of the battle raging within and a powerful
testament to the beauty of hope.To view more of his work or to contact the artist, please visit www.raypaulart.com.
Cover:
Pink Rorschach, triptych (detail: 3, right panel), 2010. Acrylic, latex, enamel on canvas, 20" × 16".
Pages: 2-3Dendritic Swarm, 2013. Acrylic, latex, enamel on canvas, printed with an image of myxofibrosarcoma
with metastases to the artist’s lung, 11" × 17".
Petal Purple, 2010. Acrylic, latex, enamel on canvas, 12" × 12".
Sweet Jane, 2007. Acrylic, latex, enamel on canvas, 37" × 3".
Private collection of the Mathematical Oncology Department at Moffitt Cancer Center, Tampa, FL.
Blue Marble, 2007. Acrylic, latex, enamel on wood, 49" × 64". Private collection.
Flowers for Phoebe, 2010. Acrylic, latex, enamel on canvas, 48" × 48". Private collection.
SP12-6796 × 40, 2013. Acrylic, latex, enamel on canvas, printed with an image of myxofibrosarcoma
with metastases to the artist’s lung, 26" × 36".
Dark Shadows, 2010. Acrylic, latex, enamel on canvas, 30" × 30".
Currant, 2014. Acrylic, latex, enamel on canvas, 20" × 20".
January 2015, Vol. 22, No. 1
Cancer Control 3
Editorial
Transfusion Medicine Issues Pertaining to Patients With Cancer
In the United States, blood transfusion was the most
common procedure performed in hospitals in 2010
and occurred in 11% of hospital stays requiring at least
1 procedure.1 Red blood cells (RBCs) are the most likely
blood component to be transfused due to their role in
treating symptomatic anemia. RBC units are often provided to patients with cancer because anemia occurs in
more than 40% of these patients.2 Most patients receiving
chemotherapy can be expected to require RBCs, platelet
transfusions, or both during the course of therapy.3 Currently, approximately 80% of all platelet transfusions are
administered to patients with hypoproliferative thrombocytopenia, generally due to chemotherapy, hematopoietic stem cell transplantation, or underlying disease.4
Although blood transfusions can be life-saving measures
and allow for more aggressive therapy, they are not
without risk. This issue of Cancer Control addresses
select issues related to transfusion medicine that pertain
to patients with cancer.
Measures to improve the safety of the blood supply
have resulted in the lowest rates of transfusion-transmissible infection and disease since blood was first used.
Although post-transfusion hepatitis occurred in about
one-third of multiple-transfused patients in the 1960s,
today transfusion-transmitted rates of hepatitis B and
C viruses each result in about 1 case per 1 million units
transfused.5,6 The risk of transfusion-transmitted HIV
infection was around 1% in metropolitan areas like San
Francisco in the early 1980s.7 Currently, the risk of HIV
transmission via blood in the United States is less than
1 per 1 million units transfused.5 Mitigation strategies to
lower the rates of nonviral transfusion adverse events
have also allowed for reaction rates well below previous
rates of about 5%; current averages are typically less than
1%. Measures such as leukoreduction, γ irradiation, and
the preparation of male-only donor plasma have lowered
risks of human leukocyte antigen (HLA) alloimmunization, transfusion-associated graft-vs-host disease, and
transfusion-related acute lung injury, respectively. The
annual transfusion reaction rates at the H. Lee Moffitt
Cancer Center & Research Institute have consistently
been 0.6% for the last 3 years, with many of these events
being fever occurring during transfusion and likely due
to neutropenia, not the blood infused.
In this issue of Cancer Control, Dr Leparc reviews
the blood donation process and safety measures currently employed to reduce the risks of transfusion
transmitted disease. Drs Dasararaju and Marques cover
4 Cancer Control
nonviral transfusion adverse events and their diagnosis, treatment, and prevention. Whether older units of
blood result in significant harm to recipients has been
questioned recently, and Drs Qu and Triulzi review the
storage lesion and summarize key study results, including data from recent randomized controlled trials.
Blood transfusion can be misused and unnecessary
transfusion is a common problem. Drs Watkins, Surowiecka, and McCullough address the appropriate use
of RBCs, plasma, and granulocytes, and Drs Fletcher,
DomBourian, and Millward cover indications for platelet transfusion. Most blood components are given for
therapeutic benefit due to anemia, bleeding, or both.
Platelets are the one component commonly used prophylactically — generally in the oncology setting for patients with hypoproliferative thrombocytopenia. Whether selected populations of patients could be moved to
receive therapeutic platelet transfusion alone is an area
of current investigation and preliminary data suggest
that this may be possible.8,9 Blood component support
in patients receiving hematopoietic stem cell transplantation can present unique challenges and this topic is
reviewed by Dr Cohn. She focuses on the pre-, peri-,
and post-transplantation treatment periods, with special
attention to ABO-incompatible recipient–donor pairings.
The transfusion service must provide blood components
to minimize hemolysis and other adverse events, such as
transfusion-associated graft-vs-host disease and transfusion-transmitted cytomegalovirus infection.
Apheresis technology can be applied in both the
donor and patient settings. Apheresis platelets, plasma, and RBCs (the equivalent of 2 units of RBCs from
1 donor) are commonly collected from volunteer donors.
Therapeutic aphereses are often performed for the treatment of several oncological diseases. As in the donor
population, blood fractions such as plasma, leukocytes,
RBCs, or platelets can be selectively removed. Unique
to therapeutic apheresis is the option to modify the
collected component as in extracorporeal photopheresis
before reinfusion back to the patient. Drs Connelly-Smith
and Linenberger review indications for use of therapeutic apheresis as well as a number of practical issues to
consider when beginning these specialized procedures.
The HLA system is crucial in our immune response;
it may play a role in our response to certain medications,
may increase our risk for certain diseases, and has a
critical function in both solid organ and hematopoietic stem cell transplantation. Dr Fung and I address
January 2015, Vol. 22, No. 1
HLA assays commonly performed today and their use
in pharmacogenomics, disease association, and platelet
transfusion and transplantation.
The American Board of Internal Medicine Foundation has initiated a campaign known as Choosing Wisely
to help health care professionals reduce the overuse
of tests and procedures, and the AABB (formerly the
American Association of Blood Banks) developed a list
of 10 recommendations in support of this campaign as
well as to promote better blood management among
patients.10 The first recommendation is to avoid transfusing more blood than absolutely necessary, noting that a
restrictive threshold of 7.0 to 8.0 g/dL should be used for
the vast majority of stable, hospitalized patients without
evidence of inadequate tissue oxygenation.10 In addition,
single RBC unit transfusions — instead of the traditional
minimum 2 units — should be the new standard for
hospitalized patients without bleeding.10 Although blood
transfusion has allowed for the aggressive treatment of
patients with cancer, it is not without risk and must be
judiciously used in this patient population.
The next 3 AABB recommendations are also apropos
to patients with cancer, cautioning health care professionals
to avoid transfusing RBCs for iron deficiency in patients
without hemodynamic instability.10 Iron deficiency anemia
should be treated with oral and/or intravenous iron supplementation in such cases. Another recommendation relates
to blood components, such as plasma, which the AABB
notes should not be routinely used to reverse warfarin
because vitamin K alone is often sufficient.10 Prothrombin
complex concentrates offer advantages over plasma transfusion in more emergent situations such as in the setting
of significant bleeding, nonelective surgery, or both. The
AABB also recommends against performing serial blood
counts on patients who are clinically stable.10 Hospitalized patients with new clinically significant conditions may
require frequent blood counts to be performed; however,
the AABB notes that serial counts in stable patients are
unlikely to benefit patient care and are likely to result in
iatrogenic anemia.10
In order to improve outcomes among our patients
requiring blood transfusion, we must apply patient
blood management (PBM), which is the use of efficacious and safe medical and surgical techniques to prevent anemia, treat anemia, or both, as well as decrease
the risk of bleeding and optimize hemostasis.11 When
providing blood transfusion therapy to our patients, we
must provide the right blood component in the right
amount at the right time to maximize the clinical benefit
and minimize any potential adverse effects.
In addition to the topics relating to transfusion
medicine, 2 Special Reports are also included in this
issue. In the first report, Dr Costa and coauthors discuss
the mobilization and transplantation patterns of autologous hematopoietic stem cells in multiple myeloma
and non-Hodgkin lymphoma. In the second, Dr Busch
January 2015, Vol. 22, No. 1
and colleagues review the functional health literacy,
chemotherapy decisions, and outcomes among a cohort
of volunteers with colorectal cancer.
Also included in the January issue of Cancer Control is a Pathology Report by Dr Jones and others who
present 2 cases of familial gastrointestinal stromal tumor
syndrome with KIT exon 11 mutations. Mr Frieling and
colleagues have authored a Tumor Biology Report discussing the current and emerging therapies for bone
metastatic castration-resistant prostate cancer.
We hope you enjoy and benefit from reading this
issue of Cancer Control.
Kaaron Benson, MD
Senior Member
Director, Blood Bank, HLA, Chemistry, Specimen Processing,
Implantable Tissues
Department of Hematopathology and Laboratory Medicine
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida
[email protected]
References
1. Pfuntner A, Wier LM, Stocks C. Most Frequent Procedures Performed
in U.S. Hospitals, 2010. Rockville, MD: Agency for Healthcare Research and
Quality; 2013. http://hcup-us.ahrq.gov/reports/statbriefs/sb149.pdf. Accessed
November 25, 2014.
2. Shander A, Knight K, Thurer R, et al. Prevalence and outcomes of
anemia in surgery: a systematic review of the literature. Am J Med. 2004;
g116(suppl 7A):58S-69S.
3. Tas F, Eralp Y, Basaran M, et al. Anemia in oncology practice: relation
to diseases and their therapies. Am J Clin Oncol. 2002;25(4):371-379.
4. Fung MK, Grossman BJ, Hillyer C, et al, eds. Technical Manual. 18 ed.
Bethesda, MD: AABB; 2014.
5. Zou S, Stramer SL, Dodd RY. Donor testing and risk: current prevalence, incidence, and residual risk of transfusion-transmissible agents in US
allogeneic donations. Transfus Med Rev. 2012;26(2):119-128.
6. Stramer SL. Tibor Greenwalt memorial award and lectureship: getting
to 1 in a million and beyond. Paper presented at: AABB Annual Meeting;
Philadelpha, PA; October 25–28, 2014
7. Busch MP, Young MJ, Samson SM, et al; Transfusion Safety Study
Group. Risk of human immunodeficiency virus (HIV) transmission by
blood transfusions before the implementation of HIV-1 antibody screening.
Transfusion. 1991;31(1):4-11.
8. Wandt H, Schaefer-Eckart K, Wendelin K, et al. Therapeutic platelet
transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study. Lancet.
2012;380(9850):1309-1316.
9. Stanworth SJ, Estcourt LJ, Llewelyn CA, et al. Impact of prophylactic platelet transfusions on bleeding events in patients with hematologic
malignancies: a subgroup analysis of a randomized trial (CME). Transfusion.
2014;54(10):2385-2393.
10. Callum JL, Waters JH, Shaz BH, et al. The AABB recommendations for
the Choosing Wisely campaign of the American Board of Internal Medicine.
Transfusion. 2014;54(9):2344-2352.
11. Society for the Advancement of Blood Management. What is patient
blood management? http://www.sabm.org/sites/www.sabm.org/files/sabmpbmawpresentation2012.pdf. Accessed November 25, 2014.
Cancer Control 5
Department of Hematopathology and Laboratory Medicine
H. Lee Moffitt Cancer Center & Research Institute
The Department of Hematopathology and Laboratory Medicine at the H. Lee Moffitt Cancer Center &
Research Institute performs a variety of routine and highly specialized diagnostic services and testing for the
care of oncology and blood and marrow transplant patients with the mission of contributing to the prevention and
cure of cancer. The department consists of the Hematology, Chemistry, Microbiology/Virology, Blood Bank, HLA,
Histocompatibility, Flow Cytometry, Specimen Processing, Bone Marrow Service, and Molecular Diagnostics
divisions. The laboratory is equipped with state-of-the-art instrumentation represented by more than 80 platforms. The Microbiology laboratory works with the Infection Control team to ensure low-infection rates for the
immunocompromised patient population, and the HLA laboratory works closely with the Blood and Marrow
Transplant Program to ensure the accurate and timely HLA typing of both patients and donors.
Hematopathology/Laboratory Medicine Department
Department Chair
Lynn Moscinski, MD
Blood Bank, HLA, Chemistry, Medical Director
Kaaron Benson, MD
Microbiology/Virology Medical Director
Ramon Sandin, MD
Moffitt International Plaza Medical Director
Elizabeth Sagatys, MD
Hematopathology Fellowship Director
Ling Zhang, MD
Hematopathologists
Pedro Horna, MD
Mohammad Hussaini, MD
Haipeng Shao, MD, PhD
Jinming Song, MD
Jianguo Tao, MD, PhD
Hailing Zhang, MD
Xiaohui Zhang, MD, PhD
Clinical Molecular Diagnostics Director
Dahui Qin, MD, PhD
Molecular/FISH Director
Kenian Liu, PhD
This academic department participates in the teaching of medical students, residents, and clinical hematopathology
fellows in its accredited fellowship program. Research is also a significant component of the academic mission of
the department and its pathologists are engaged in collaborating with other Moffitt Cancer Center investigators
and researchers on clinical trials and the publication of study results. One of the main focuses of the department
has been the identification and application of new prognostic markers in the myeloid malignancies of bone
marrow, particularly myelodysplasia and acute myelogenous leukemia. The pathologists also work with other Moffitt
programs in creating algorithmic pathways that provide a standardized tool to guide patient care and treatment
plans as well as the translation of new discoveries into clinical diagnostics — new testing and methodologies are
continuously being added.
For more information about the Department of Hematopathology and Laboratory Medicine,
please call 813-745-4162 (during normal business hours).
www.MOFFITT.org
6 Cancer Control
January 2015, Vol. 22, No. 1
Blood transfusion is an invasive medical
procedure that carries inherent hazards,
so a risk–benefit profile must be considered
in patients with cancer.
Ray Paul. Dendritic Swarm, 2013. Acrylic, latex, enamel on canvas printed with
an image of myxofibrosarcoma with metastases to the artist’s lung, 11" × 17".
Safety of the Blood Supply
German F. Leparc, MD
Background: The transfusion of blood components plays a significant role as supportive therapy in the treatment of patients with cancer. Although blood transfusions help manage complications arising from either
the patient’s primary condition or associated with therapeutic intervention, their use introduces a new set of
risks; therefore, health care professionals must be aware of the potential morbidity introduced by using blood
components and endeavor to optimize outcomes by ordering transfusions only when the benefits outweigh the
inherent risks.
Methods: This article sought to review the published literature, including the epidemiology of diseases transmissible
via transfusion, performance characteristics for assays used for blood donor screening, surveillance activities to
detect newly emergent pathogens, and biovigilance activities reported by public health authorities.
Results: Effective measures have been implemented to significantly decrease the risk of transmissible diseases
associated with transfusion. Reports of viral disease transmitted via transfusion have been nearly eliminated,
particularly since the introduction of molecular-based detection technology. The transmission of bacteria
and parasites still represents a threat to the use of cellular blood components. Transfusion-associated human
prion disease has not been reported in the United States. Immune-mediated reactions due to donor–recipient
incompatibility remain a challenge.
Conclusions: Transmissible agents most commonly associated with risks due to transfusion are no longer a
major threat; however, a significant challenge remains with regard to addressing the need for quick response
mechanisms to manage emerging pathogens with the potential for rapid spread, either unintentionally
(eg, globalization) or intentionally (eg, bioterrorism). The use of technology to reduce pathogens holds promise
for further increasing the safety profile of blood transfusion.
Background
Although many of the risks associated with blood
transfusions have been recognized ever since the be-
From OneBlood and Creative Testing Solutions, St Petersberg, Florida.
Submitted June 8, 2014; accepted September 11, 2014.
Address correspondence to German F. Leparc, MD, OneBlood, 10100
Dr Martin Luther King Jr Steet North, St Petersburg, FL 33716.
E-mail: [email protected]
No significant relationship exists between the author and the companies/organizations whose products or services may be referenced
in this article.
January 2015, Vol. 22, No. 1
ginning of the use of transfusions, the emergence of
HIV transmission brought the safety of the blood supply into the limelight of the public. Since then, significant resources have been committed to implementing
strategies to reduce the risk of transfusion-transmitted
disease. Although challenges remain, significant advances have been made.
A tight, multilayered safety net has been woven
into the system. Volunteer donors must meet strict
criteria, aseptic techniques are used to collect blood in
single-use disposable containers, testing is performed
for various markers of present or past infection, and
Cancer Control 7
passive and active biovigilance activities are in place
before and after blood components are transfused.
In addition to the risk of transmissible diseases,
blood components carry inherent risks associated
with the presence of immunoactive effectors that interact with the host (blood recipient). These agents
vary and can include immunoglobulins (antibodies),
antigenic substances (phenotypes on cellular elements
and plasma proteins), and various biological response
modifiers (eg, cytokines, chemokines). Unlike chemical drugs and biological agents manufactured in a
controlled pharmacological setting, blood components
exhibit significant biological variability that impacts
the achievement of desired outcomes as well as the
manifestation of undesired adverse events.
When considering the safety of blood transfusion, one must discriminate between the safety of the
product to be transfused (ie, the biological contents)
and the safety of the transfusion process (ie, pretransfusion testing, product administration, dosage,
presence of indications or contraindications, risk vs
benefit of such an intervention). In this manuscript,
the aspects surrounding the safety of the transfusion
product alone have been considered.
Transfusion-Transmitted Viral Agents
Hepatitis B Virus
Not long after the transfusion of whole blood or its
components became available in routine medical and
surgical treatments was its association with hepatitis
virus infection recognized. The introduction of the test
for hepatitis B surface antigen (HBsAg) in the early
1970s allowed the interdiction of units collected from
individuals with either subclinical acute or chronic
forms of the infection.1 However, the kinetics of the
hepatitis B virus (HBV) infection leaves 2 different
periods when screening for the presence of HBsAg
fails to prevent transmission: (1) an early acute phase
when the viral load is below the assay’s limit of detection, and (2) a late chronic phase when HBsAg levels
gradually become undetectable although infectivity
remains. The introduction of molecular techniques
(nucleic acid testing [NAT]) decreases the serological
period of infectivity by decreasing the limit of detection for the presence of the viral genome. Laboratories
in numerous countries, including the United States,
have also added a test to detect the presence of antibodies directed against a viral core protein (hepatitis
B core antibody) to detect chronic carriers who may
have levels of viremia below those detectable even
by molecular techniques, a condition known as occult
hepatitis B.2 The use of the 3 markers — HBsAg, hepatitis B core antibody, and HBV-NAT — has reduced the
residual risk of transfusion-transmitted HBV infection
to approximately 1 per 1 million donations, and the
rate of clinical hepatitis continues to decrease as a
8 Cancer Control
larger segment of the population becomes immunized
through vaccination.3
Hepatitis C Virus
Following the implementation of first- and second-generation assays for HBsAg and the development of
serological tests for hepatitis A virus, a distinct viral
entity other than the 2 associated with the majority
of cases of post-transfusion hepatitis was detected.
After decades of work, hepatitis C virus (HCV) was
molecularly characterized in the late 1980s using cloning techniques.4 It was a significant achievement because the virus could not be sustained in cell cultures.
Screening tests were developed to detect the presence
of anti-HCV antibodies and helped identify asymptomatic HCV carriers in the blood donor population. The
use of the screening assay represented a significant
advance because approximately 80% of individuals
who become infected with HCV remain viremic for
the remainder of their lives (unless treated).5 Most of
these individuals are also asymptomatic for decades;
by contrast, about 20% of those infected with HCV
have spontaneous viral clearance.5 However, because
of the prolonged seroconversion period, which lasts
for more than 50 days, approximately 1 out of 230,000
donations with no demonstrable antibodies contain
viral RNA.6 The introduction of NAT to detect viremia
soon after a 10-day, ramp-up viral replication period
has reduced the residual risk of transfusion-transmitted HCV infection to 1 in 1.93 million donations.7
HIV
As the worldwide HIV epidemic unfolded, blood transfusion was recognized early on as an efficient means
of HIV transmission. The emergence of this retrovirus
focused attention on the safety of the blood supply
and the importance of the development of rapid-response mechanisms to detect the rise of new threats
to protect blood recipients. A serological test to detect
the presence of anti-HIV antibodies was introduced in
1985 that allowed the interdiction of the vast majority
of HIV-infected units.8 Similar to other screening assays based on the detection of donor seroconversion,
infection in the donor could not be detected for approximately 22 days; however, this period was reduced
by 11 days with the introduction of NAT.9 As a result,
the residual risk of HIV transmission associated with
transfusion has been reduced to 1 in 2.135 million.10
West Nile Virus
West Nile virus is an emergent pathogen first isolated
in samples obtained from patients in Uganda in 1937.
Its presence was unknown on the North American
continent until 1999 when it was found in patients
diagnosed with neurological disease.11 Several species
of mosquitos function as vectors for the virus, which
January 2015, Vol. 22, No. 1
finds its reservoir in migrating birds; humans and
horses are accidental hosts. More than 90% of individuals infected with West Nile virus remain asymptomatic, and, of those affected, mild, flu-like symptoms
without sequelae are the most common presentation;
however, 0.6% of infected persons will progress to
neuroinvasive disease that results in meningoencephalitis and possibly death.12 Individuals who remain
asymptomatic but donate blood while viremic pose
a risk to blood recipients, particularly among those
who are immunosuppressed, the elderly, and infants.
The risk of transmission is highest during the months
when both the reservoir bird and mosquito populations peak, which occurs predominantly during summer, possibly extending to early fall in some regions
of the United States. In 2002, the implementation of
NAT for West Nile virus decreased the risk of transmission; however, residual risk rates are highly variable
and depend on climactic and geographical factors that
modify the location and duration of endemic areas.13
Annual reports indicate a paucity of cases linked to
blood transfusion since 2010.14
confirmed transmissions of HHV-8 via the same route
have not been linked to the presentation of diseases
known to be associated with it (eg, Kaposi sarcoma,
malignant lymphoproliferative disorders).
Parvovirus B19
Infection with parvovirus B19, a nonenveloped erythrovirus, manifests differently in distinct patient populations. In utero, the infected fetus develops severe
anemia that results in hydrops fetalis; in children, the
infection results in the exanthematous fifth disease;
and, in adults, it may result in mild disease, including
fever, myalgia, rash, arthropathy, and, occasionally, red
cell aplasia in vulnerable individuals with ongoing
hemolytic processes (eg, autoimmune or drug-related
anemias, sickle cell disease). Concerns exist regarding the hypothetical possibility of the compromise
of hematopoietic tissue engraftment due to parvovirus infection during the early transplantation stages;
however, no reports of such associations have been
published. The transmission of parvovirus B19 via
transfusion has been documented, but morbidity has
been limited, even in immunocompromised patients.18
This is despite epidemiological evidence that the
virus is a relatively common contaminant in the blood
supply and the incidence of transfusion-transmitted
parvovirus B19 infection is likely under-reported.19
Human T-Cell Lymphotropic Virus
The potential for HIV transmissibility through blood
transfusion has raised concern about other retroviruses that, although they are not as pathogenic, could
spread to the general population through the use of
blood components. Two strains of human T-cell lymphotropic virus (HTLV), HTLV-1 and HTLV-2, were targeted for detection. Although HTLV-1 has been linked
to adult T-cell leukemia, HTLV-associated myelopathy,
and tropical spastic paraparesis, no firm link to disease entities has been found for HTLV-2.15 The virus
is transmitted through cellular components alone and
infectivity of the product declines with storage time,
particularly when stored beyond 10 days.15 A total of
1% of those infected will develop disease associated
with the infection. An immunoassay approved by the
US Food and Drug Administration (FDA) is used to
detect the presence of anti-HTLV-1 and 2 antibodies,
although its rate of specificity is not optimal.16 The
residual risk of transmission is low (1 in 3 million).10
Hepatitis A and E Viruses
Although hepatitis A and E viruses are both predominantly transmitted via the oral–fecal route, sporadic
transmissions via blood transfusion have been reported. In most of the reported cases, mild, temporary liver inflammation has occurred. Because the incidence
of transfusion-associated transmission is low in most
developed countries (although some regions within
developed countries may show significant endemicity
rates), testing the blood supply is not warranted at this
time.20 However, given that pathogen-reduction methods have not eliminated the risk of hepatitis A virus
transmission, and the incidence of hepatitis E virus
is increasing in Europe, implementing NAT screening
methods is currently under investigation.21
Herpesvirus
A significant segment of patients with cancer are
particularly vulnerable to herpesviruses because
of the immune compromise associated with cancer
treatment. Cytomegalovirus (CMV) and human herpesvirus (HHV) 8 are cell-associated pathogens that
can be transmitted through the transfusion of cellular blood components. Recommendations to mitigate the transmission include the use of CMV-seronegative, leukoreduced cellular blood components,
or both.17 Although the clinical manifestations of
transfusion-transmitted CMV have been reported,
Dengue and Chikungunya
Both members of the Arboviridae family are expanding their traditional geographical boundaries
together with the range of their vector, the Aedes
aegypti mosquito, and both are poised to extend their
range further as another member of the Aedes group
(A albopictus) is an even more efficient vector for the
chikungunya virus when a specific mutation in the
viral envelope is present.
Dengue virus is a mosquito-borne, single, positive-stranded RNA flavivirus with a wide distribution
across the tropical and subtropical regions of the
January 2015, Vol. 22, No. 1
Cancer Control 9
world. Four serotypes of similar pathogenicity have
been identified (a fifth serotype has been proposed
but is pending further characterization). In specific
regions, more than 1 serotype may coexist. Although
the World Health Organization estimates that the disease burden is more than 100 million cases, this is
likely an underestimation given the large population
in the geographical span of its vectors.22 Typically,
individuals infected for the first time develop fever,
headache, muscle and joint pains, and a characteristic
skin rash similar to measles. In a small proportion of
cases the disease develops into life-threatening dengue hemorrhagic fever, resulting in thrombocytopenia,
bleeding, and capillary leakage that may progress into
dengue shock syndrome. The reason that some people
experience more severe forms of dengue, such as dengue hemorrhagic fever, is multifactorial. Among the
possible causes is a cross-serotypic immune response,
which occurs when a person who was previously infected with dengue becomes infected for the second,
third, or fourth time. Through a mechanism known as
antibody-dependent enhancement, the previous antibodies to the old strain of dengue virus interfere with
the immune response to the current strain, paradoxically leading to more viral entries and uptakes that
correlate with the increased severity of the disease.23
Chikungunya is an alphavirus with a positive
sense, single-stranded RNA genome. Following a short
incubation period, fever, intense headache, maculopapular rash, and severe joint and muscle pain ensue. An outbreak in the Reunion Island in the Indian
Ocean, a region at the center of the historical range for
the disease that extends from East Africa to Southeast
Asia, was reported in 2005 to 2006.24 Given the development of tourism in the region, outbreaks traced
to tourists returning from Reunion Island were later
reported in Europe.25 Concerns about the extension
of the endemic areas beyond the African and Asian
continents have proven valid. Epidemiological surveillance has now identified cases in the Caribbean and
sporadic outbreaks are occurring in the southeastern
United States.26
Reports of transfusion-transmitted dengue in
endemic regions have been published,27 although no
cases have been reported of chikungunya transmitted
via blood transfusions. Due to the significant overlap
between the regions where dengue and chikungunya and malarial parasites are endemic, travel overseas disqualifies most potential blood donors who
return to the United States and are infected after
being abroad. However, as the geographical range
continues to extend for both viruses, the potential for
blood-mediated transmission does exist. At the time
of publication, no assays licensed by the FDA are
available for either virus. Sporadic, local outbreaks of
dengue have been reported in Hawaii, Florida, and
10 Cancer Control
South Texas,28,29 as well as chikungunya transmission
in Florida.26 Through cooperation with public health
authorities, surveillance and suspension of blood collection from areas affected have been successful in
avoiding the spread of blood-borne infections in the
United States.26,28,29
Ebola
Ebola is a filovirus that has recently caused disease
outbreaks in several West African countries. In addition, imported cases in the United States and Western
Europe have been reported and are associated with
health care workers returning from epidemic areas.30
Ebola is transmitted when an infected patient is symptomatic following the incubation period. Currently,
individuals returning from Ebola epidemic areas are
deferred from donating blood for 1 year because malarial travel restrictions apply to the same regions.30-32
To address the potential transmission through local
contact, blood centers are also asking individuals who
have been identified by public health officials as possibly exposed to a patient infected with Ebola virus
not to donate blood for 28 days following the last
contact with the infected person.30-32 No FDA-licensed
assays exist to detect Ebola infection in donors.30 No
cases of transfusion-acquired Ebola infection have
been reported.30-32 The use of convalescent plasma
for treatment remains investigational.32
Bacterial Infections
Contamination of blood components with bacteria
poses a significant challenge, particularly for platelets,
because they cannot be stored at sufficiently low temperatures that have a bacteriostatic effect. The source
of bacteria may be endogenous (eg, subclinical bacterial endocarditis, osteomyelitis, syphilis, dental abscess) or, more commonly, tied to a skin contaminant.
In addition, during storage, the number of bacteria
present in the container may continue to significantly
increase up to the time of transfusion.33 The result
may be that a sample from a unit of platelets cultured
earlier (typically 24 hours following blood collection)
does not necessarily reflect the current bacterial load
prior to transfusion. Although alternative “close to release” assays have become available, none has proven
to be practical for use outside of the nonemergent
clinical setting. Currently, culture methods are capable
of interdicting approximately 50% of contaminated
units; however, most of the contaminated units not
removed from inventory are transfused in the initial
storage period before the bacterial load reaches concentrations that could have clinical consequences for
the recipient.34 Therefore, while the rate of bacterial
detection in platelet units is approximately 1 in 5,000,
the incidence rate of significant morbidity associated
with the transfusion of bacterially contaminated plateJanuary 2015, Vol. 22, No. 1
lets ranges from 1 in 70,000 to 118,000.35 The severity
of the reaction depends on the amount of bacteria as
well as their pathogenicity, which is associated with
their capacity to induce septic shock and disseminated
intravascular coagulation. In general, endotoxin-producing, gram-negative bacteria have a high correlation
with significant morbidity and mortality.
The use of pathogen-reduction technologies
applied to platelet components effectively eliminates
the transfusion of units containing viable bacteria;
however, no such technology has been licensed by
the FDA for use in the United States.
Serological testing for syphilis has been performed
since the early beginnings of transfusion. Treponema
pallidum has been transmitted via transfusion when
blood was reinfused within 24 hours of collection,
and introducing serological testing for hepatitis rendered the practice of immediate use unfeasible, thus
eliminating the transmission of syphilis through transfusion. Blood donors are still screened for syphilis,
although no cases associated with blood component
transfusion have been reported since the late 1960s.36
Another member of the Spirochaeta family that
has been the subject of studies is Borrelia burgdorferi, the causative agent of Lyme disease. Although
the theoretical risk of transmission through transfusion has been posed, no case has been documented.
Furthermore, in studies of recipients of components
from DNA-positive donors, no evidence of infection
was ever found.22
Rickettsial agents may be transmitted via blood
transfusion.37 These obligate, intracellular bacterial
organisms remain viable even after 2 or more weeks
of storage. The species and disease entities reported to be associated with blood transfusion as the
exposure event are Anaplasma phagocytophilum
(human granulocytic anaplasmosis), Coxiella burnetii
(Q fever), and Rickettsia rickettsii (Rocky Mountain
spotted fever). Given that the number of cases reported is low, no specific preventive measures beyond
proper biovigilance are recommended.22
1 in several million units.22 In the United States, about
5 cases of malaria associated with transfusion have
been published since 2000.22 Most cases were traced to
immigrants from endemic regions who then remained
asymptomatic for several years after being considered
successfully treated. Recipients of red blood cells from
asymptomatic, infected donors develop symptoms
1 month or more following transfusion; because of
the unusual transmission route and its protean clinical presentation, the diagnosis is typically made after
ruling out several other potential causes.
Parasite Diseases With Possible
Transmission via Blood Transfusion
The tick-borne intraerythrocytic parasite Babesia microti, as well as other closely related members of the
Babesia species, such as B duncani and B divergens,
have been transmitted by blood transfusion in almost
100 reported cases, making this species the most frequently transmitted parasite via transfusion in the
United States.40 The parasite uses wild rodents and
deer as mammalian hosts and Ixodes ticks as vectors.
In endemic areas of New England and the upper
Midwest, serology surveys have found seroprevalence
rates of around 2%, mostly for B microti.41 In western
states, B duncani is the predominant variant. The
density of the deer population in suburban areas has
increased in the last few decades, so the number of
Malaria
Because the number of autochthonous cases occurring in the United States in the last several decades
has been limited to a handful, the risk of transmission
is confined to the collection of blood from individuals
who immigrate from or return from travel to endemic
areas in which any of the 4 species of Plasmodium can be found.38 No assays have been licensed by
the FDA to detect malarial parasites or antibodies in
blood donors. Nevertheless, eliminating blood collection from at-risk individuals has reduced the risk
of transfusion-transmitted malaria to approximately
January 2015, Vol. 22, No. 1
American Trypanosomiasis (Chagas Disease)
The transmission of Trypanosoma cruzi via blood
transfusion was recognized in endemic countries
(mostly countries in the Western Hemisphere, except
the United States and Canada) early after transfusion
therapy became available. Seroprevalence studies conducted in Latin America have shown that 12% to 25%
of seronegative recipients of fresh whole blood were
found to seroconvert after receiving cellular blood
components from infected donors.39 Detectable clinical disease 20 to 40 days after transfusion is more
common in patients who are immunosuppressed;
however, among immunocompetent recipients, approximately 30% of those who carry the parasite will
develop cardiac or gastrointestinal clinical features
characteristic of Chagas disease at least 20 years
following transfusion.39
Migrants from endemic areas were identified in
7 documented cases associated with transfusion in
the United States and Canada, but more undetected,
subclinical transmissions have likely occurred.39 As a
result, blood establishments in both countries have implemented serological screening for all blood donors
for the presence of anti–T cruzi antibodies to identify
and interdict blood components with the potential for
transmitting the parasite to recipients.39 Given this
measure, the risk of transmission via transfusion is
now considered negligible.39
Babesiosis
Cancer Control 11
donors carrying the parasite in their blood has also
risen and resulted in more cases linked to transfusions
every year. Patients who are immunocompromised or
asplenic are vulnerable to a severe form of babesiosis,
which is characterized by fever, hemolytic anemia,
thrombocytopenia, and, in the most severe of cases,
disseminated intravascular coagulation and multiorgan failure. Immunocompetent individuals who acquire the parasite either by tick bite or transfusion
may remain asymptomatic or they may present with
mild, flu-like illness. Asymptomatic individuals may
remain parasitemic for months or even years. The FDA
has not licensed any assays to detect current or past
infestation in blood donors, so donor screening is
limited to questioning potential donors about a prior
diagnosis of babesiosis. Although the detection of
parasites through NAT assays is the most effective way
to interdict parasitemic units, given its complexity and
cost, the detection of antibodies to Babesia appears
to be the most practical donor screening mechanism.
At the time of publication, 2 different methodologies
are under development.
Leishmaniasis
Leishmania donovani may be transmitted via transfusion and causes severe clinical disease in immunosuppressed and newborn recipients.42 All reported cases
have occurred in hyperendemic areas of the world
(eg, the Middle East). As a result, the temporary deferral of individuals returning from regions of the world
in which Leishmania poses a threat to the population
is used to eliminate potential transmission by blood
transfusion.
Human Prion Disease
Disease entities associated with prion infection include classical and sporadic Creutzfeldt–Jakob disease
(CJD), infectious CJD (kuru associated with cannibalism and its iatrogenic form), familial or heritable
(Gerstmann–Sträussler–Scheinker syndrome), and
variant CJD.
Variant CJD prions alone have been associated
with blood transfusion. Four cases were reported in
recipients of nonleukoreduced red blood cells and
in 1 patient with hemophilia who was treated with
clotting-factor concentrates sourced from the United Kingdom.43 Three of the individuals transfused
with red blood cells developed clinical variant CJD
6.3 to 8.5 years after transfusion. The patient with
hemophilia and 1 red blood cell recipient had prions detected in tissue but no clinical disease. In all
cases, the sources were asymptomatic donors at the
time of donation but who later developed clinical
variant CJD.43 Experimental transfusion models using
sheep have showed that transmission occurs in 36% of
exposed animal recipients.44
12 Cancer Control
At the time of publication, no assays reliably
detect presymptomatic or asymptomatic infection.
For that reason, intervention to prevent variant CJD
transmission via transfusion is limited to the exclusion
of donors exposed to regions where variant CJD has
the potential to enter the food supply as the agent
of bovine spongiform encephalitis, which infected
cattle in the United Kingdom. This exclusion extends
to individuals who spent at least 3 months in the
United Kingdom from 1980 through 1996, at least
5 years in Europe since 1980, or those who received
transfusions in the United Kingdom or France since
1980. The residual risk of infection with variant CJD
in the United States is estimated to be negligible.
Immune-Mediated Reactions
Hemolysis Due to Serological Incompatibility
All transfusable blood components are labeled to
indicate the blood type of the donor as well as the
screening result for the detection of unexpected
antibodies against red blood cell antibodies. Blood
components containing plasma with unexpected (ie,
other than anti-A and/or anti-B) isoagglutinins are
not transfused. However, under certain circumstances,
units of plasma or platelets incompatible with the
red blood cells of the recipients may be transfused.
To avoid hemolytic reactions under such circumstances (particularly for platelet components containing
significant amounts of supernatant plasma), at least
1 of the following strategies should be used:
•Limit the total volume of ABO-incompatible
plasma by restricting the total plasma volume
to be transfused, reducing the plasma volume,
or platelet washing
•Store in platelet additive solutions to reduce
the residual plasma by two-thirds
•Obtain isoagglutinin titers to eliminate donors
with high levels of hemolysins
Transfusion-Related Acute Lung Injury
Transfusion-related acute lung injury is most
commonly associated with the transfusion of blood
components containing a plasma volume that exceeds
100 mL. In more than one-half of observed transfusion-related acute lung injury, antihuman leukocyte
antigen (anti-HLA) antibodies (classes 1, 2, or both)
or antihuman neutrophil (anti-HNA) antibodies can
be detected in the transfused product. Although the
pathophysiology of transfusion-related acute lung
injury has not been elucidated, the antibodies in the
donor that interact with the leukocytes of the recipient
are considered to be a significant risk factor.45 As a
result, mitigation strategies involving the selection of
donors not likely to have developed those antibodies (eg, untransfused men, women who have never
January 2015, Vol. 22, No. 1
been pregnant or never received a transfusion) and
testing donors more likely to have developed antibodies (eg, women who have been pregnant) have been
developed. Although HLA antibody screening assays
are available, no assays can be practically applied
to detect anti-HNA. Furthermore, antibodies are not
detected in a large number of cases of transfusionrelated acute lung injury; thus, alternative pathways
for neutrophil priming and activation involving lipid
molecules, microaggregates expressing CD40 receptors, and microparticles formed during cellular component storage are underway.46
Graft-vs-Host Disease
Graft-vs-host disease is a life-threatening complication
of transfusion and is mediated by post-transfusion
clonal amplification of the donor’s lymphocytes in the
recipient. This action occurs as a result of a patient’s
inability to suppress lymphocyte proliferation due to
cellular immunodeficiency associated with his or her
primary condition or immunosuppressive therapy.
Vulnerable patient populations include premature
infants, recipients of hematopoietic stem cell transplantation, patients treated with fludarabine, patients
transfused with cellular components collected from
direct blood relatives,47 and individuals with hereditary
immunodeficiencies. Blood recipients included in any
of the categories above should receive irradiated cellular blood components alone; the radiation dose must
be sufficient to stop the clonal expansion of donor
lymphocytes (estimated at 25 Gy). Pathogen-reduction
procedures that use amotosalen followed by irradiation with ultraviolet light have been reported to be
appropriate.48 The use of high-efficiency leukocyte depletion filters is not effective as a preventive measure.
Additional Mitigation Strategies
to Enhance Safety
Although testing for markers of transmissible disease
and applying special methods in the preparation of
blood components provide a strong foundation and
support the safety of the blood supply, blood establishments have implemented additional safety layers
to enhance the therapeutic profile of transfusable
blood components.
Donor Recruitment and Selection
The use of volunteer, nonremunerated blood donors
is an effective means for obtaining safe source material for blood transfusion. To obtain donations from
segments of the population with the lowest incidence
levels for transmissible diseases, each donor must be
subjected to an extensive medical questionnaire to
assess his or her medical history, travel, and behavior
associated with potential risks of exposure to pathogens
that may be transmitted by transfusion. For example,
January 2015, Vol. 22, No. 1
travel to endemic areas for tropical disease temporarily
disqualifies individuals until appropriate incubation
periods have lapsed, and a history positive for viral
hepatitis, drug use, or male-to-male sexual contact
will result in indefinite deferral from blood donation
under current US government regulations. Eligibility
and disqualification criteria are established through
governmental regulations as well as a set of standards
established by professional societies. In addition,
a physical examination that includes vital signs is also
performed. All donors are provided with instructions
to allow them to report potential prodromic symptoms
of infection within 72 hours following donation.
Leukocyte Reduction
Current routine methods of filtration remove leukocytes from cellular blood components. Affinity filters
that use physical properties as well as electrical static
charges to remove the target cells are efficient devices
that eliminate more than 99.999% of the white blood
cells in the original blood collection with minimal loss
of red blood cells or platelets.49 Using differential centrifugation, high-efficiency apheresis instruments are
also capable of harvesting large numbers of platelets
with minimal loss of white blood cells.
The depletion of leukocytes decreases the rates
of immune sensitization and febrile nonhemolytic
reactions. It also plays an important role in the prevention of CMV, HTLV-1, and HTLV-2 transmission and
the removal of other intracellular pathogens.
Pathogen Reduction and Inactivation
The elimination of microorganism transmission
through blood components is a goal of transfusion
practice; however, the chemical or physical processes
used to achieve that goal must maintain the viability
and functionality of the treated product.50
Plasma intended for transfusion may be treated with either methylene blue or solvent or detergent solutions. The former inactivates most viruses,
bacteria, and parasites after forming stable chemical
bonds when exposed to visible light. The latter acts
by disrupting the membranes of most microorganisms
with the exception of nonenveloped viruses such as
hepatitis A and parvovirus B19. Both types of methods
have been implemented in Europe for several years
and one was approved for use in the United States
in 201351; however, neither method can be used on
cellular components.
Platelet components may be treated with a psoralen (amotosalen) or riboflavin and then subsequently subjected to ultraviolet irradiation to stabilize the
disruptive bonds made by those chemicals with DNA/
RNA molecules. Pathogen-reduction systems for platelets are not available for use in the United States. An
amotosalen-based system called Intercept (Cerus, ConCancer Control 13
cord, California) is in use in some countries in Europe
and the Middle East, and Mirasol (Terumbo BCT, Lakewood, Colorado), which is a riboflavin-based system,
is undergoing several clinical trials (NCT01740531,
NCT01907906, and NCT00261924).
Given the high hemoglobin content in red blood
cell components, methods requiring ultraviolet irradiation are not feasible. Although some chemicals have
been identified that achieve significant pathogen-reduction levels, the potential formation of red blood
cell neoantigens resulting in the immune destruction
of treated cells has hampered progress.52 These systems are still in experimental phases.
Biovigilance
Procedures to quickly detect the possible spread of
transmissible diseases via blood transfusion provide
yet another safety layer for protecting the blood
supply. Collaborating with public health officials by
sharing surveillance data (eg, serosurveys of sentinel chickens for flavivirus outbreaks), investigating
recipients of units from donors who seroconvert
on subsequent donations (a process called “donor
lookback”), or retesting donors who had their blood
transfused to a patient who experienced a post-transfusion transmissible disease are some of the methods that can be used. In the laboratory, using samples from serial bleedings in recent seroconverted
individuals provides valuable insights into the biology
of infection with a particular pathogen and the different serological markers needed to detect infection in
asymptomatic but infectious individuals.
Conclusions
Transmissible agents most commonly associated with
risks due to transfusion are no longer a major threat;
however, addressing the need for quick response
mechanisms to manage emerging pathogens that
may unintentionally or intentionally spread remains
a challenge. The use of technology to reduce pathogens holds promise for further increasing the safety
profile of blood transfusion.
In addition, blood transfusion plays an important
role in supporting patients with cancer. A multilayered strategy has raised the safety profile of blood
components to acceptable levels; however, treatment
with blood transfusions must be considered within the
broader context of risks and benefits that go beyond
strict product safety. Many aspects related to the interactions between the allogeneic components transfused
must be reviewed when assessing the risks and benefits of transfusion therapy for patients with cancer.
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14 Cancer Control
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paraparesis (HAM/TSP). Acta Neurol Belg. 2011;111(1):41-44.
16. Stramer SL, Notari EP IV, Zou S, et al. Human T-lymphotrophic virus
antibody screening of blood donors: rates of false-positive results and evaluation of a potential donor reentry algorithm. Transfusion. 2011;51(4):692-701.
17. Vamvakas EC. Is white blood cell reduction equivalent to antibody
screening in preventing transmission of cytomegalovirus by transfusion?
A review of the literature and meta-analysis. Transfus Med Rev. 2005;19(3):
181-199.
18. Plentz A, Hahn J, Knöll A, et al. Exposure of hematologic patients to
parvovirus B19 as a contaminant of blood cell preparation and blood products.
Transfusion. 2005;45(11):1811-1815.
19. Schmidt M, Themann A, Drexler C, et al. Blood donor screening for
parvovirus B19 in Germany and Austria. Transfusion. 2007;47(10):1775-1782.
20. Kuniholm MH, Purcell RH, McQuillan GM, et al. Epidemiology of hepatitis E virus in the United States: results from the Third National Health and
Nutrition Examination Survey, 1988-994. J Infect Dis. 2009;200(1):48-56.
21. Cleland A, Smith L, Crossan C, et al. Hepatitis E virus in Scottish blood
donors. Vox Sang. 2013;105(4):283-289.
22. Stramer SL, Hollinger FB, Katz LM, et al. Emerging infectious disease
agents and their potential threat to transfusion safety. Transfusion. 2009;(49
suppl 2):1S-29S.
23. Leong AS, Wong KT, Leong TY, et al. The pathology of dengue hemorrhagic fever. Semin Diagn Pathol. 2007;24(4):227-236.
24. Josseran L, Paquet C, Zehgnoun A, et al. Chikungunya disease outbreak, Reunion Island. Emerg Infect Dis. 2006;12(12):1994-1995.
25. Parola P, de Lamballerie X, Jourdan J, et al. Novel chikungunya virus
variant in travelers returning from Indian Ocean islands. Emerg Infect Dis.
2006;12(10):1493-1499.
26. Centers for Disease Control and Prevention. First chikungunya case
acquired in the United States reported in Florida. http://www.cdc.gov/media/
releases/2014/p0717-chikungunya.html. Accessed October 10, 2014.
27. Tomashek KM, Margolis HS. Dengue: a potential transfusion-transmitted disease. Transfusion. 2011;51(8):1654-1660.
28. Adalja AA, Sell TK, Bouri N, et al. Lessons learned during dengue
outbreaks in the United States, 2001-2011. Emerg Infect Dis. 2012;18(4):
608-614.
29. Centers for Disease Control and Prevention. Locally acquired dengue -Key West, Florida, 2009-2010. MMWR Morb Mortal Wkly Rep. 2010;59(19):
577-581.
30. American Association of Blood Banks; America’s Blood Centers; American Red Cross. Joint statement regarding Ebola and the safety of the blood
supply. http://www.americasblood.org/media/50695/stmnt_ebola_joint_1410.
pdf. Accessed November 4, 2014.
January 2015, Vol. 22, No. 1
31. American Association of Blood Banks. Association bulletin #14-08.
http://www.aabb.org/programs/publications/bulletins/Documents/ab14-08.pdf.
Accessed November 4, 2014.
32. America’s Blood Centers. Q & A with ABC chief medical officer Louis
Katz – Ebola virus: what you need to know. http://hospitals.unitedbloodservices.
org/abcnews/ABC_10_24_14.pdf. Accessed November 4, 2014.
33. Brecher ME, Hay SN. Bacterial contamination of blood components.
Clin Microbiol Rev. 2005;18(1):195-204.
34. Schezenmeier H, Walther-Wenke G, Müller TH, et al. Bacterial contamination of platelet concentrates: results of a prospective multicenter study
comparing whole blood-derived platelets and apheresis platelets. Transfusion.
2007;47(4):644-652.
35. Eder AF, Kennedy JM, Dy BA, Notari EP, et al; American Red Cross
Regional Blood Centers. Bacterial screening of apheresis platelets and residual risk of septic transfusion reactions: the American Red Cross experience
(2004-2006). Transfusion. 2007;47(7):1134-1142.
36. Katz LM. A test that won’t die: the serologic test for syphilis. Transfusion.
2009;49(4)617-619.
37. Leiby DA, Gill JE. Transfusion-transmitted tick-borne infections: a cornucopia of threats. Transf Med Rev. 2004;18(4):293-306.
38. Kitchen AD, Chiodini PL. Malaria and blood transfusion. Vox Sang.
2006;90(2):77-84.
39. Benjamin RJ, Stramer SL, Leiby DA, et al. Trypanosoma cruzi infection
in North America and Spain: evidence in support of transfusion transmission.
Transfusion. 2012;52(9):1913-1921.
40. Leiby DA. Transfusion-transmitted Babesia spp.: bull’s-eye on Babesia
microti. Clin Microbiol Rev. 2011;24(1):14-28.
41. Levin AE, Williamson PC, Erwin JL, et al. Determination of Babesia
microti seroprevalence in blood donor populations using an investigational
enzyme immunoassay. Transfusion. 2014;54(9):2237-2244.
42.Cardo LJ. Leishmania: risk to the blood supply. Transfusion.
2006;46(9):1641-1645.
43. Hewitt PE, Llewelyn CA, Mackenzie J, et al. Creutzfeldt-Jakob disease
and blood transfusion: results of the UK Transfusion Medicine Epidemiological
Review study. Vox Sang. 2006;91(3):221-230.
44. Dodd RY, Busch MP. Animal models of bovine spongiform encephalopathy and vCJD infectivity in blood: two swallows do not a summer make.
Transfusion. 2002;42(5):509-512.
45. Toy P, Gajic G, Bacchetti P, et al; TRALI Study Group. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012;119(7):1757-1767.
46. Van Bruggen R, de Korte D. Prevention of non-immune mediated transfusion-related acute lung injury; from blood bank to patient. Curr Pharm Des.
2012;18(22):3249-3254.
47. Agbaht K, Altintas ND, Topeli A, et al. Transfusion-associated graftversus-host disease in immunocompetent patients: case series and review
of the literature. Transfusion. 2007;47(8):1405-1411.
48. Mintz PD, Wehrli G. Irradiation eradication and pathogen reduction.
Ceasing cesium irradiation of blood products. Bone Marrow Transplant.
2009;44(4):205-211.
49. Shapiro, MJ. To filter blood or universal leukoreduction: what is the
answer? Crit Care. 2004;8(suppl 2):S27-S30.
50. Goodrich RP, Custer B, Kell S, et al. Defining “adequate” pathogen reduction performance for transfused blood components. Transfusion.
2010;50(8):1827-1837.
51. Octapharma USA. FDA approves Octaplas expanding Octapharma
U.S. transfusion medicine therapies. http://www.octaplasus.com/uploads/octaplas_approval_01-18-13.pdf. Accessed October 10, 2014.
52. Wagner SJ. Developing pathogen reduction technologies for RBC
suspensions. Vox Sang. 2011;100(1):112-121.
January 2015, Vol. 22, No. 1
Cancer Control 15
Transfusions confer such risks
as acute TRALI, alloimmunization,
and iron overload, so they must be used
only when benefits outweigh the risks.
Ray Paul. Petal Purple, 2010. Acrylic, latex, enamel on canvas, 12" × 12".
Adverse Effects of Transfusion
Radhika Dasararaju, MD, and Marisa B. Marques, MD
Background: Patients with malignancy comprise a unique group for whom transfusions play an important
role. Because the need for transfusions may span a long period of time, these patients may be at risk for more
adverse events due to transfusion than other patient groups.
Methods: A literature search on PubMed that included original studies and reviews was performed. The results
were summarized and complemented by our clinical experience. Long-term complications of transfusions, such
as transfusion-associated graft-vs-host disease, alloimmunization, transfusion-related immunomodulation, and
iron overload, are discussed.
Results: Transfusion-related acute lung injury, transfusion-associated circulatory overload, and hemolytic
transfusion reaction are deadly complications from transfusion. These adverse events have nonspecific presentations and may be missed or confused with a patient’s underlying condition. Thus, a high level of suspicion
and close monitoring of the patient during and following the transfusion is imperative. Common reactions
(eg, febrile nonhemolytic transfusion reaction, allergic reaction) are not life threatening, but they may cause
discomfort and blood product wastage.
Conclusions: Every transfusion carries risks of immediate and delayed adverse events. Therefore, oncologists
should prescribe transfusion for patients with cancer only when absolutely necessary.
Introduction
Patients with malignancy comprise a unique group
for whom transfusions play an important — and
sometimes lifesaving — role. Typically, patients with
cancer are pancytopenic, immunosuppressed, or both,
and these conditions affect their transfusion needs
as well as the interpretation of signs and sympFrom the Department of Pathology, University of Alabama at
Birmingham, Birmingham, Alabama.
Submitted June 16, 2014; accepted October 14, 2014.
Address correspondence to Marisa B. Marques, MD, University of
Alabama at Birmingham, Department of Pathology, WP P230G,
619 – 19th Street South, Birmingham, AL 35249. E-mail: mmarques
@uab.edu
No significant relationships exist between the authors and the
companies/organizations whose products or services may be
referenced in this article.
16 Cancer Control
toms of possible reactions. Because their need for
transfusions may span a long period of time, this
patient population may be at risk of experiencing
more adverse events due to transfusion than any other
patient group. That being said, a 4-year study by
Huh and Lichtiger1 revealed that reactions occurred
less frequently in patients with cancer and that
febrile nonhemolytic transfusion reactions (FNHTRs)
and allergic reactions were the most common (51.3%
and 36.7%, respectively). FNHTRs are particularly
difficult to differentiate from the patient’s underlying illness, considering that many are already febrile
before the transfusion. A thorough review of vital signs
before and after the transfusion, associated signs and
symptoms, and timing of the increased temperature
are essential to make the correct diagnosis. To prevent
FNHTRs, transfusion services strive to offer leukoreduced
January 2015, Vol. 22, No. 1
products alone to patients with cancer. Leukoreduced
red blood cells (RBCs) and platelets have the added advantage of mitigating the risk of cytomegalovirus (CMV)
transmission because they are CMV safe.2
Table 1. — Signs and Symptoms of Acute Transfusion Reactions
Sign/Symptom
Possible Transfusion Reaction
Fever
FNHTRa
AHTR
TRALI
Microbial contamination
Itching
Rash
Urticaria
Wheezing
Facial edema
Allergic reaction
ecrease oxygen saturation
D
to < 90% on room air
TACO
TRALI
Dyspnea
Respiratory distress
Cyanosis
AHTR
Allergic reaction
Microbial contamination
TACO
TRALI
Hypertension
Tachycardia
TACO
Hypotension
AHTR
Allergic reaction
Microbial contamination
TRALI
Pain at IV infusion site
Abdominal/chest/flank pain
AHTR
Allergic reaction
Premedication Prior to Transfusion
In 2007, according to Geiger and Howard,3 physicians at a research hospital prescribed an antipyretic
and an antihistamine (usually acetaminophen and
diphenhydramine) prior to almost 70% of transfusions.
This figure is higher than the rest of the United States
at about 50%. Although the practice of premedication
to prevent FNHTRs and allergic reactions is likely to
continue, several published reports have questioned
its validity. A prospective study of hematology/oncology patients suggested that premedication use can
be decreased without increasing reaction rates and
that prestorage leukoreduction, reduced plasma from
platelet units, or both diminish but do not eliminate
FNHTRs.4 Another study concluded that, although routine pretransfusion antipyretics reduce patient inconvenience and morbidity rates associated with FNHTRs,
as well as decrease product wastage, the process is
not cost effective.5 A randomized controlled trial of
315 patients with leukemia or post–stem cell transplantation without a history of transfusion reactions
showed that premedication and bedside leukoreduction
significantly decreased the risk of FNHTRs.6 And,
more recently, a systematic review found no evidence
to justify premedication to prevent FNHTRs and allergic reactions regardless of patient history.7
Acute Transfusion Reactions
Although FNHTRs and allergic reactions are common
and familiar to most health care professionals, these
reactions are not as life threatening as acute hemolytic
transfusion reactions (AHTRs), transfusion-associated
circulatory overload (TACO), and transfusion-related
acute lung injury (TRALI). According to the US Food
and Drug Administration (FDA), 30 to 44 patients
died due to transfusion reactions per year in the United States between 2009 and 2013.8 The top 3 causes of transfusion-related fatalities for the combined
5 years were TRALI at 38%, TACO at 24%, and AHTRs
at 22%.8 The remaining deaths were caused by microbial contamination at 10%, anaphylaxis at 5%, and
other causes, such as transfusion-associated graft-vshost disease (TA-GVHD) and hypotension, at 1%.8 The
dilemma for the health care team caring for patients
with cancer who develop a reaction is to determine:
(1) If the signs and symptoms represent a true reaction or a coincidence (ie, fever), and (2) how serious
a reaction is if it has occurred. The differentiation
between the patient’s underlying status and a reaction
to explain new signs and symptoms, as well as the
type of reaction, is difficult to ascertain because of
January 2015, Vol. 22, No. 1
AHTR = acute hemolytic transfusion reaction, FNHTR = febrile nonhemolytic transfusion reaction, IV = intravenous, TACO = transfusion-associated circulatory overload, TRALI = transfusion-related acute lung injury.
a
Fever is most often due to underlying infection among patients with cancer,
especially if the blood product (red blood cells or platelets) is leukoreduced.
From references 9 to 15.
the nonspecific manifestations of transfusion-related adverse events (Table 1).9-15 Fever, chills, nausea,
vomiting, pain, itching at the intravenous (IV) insertion site, variations in blood pressure, tachycardia,
dyspnea, and restlessness are among the most common reasons a reaction is suspected. Although fever
may indicate an FNHTR, it may also be a sign of a
potentially fatal complication such as AHTR or sepsis.
For this reason, transfusion administration guidelines
must be strictly followed to avoid a reaction, such
as an AHTR, caused by the infusion of the incorrect
unit to the patient and to detect one as soon as it
occurs.9,16 Because the severity of the reaction and its
consequences are directly proportional to the volume
of incompatible product transfused, early recognition and rapid intervention are essential to minimize
harm. After stopping the transfusion at the earliest
sign of reaction, the IV access line should be kept
open with normal saline. The next critical step is to
check that the blood product was intended for that
recipient.9 Immediately thereafter, the remainder of
the unit with the attached tubing and compatibility
label or “bag tag” must be sent to the transfusion service (ie, blood bank) accompanied by a description of
the clinical picture, vital signs before and during the
transfusion, and a sample of the patient’s blood. Fresh
Cancer Control 17
urine should also be sent if hemolysis is suspected. In
the blood bank, a clerical check is repeated and pretransfusion data, such as ABO type, antibody screen,
crossmatch result if packed RBCs were implicated, and
any other pertinent history are reviewed. Because the
laboratory workup is aimed at detecting or excluding
hemolysis, such workup starts with the inspection of
the plasma color followed by a direct antiglobulin test
(DAT) and screening for free hemoglobin in plasma
and urine.17 A newly positive post-transfusion DAT
result compared with a negative DAT pretransfusion
result suggests an AHTR.17 In such cases, the patient’s
clinical team must be notified as soon as possible so
aggressive hydration can be initiated to limit the deleterious effects of free plasma hemoglobin. A negative
laboratory workup is expected for all other types of
adverse effects of transfusions (Table 2).9-15,17-21
Acute Hemolytic Transfusion Reaction
Most often, AHTRs are caused by immune incompatibility between the donor and the recipient (typically, antigen-positive RBCs are transfused to a patient
with the corresponding antibodies).22 The most severe AHTR is due to immunoglobulin (Ig) M anti-A,
usually from a processing error in which the wrong
blood was sent to the transfusion service with the
patient’s name, or from failing to perform a patient
identification check at the bedside and transfusing
a unit of RBCs intended for someone else.16 In the
last 5 years, 13 patients died from an ABO-mediated AHTR.8 In addition, non-ABO antibodies caused
more than twice as many fatal AHTRs in the same
time-period (29 deaths).8 As seen in Table 2, a variety
of symptoms may denote an AHTR.9-15,17-21 Because the
volume of incompatible blood transfused correlates
with the severity of the reaction, it is important for
transfusionists to stay with the patient for the first
few minutes of every transfusion and then advise the
patient to immediately notify the nursing staff if any
new symptoms occur. Other variables that affect the
severity of an AHTR include the recipient antibody
type and titer. Because AHTRs may also be delayed,
patients should be instructed on how to report any
symptoms that develop within 24 hours, especially if
they were transfused as outpatients.
Hemolysis due to anti-A and anti-B is mainly
intravascular because IgM readily activates complement, inducing the formation of a membrane attack
complex.22 In turn, complement activation leads to
the release of vasoactive amines, histamine, and other inflammatory cytokines such as interleukins and
tumor necrosis factor α, which activate coagulation
and fibrinolysis. In addition, complement-activation
products and cytokines cause hypotension. Free plasma hemoglobin is both damaging to the endothelium
and a nitric oxide scavenger, causing vasoconstriction
18 Cancer Control
and hypoxia.10 Hemolysis mediated by IgG antibodies
(non-ABO) is mainly extravascular through phagocytosis of the transfused RBCs by splenic macrophages
via their Fc receptors. However, in patients with
high-titer IgG antibodies to RBC antigens, combined
extravascular and intravascular hemolyses may occur.
Patients with cancer are also at risk of an AHTR
when receiving ABO-incompatible platelets with anti-A, anti-B, or both in the plasma.23 To minimize this
risk, transfusion services are expected to avoid units
with high-titer ABO antibodies, if known, because
testing is not routine at all institutions. In the event
that hemolysis is suspected following incompatible
platelets, a post-transfusion DAT would provide useful
information. Hemolysis can also occur from improper
storage of RBCs, leading to thermal, mechanical, or
osmolar injury and, rarely, bacterial contamination.
The concomitant infusion of hypotonic solutions or
medications with RBCs also results in hemolysis and
is not recommended.24 Rh immunoglobulin (passively
acquired IgG anti-D) or intravenous immunoglobulin
(IVIG; which contains anti-A and anti-B) can also
cause hemolysis, and this complication should be
promptly recognized.25-27
A suspected AHTR is confirmed by a change in
plasma color and a positive result on DAT for IgG,
complement, or both.17 In such patients, an extended
workup may include haptoglobin, lactate dehydrogenase, bilirubin, plasma-free hemoglobin, creatinine,
and a disseminated intravascular coagulation profile.
Management is mainly supportive with IV fluids,
diuretics, vasopressors, and blood products if bleeding
induced by disseminated intravascular coagulation
ensues.9 Strict adherence to patient identification procedures, and proper specimen collection practices
help prevent AHTRs and improve transfusion safety.16
Transfusion-Related Acute Lung Injury
Twenty years ago, the American-European Consensus
Conference published a definition of acute lung injury.28 Ten years later, TRALI was defined as new-onset
acute lung injury within 6 hours of transfusion with a
PaO2:FIO2 ratio of no more than 300 mm Hg or oxygen
saturation of at least 90% on room air and bilateral
infiltrates on chest radiography in the absence of left
atrial hypertension.11,12 TRALI is most often caused by
antibodies to human leukocyte antigens (HLAs) or
human neutrophil antigens (HNAs) in the transfused
blood product given to a patient whose leukocytes
express the cognate antigen.29
It is believed that TRALI follows a 2-hit model:
(1) Neutrophils are primed and sequestered in the
lungs due to an underlying clinical condition, and
(2) they become activated by the infusion of antibodies or biological response modifiers (ie, cytokines
and lipids accumulated in the blood product).30,31
January 2015, Vol. 22, No. 1
Table 2. — Possible Diagnoses for Immediate Adverse Events of Transfusion
Symptoms
Diagnosis
Symptoms
AHTR
Fever, chills, dyspnea
Hypotension, shock, DIC
Red or brown urine
Chest/flank/abdominal pain
Nausea and vomiting
Pain at IV infusion site
Renal ischemia and failure
Oliguria/anuria
Hypotension and dark urine may be the
initial signs in anesthetized patients
Microbial Contamination
DAT positive (may be negative if all
incompatible red cells destroyed)
Hemolyzed plasma, hemoglobinuria
Antibody screen positive; negative if due
to ABO incompatibility
Eluate with alloantibody or anti-A or anti-B
Falling hematocrit level
Haptoglobin decreased, LDH increased
If DAT negative, consider thermal, osmotic,
mechanical, or chemical cause
Fever
Chills
Hypotension
Shock
DIC
Vomiting, diarrhea
TRALI
Onset within 6 hours of transfusion
Dyspnea
Oxygen saturation < 90%
Cyanosis
Hypotension
Fever
Chills
Hypoxia (PaO2/FIO2 ratio ≤ 300 mm Hg)
Pulmonary artery pressure < 18 mm Hg
TACO
Urticaria
Itching
Rash
Wheezing
Negative for AHTR
Mainly clinical diagnosis
Anaphylactic Transfusion Reaction
Negative for AHTR
High brain natriuretic peptide
Respiratory distress
Dyspnea
Bronchospasm
Sweating
Flushing
Nausea, vomiting, abdominal
cramps
Substernal pain
Hypotension
Shock
Localized angioedema
Transfusion-Associated Dyspnea
Dyspnea
Cyanosis
Onset within 24 hours of transfusion
Negative for AHTR
Gram stain and culture positive
of implicated unit (usually
platelets)
Allergic Transfusion Reaction
Negative for AHTR
Transient leukopenia
Chest radiography with bilateral pulmonary
infiltrates
Dyspnea
Oxygen saturation < 90%, cyanosis
Nonproductive cough, orthopnea
Hypertension, tachycardia
Left atrial hypertension, congestive heart
failure
New ST segment and T wave change on
electrocardiography
Diagnosis
Negative for AHTR
IgA deficiency with class-specific or subclass-specific anti-IgA
(later determination)
FNHTR
Negative for AHTR, TACO, TRALI, and
allergic reactions
Temperature rise within
4 hours of transfusion,
not caused by underlying
condition, with or without
chills or rigors
Negative for AHTR
AHTR = acute hemolytic transfusion reaction, DAT = direct antiglobulin test, DIC = disseminated intravascular coagulation, FNHTR = febrile nonhemolytic transfusion reaction,
Ig = immunoglobulin, IV = intravenous, LDH = lactate dehydrogenase, TACO = transfusion-associated circulatory overload, TRALI = transfusion-related acute lung injury.
From references 9 to 15 and 17 to 21.
In addition to the lungs, neutrophils accumulate in
other organs (eg, liver, central nervous system), likely
contributing to the morbidity and mortality of TRALI.32 A case-nested study reported that patients with
hematological malignancies undergoing induction
chemotherapy were at increased risk for TRALI.33 In
addition, TRALI may occur in patients with neutropenia, presumably by the infusion of vascular endothelial growth factor or antibodies to HLA class II that
bind to pulmonary endothelium and cause pulmonary
leak.34 Because plasma from females was implicated in
January 2015, Vol. 22, No. 1
most initial cases of TRALI, almost all units of plasma
currently manufactured in the United States are from
male donors.35 Since this change, the risk of TRALI
from plasma is comparable with that from RBC and
platelet products.8
TRALI is a diagnosis of exclusion because it is
clinically indistinguishable from other causes of respiratory distress (see Table 2). Thus, when patients
develop sudden dyspnea, hypoxia, and hypotension
during or within 6 hours of transfusion, the possibility
of TRALI must be considered. Although fever is also
Cancer Control 19
common, it may not initially occur. In addition to the
laboratory workup to exclude hemolysis, a complete
blood count may show acute neutropenia, which is
a useful marker of TRALI.18,19 Chest radiography supports the diagnosis of TRALI with newly developed
bilateral pulmonary infiltrates, but the infiltrates can
also be seen in cases of TACO and other causes of
acute lung injury.
Treatment for TRALI consists of respiratory support and pressors. Although some patients receive
corticosteroids, steroids have not been proven to be
beneficial and diuretics are not indicated.31 Mortality
rates range from 5% to 25%, and, with vigorous respiratory support, 80% of patients recover within 48 to
96 hours.36 Confirmation of TRALI occurs when anti-HLA or anti-HNA in the serum of the donor matches
the phenotype of the patient.36 Any donor implicated
in a case of TRALI should be indefinitely deferred
from donating blood in the future.
Transfusion-Associated Circulatory Overload
The true morbidity and mortality rates of TACO are
unknown due to the uncertain prevalence of TACO.
Because TACO is now the second leading cause of
transfusion-associated fatality in the United States, it is
likely that awareness of its life-threatening potential has
increased.8 By contrast to TRALI, which is difficult to
prevent except by minimizing transfusions and avoiding
donors with HLA and HNA antibodies, TACO is conceivably preventable.13,37,38 Health care professionals should
identify transfusion recipients unable to effectively process the volume challenge and either avoid transfusions
altogether, prescribe the smallest possible number of
units, and/or ensure a slow infusion rate. The risk of
TACO increases with age and the number of units transfused, especially in patients with congestive heart failure,
chronic pulmonary disease, anemia, or those receiving
plasma products.37,38 TACO should be suspected when
the patient develops new or exacerbated respiratory
distress, pulmonary edema, or evidence exists of left
or right heart failure or elevated central venous pressure (see Table 2). These signs and symptoms usually
present within 2 hours of the transfusion onset but may
take up to 6 hours to manifest.13 It is often difficult to
distinguish TACO from TRALI, although hypertension
(not hypotension) is expected. If available, a high brain
natriuretic peptide level or pro–brain natriuretic peptide
may help diagnose TACO.20 In addition to slow infusion rates and close monitoring for the development of
symptoms, concurrent infusion of other fluids should
be avoided. Furthermore, peritransfusion diuretics can
considerably decrease the risk of TACO.38
Transfusion-Associated Dyspnea
Transfusion-associated dyspnea is defined as acute
respiratory distress occurring within 24 hours of trans20 Cancer Control
fusion that is not explained by the patient’s underlying
medical condition and does not meet the criteria for
TRALI, TACO, or an allergic reaction.21,39
Microbial Contamination
Although bacterial contamination of RBCs is
extremely rare, bacterial overgrowth in platelet units
continues to be possible despite the implementation
of various detection methods in the last 10 years.40
Bacterially contaminated platelets are the most common transfusion-transmitted disease and present a
particular risk to patients with cancer due to their
considerable exposure to platelets and their frequent
immunocompromised state. Introduction of skin flora
into the collected unit during phlebotomy, storage of
the unit at room temperature or, rarely, asymptomatic
donor bacteremia, all contribute to the risk. Although
the presence of bacteria is often unsuspected, Fig 1
shows a unit in which the growth of methicillin-resistant Staphylococcus aureus caused fibrin clots and
helped to prevent the unit from being issued from our
transfusion service. Subsequent culture confirmed the
clinical suspicion of bacterial contamination. In the
last 5 years, S aureus infections have accounted for
the majority of deaths due to infected platelet units,
although other gram-positive and gram-negative organisms have also been implicated.8
Parasites that infect RBCs, such as Babesia
microti or various malarial species, are the most likely
etiology of infection from RBCs.41 Awareness of these
transfusion-transmitted infections is of particular importance for oncologists. Babesiosis or malaria would
not be suspected as the cause of unexplained fever in
patients who lack the usual risk factors (eg, travel to
an endemic area). Furthermore, the diagnosis requires
a high level of suspicion and expert review of the patient’s peripheral blood (Fig 2). Thus, it is imperative
that transfusion-transmitted infections be included
in the differential diagnosis of fever in patients with
cancer and should be followed by the specific diagnostic laboratory evaluation as soon as symptoms
develop. Splenectomized patients are at significantly
increased risk of developing severe babesiosis, which
carries a grave prognosis. In such circumstances, RBC
exchange may be indicated to decrease the parasite
burden in critically ill patients.42 Because donor testing
does not include assays for babesiosis and malaria,
prevention is based on history of exposure, which can
be ineffective. Polymerase chain reaction and indirect
immunofluorescence are being investigated to screen
donors but are not yet in use.41,43
Due to their immunocompromised state, patients
with cancer are also at risk for other infections, including those due to CMV, parvovirus B19, and West Nile
virus. Because leukoreduction nearly eliminates the
risk of CMV infection and polymerase chain reaction
January 2015, Vol. 22, No. 1
Fig 1. — Unit of apheresis platelets contaminated with methicillin-resistant
Staphylococcus aureus discovered on day 5.
Fig 2. — Peripheral blood smear of a patient with babesiosis (hematoxylin
and eosin, × 1000). Courtesy of James Kelley, MD, PhD.
for West Nile virus infection is routinely performed in
donors, these infections are no longer significant concerns.2,44 However, parvovirus B19 remains a threat.45
Transfusion through indwelling central venous
catheters with subclinical microbial colonization may
lead to a septic reaction.46
Allergic Transfusion Reactions
Minor allergic reactions manifested as pruritus and
rash are common transfusion reactions, but they are
benign and usually easily treated. However, allergic
reactions can also represent life-threatening systemic
anaphylaxis with hypotension and respiratory distress.14 Typically, they are IgE-mediated type 1 hypersensitivity reactions, leading to mast cell activation
and the release of inflammatory mediators. Complement fixation and macrophage-derived cytokines may
also contribute to allergic symptoms. Although the
exact offending agent is typically unknown, these
reactions occur when the patient has been presensitized to an immunologically active compound in the
plasma of the donor. Examples of allergens include
foods, medications, and polymorphic forms of serum
January 2015, Vol. 22, No. 1
proteins other than IgA, like haptoglobin, C3, C4,
transferrin, and albumin. The passive transfer of IgE
antibodies to common environmental allergens and
anaphylatoxins or platelet biological response mediators (eg, cytokines, chemokines) generated during
storage also plays a role.14
For patients with mild symptoms such as pruritus or rash, transfusion may be restarted under close
supervision and at a slower rate following treatment
with an antihistaminic and if symptomatic improvement is seen; however, this practice is controversial.
Severe allergic reactions are caused by antibodies
to plasma proteins (eg, IgA, haptoglobin). IgA-related
anaphylactic reactions occur in IgA-deficient patients
with serum IgA levels below 0.05 mg/dL who have
developed class-specific IgA antibodies, even without
any previous pregnancy or transfusion (“naturally occurring”).14,15 Anaphylaxis causes bronchoconstriction
that results in respiratory distress, wheezing, stridor,
angioedema, and hypotension (see Tables 1 and 2).
Prompt action should be taken to maintain oxygenation and improve blood pressure.9,14,15 Epinephrine
may be intravenously or intramuscularly administered
in addition to corticosteroids and antihistaminics.
If bronchospasm is present, then respiratory symptoms may not respond to epinephrine; adding a β2
agonist or aminophylline may be required.9,14,15
Severe reactions should be further investigated to determine their etiology and to prevent their
occurrence in future transfusions. Patients with an
IgA deficiency and anti-IgA should be transfused
products from IgA-deficient donors alone or given
RBC washed units.14 For platelets, plasma reduction decreases the incidence of allergic reactions.14
In emergent situations, regular products may be given
after premedication with antihistamines and steroids
if the risk of withdrawing the transfusion is higher
than the risk of anaphylaxis. The newly approved
platelet additive solution, PAS C, replaces most
of the plasma in the unit, decreasing the risk of allergic reactions and FNHTRs.47
Febrile Nonhemolytic Transfusion Reaction
FNHTRs are the most common immediate adverse
event of transfusion in patients with cancer.1 They
are characterized by a temperature of 100.4°F (38°C)
or an increase of 1.8°F or 1°C from the pretransfusion value, with or without chills, during or within
4 hours following the completion of the transfusion,
occurring more often with platelets than RBCs (see
Tables 1 and 2).9 FNHTRs are a consequence of the
passive transfer of stored cytokines or due to recipient
antibodies against HLAs, HNAs, or platelet antigens
that stimulate the release of cytokines.
When receiving leukoreduced products, FNHTR
is a diagnosis of exclusion and other possibilities like
Cancer Control 21
AHTR, microbial contamination, TRALI, medication
adverse events, or an underlying infection should be
considered first, because prestorage leukoreduction
makes FNHTRs unlikely.48 For patients experiencing
recurrent FNHTRs despite leukoreduction, washed
RBCs in 2 L saline and premedication with an antipyretic may be useful.9 In addition, these patients
could be given a narcotic analgesic for chills, rigor,
or both.
Delayed Adverse Events of Transfusions
Delayed Hemolytic Transfusion Reaction
Delayed hemolytic transfusion reactions (DHTRs)
can be expected between 3 and 10 days following a
transfusion of apparently compatible RBCs in patients
with RBC antibodies with a low titer and which went
undetectable during pretransfusion testing. Following
the transfusion of RBCs containing the antigen the
patient had been presensitized against, an anamnestic
response occurs with a rapid increase in the antibody
titer between 1 and 2 weeks. Because these antibodies
are IgG and recognize antigens of the Kidd, Duffy,
Kell, Rh, and MNS systems, extravascular hemolysis
is expected.49 Patients may complain of weakness
and jaundice, and the laboratory workup will show
a drop in hematocrit level, circulating microspherocytes, increased levels of lactate dehydrogenase and
bilirubin, and a positive result on DAT.17 Using a type
and screen procedure, a new RBC alloantibody can
be identified unless the antibody has bound to the
transfused RBCs. In those cases, an elution is essential to determine the antibody specificity. A positive
DAT result following the transfusion due to a new
alloantibody but without signs of hemolysis occurs
more often than a DHTR and is termed a delayed
serological transfusion reaction.50
Transfusion-Associated Graft-vs-Host Disease
Recipients of transfusion who are immunocompromised are at risk for developing TA-GVHD, a potentially fatal complication.51,52 The transfusion of viable
T lymphocytes and the patient’s inability to mount an
immune response, either due to immunosuppression
or due to similarity in HLA (such as when a donor
is a first-degree relative), allows the lymphocytes
to survive and proliferate in the recipient. Patients
with lymphoid malignancies (particularly Hodgkin
lymphoma), those undergoing chemotherapy with
purine analogs or fludarabine, or those with cellular
immunodeficiency, as well as neonates, are at risk for
developing TA-GVHD.52 Clinically, TA-GVHD is similar
to GVHD post–stem cell transplantation, but it occurs
earlier (≤ 2 weeks of the transfusion) and suppresses
bone marrow.52-54 TA-GVHD presents as a rash with
fever, diarrhea, cholestasis, nausea, vomiting, and pancytopenia. Diagnosis is usually clinical, supported by
22 Cancer Control
biopsies from the skin, liver, or gastrointestinal tract,
and sometimes with molecular techniques to determine genetic chimerism. The mortality rate is high
because no effective treatment has been ascertained
and the neutropenia caused by TA-GVHD is profound.
The best strategy for health care professionals is to
prevent the occurrence of TA-GVHD by irradiating
the cellular blood components.55
Post-Transfusion Purpura
Post-transfusion purpura is a rare immunological
phenomenon characterized by sudden thrombocytopenia that takes place 2 to 14 days following a
blood transfusion.56 It is caused by platelet alloantibodies (mostly anti-HPA-1a) in a patient previously
sensitized from pregnancy or transfusion. Because the
thrombocytopenia is typically severe (< 10 × 109/L),
patients complain of petechial, purpura, or mucosal
bleeds. The diagnosis of post-transfusion purpura is
confirmed by the detection of platelet-specific alloantibodies in the serum.57 Most cases are self-limited
and the platelet count recovers within 3 weeks. IVIG
alone or in combination with corticosteroids is the
mainstay of treatment.56 Patients with severe bleeding
may benefit from platelet transfusions, preferably with
units lacking the offending antigen.
Red Blood Cell Alloimmunization
The transfusion of RBCs may induce alloantibodies,
potentially causing major problems in chronically
transfused patients such as those with myelodysplastic
syndromes.58 Chronically transfused patients who are
also minorities may be at greater risk when receiving RBCs from a primarily Caucasian donor population, as is typically seen in patients with sickle cell
disease. Although clinical factors that affect the rate
of alloimmunization have been suggested, predicting
which patients will form 1 or more alloantibodies
after each RBC transfusion is not possible.59 Sanz
et al60 reported that alloimmunization occurred in
15% of transfusion-dependent patients with myelodysplastic syndromes or chronic myelomonocytic
leukemia and that the incidence of alloimmunization
increased with the number of donor units.
Platelet Alloimmunization
Because platelets express HLA- and platelet-specific antigens, they may also induce alloantibodies.61
Sensitization may occur from pregnancy, transfusion,
or transplantation and lead to platelet refractoriness
(lack of appropriate response from transfusion). Although clinical factors, such as fever, sepsis, disseminated intravascular coagulation, splenomegaly, and
active bleeding, as well as drug use, are more likely
to cause decreased response from platelet transfusions than alloantibodies, the latter may be difficult
January 2015, Vol. 22, No. 1
to overcome. Because ABO incompatibility may compromise post-transfusion platelet count increments,
patients may benefit from a trial of ABO-compatible
platelets before the initiation of HLA-matched platelet
transfusions.23,61 The best strategy to prevent platelet
refractoriness is to avoid alloimmunization by using
exclusively leukoreduced RBCs and platelets. Alloimmunization to the D antigen (Rh) may be another
concern if Rh-negative patients receive Rh-positive
platelet transfusions. Rh antigens are not expressed
on platelets, but they are present in the few RBCs in
each unit of platelets. Although one study has concluded that the risk of developing anti-D is negligible
and does not warrant the use of Rh immunoglobulin
to prevent it,62 health care professionals should make
a decision on a case-by-case basis when treating a
patient who may become pregnant in the future.
Transfusion-Related Immunomodulation
Several lines of evidence, both in vitro and in vivo,
have suggested that allogeneic transfusions alter the
recipient’s immune system and his or her ability to respond to infections and tumor antigens.58,63 However,
transfusion-related immunomodulation (TRIM) continues to be a debatable complication of transfusion.64
TRIM may be multifactorial and possibly mediated
by allogeneic mononuclear cells, leukocyte-derived
soluble mediators, or soluble HLA peptides, among
others. A review by Refaai and Blumberg65 of TRIM
summarizes the effects of transfusion in the immune
system as the following:
• Decreased Th1 and increased Th2 cytokine
production in vitro
• Reduced responses in mixed lymphocyte culture
• Decreased proliferative response to mitogens or
soluble antigens in vitro, thus causing impaired
delayed-type hypersensitivity skin responses
• Increased CD8 T cells or suppressor function
in vitro
• Decreased natural killer cells and activity
in vitro
• Decreased CD4 helper T cells
• Decreased monocyte/macrophage function
in vitro and in vivo
• Enhanced production of anti-idiotypic antibodies suppressive of mixed lymphocyte response
in vitro
• Decreased cell-mediated cytotoxicity against
target cells in vitro
• Humoral alloimmunization to cell-associated
and soluble antigens
• Increased T-regulatory cells and function
Iron Overload
In addition to patients with hemoglobinopathies
(eg, thalassemia, sickle cell disease), those with
January 2015, Vol. 22, No. 1
myelodysplastic syndromes and aplastic anemia
often require chronic transfusion support. Transfusion
dependency in myelodysplastic syndromes has been
associated with worse outcomes, including decreased
rates of survival.66 Chronic transfusions cause significant iron overload because iron absorption is tightly
regulated and the body has limited ability to excrete
excess iron.67 Considering that 1 unit of RBCs has
200 to 250 mg of iron, most patients will develop iron
overload after transfusion of 10 to 20 units. Deposition
of iron in the parenchymal tissues and reticuloendothelial cells causes progressive end-organ damage such
as hepatomegaly and liver dysfunction, heart failure,
hypogonadism, diabetes mellitus, skin pigmentation,
and arthropathy. For this reason, the debate regarding
iron chelation therapy in myelodysplastic syndromes
is currently ongoing despite the lack of data from
randomized controlled trials.68
Conclusions
Transfusion safety encompasses the continuum from
donor qualification and screening to the appropriate
choice of blood components and the monitoring of patients for adverse events.69 Patients with malignancy
constitute a unique group, especially when diseaseor treatment-induced bone marrow failure causes
severe pancytopenia and demands transfusions.
Furthermore, their clinical condition may contribute
to transfusion reactions while making their recognition more challenging. Although extensive and
strong evidence supports a restrictive transfusion
approach, the data are limited to patients without malignancies; therefore, extrapolation is not
possible.70 Nonetheless, a judicious approach to
transfusion, as well as the administration of single
units followed by patient assessment, will help to
decrease the likelihood of adverse events in patients
with cancer undergoing transfusion.
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January 2015, Vol. 22, No. 1
Cancer Control 25
The clinical significance of storing RBCs
is controversial, although new data
suggest the RBC storage lesion does not
affect clinical outcomes in select patients
receiving transfusions.
Ray Paul. Sweet Jane, 2007. Acrylic, latex, enamel on canvas, 37" × 37". Private
collection of the Mathematical Oncology Department at Moffitt Cancer Center,
Tampa, FL.
Clinical Effects of Red Blood Cell Storage
Lirong Qu, MD, PhD, and Darrell J. Triulzi, MD
Background: Well-characterized biochemical, structural, and physiological changes occur when red blood
cells (RBCs) are stored for a period of time and are collectively called the storage lesion.
Methods: Key study results are summarized and contrasted and new data from recently completed randomized
controlled trials will be discussed.
Results: It is unclear whether in vitro changes to RBCs that occur during storage are clinically relevant. The
clinical effects of RBC storage have been the focus of observational studies in recent years. However, these
studies lack any consensus, possibly because of methodological limitations.
Conclusions: The clinical significance of storing RBCs is controversial, although new data from randomized
controlled trials of neonates and patients undergoing cardiac surgery suggest that the duration of RBC storage
is not associated with adverse clinical outcomes in these patient populations.
Introduction
According to a survey conducted in part by the US
Department of Health and Human Services, more
than 13 million units of red blood cells (RBCs) were
transfused in the United States in 2011.1 The mean
time of storage duration for a unit of RBCs at transfusion was 17.9 days.1 The maximum allowable
storage duration for RBC is defined by the US Food
and Drug Administration (FDA) and depends on the
storage media. In the United States, AS-1, AS-3, and
AS-5 are frequently used as additive solutions and
can be stored for up to 42 days at a temperature of
33.8 to 42.8°F (1–6°C). During the storage of RBCs,
From the Department of Pathology, University of Pittsburgh, and
the Institute for Transfusion Medicine, Pittsburgh, Pennsylvania.
Submitted July 17, 2014; accepted November 12, 2014.
Address correspondence to Darrell J. Triulzi, MD, Department of
Pathology, Institute for Transfusion Medicine, 3636 Boulevard of
Allies, Pittsburgh, PA 15213. E-mail: [email protected]
No significant relationships exist between the authors and the
companies/organizations whose products or services may be
referenced in this article.
26 Cancer Control
well-characterized biochemical, metabolic, structural, inflammatory, and physiological changes occur
that are collectively known as the “storage lesion.”
Although the storage lesion has been well documented and demonstrated in vitro, the clinical relevance of
these changes on patient outcomes remains unclear.
Ongoing interest exists in the relationship between
the duration of RBC storage and clinical outcomes
among recipients of transfusions, beginning with the
publication of a small, randomized, single-center trial
in 1989 that compared the effects of fresh whole blood
(< 12 hours old) with stored blood (2–5 days old) in
patients who underwent cardiac surgery.2 Interest in
the subject was further galvanized by the publication
of a retrospective study by Koch et al3 who reported that patients who underwent cardiac surgery and
received “older” blood (> 14 days old) had worse
outcomes than those who received fresher blood
(≤ 14 days old). This heightened awareness of the
controversy resulted in an increase of observational
studies, small studies, randomized controlled trials
(RCTs), and phase 3 RCTs to address this issue.
January 2015, Vol. 22, No. 1
One systematic review provided a detailed summary of relevant publications in adult patients during
the last 3 decades (1983–2012).4 The authors of the
review identified 55 studies for detailed qualitative
synthesis, most of which were retrospectively performed at a single institution; 8 (14.5%) were small
randomized studies, 3 of which were conducted using
healthy volunteers. Twenty-six of the studies (47%)
suggested that stored RBCs were adversely affected
in at least 1 clinical end point, whereas the remaining 29 studies (53%) revealed no difference in effect.
The authors concluded that the evidence did not definitively indicate that fresher RBCs were clinically
superior to older RBCs.4 It is worth noting that they
did not perform a quantitative meta-analysis due to
the considerable heterogeneity among studies and a
concern of numerous biased studies they identified
in their systematic review.4
Two other meta-analyses of studies from mostly observational data have resulted in conflicting
results.5,6 Wang et al5 performed a meta-analysis on
21 studies published between 2001 and 2011, including 6 studies of cardiac surgery and 6 studies reviewing trauma, that totaled 409,966 patients. They showed
that RBC storage was associated with an increased risk
of mortality (pooled odds ratio [OR], 1.16; 95% confidence interval [CI]: 1.07–1.24; P = .0001), pneumonia
(pooled OR, 1.17; 95% CI: 1.08–1.27; P = .0001), and
multiple organ dysfunction syndrome (pooled OR,
2.26; 95% CI: 1.56–3.25; P < .0001).5 A meta-analysis
by Vamvakas et al6 of studies that included adjusted
results for mortality found that the storage duration
was not associated with an increased risk of mortality.
There are several possible explanations for the
conflicting conclusions from these mostly observational studies. A retrospective study design does not
control for known or unrecognized factors that may
be clinically important, including baseline patient
characteristics, underlying disease, volume transfused, transfusion of other blood components, and
follow-up period. Sicker patients receive more blood
transfusions than their counterparts, and, thus, have
a greater likelihood of receiving at least 1 older unit.
An observational study cannot determine whether
worse outcomes are due to the need for transfusion
or the transfusion itself (confounded by indication).
Varied rates of mortality (eg, 7 vs 28 days) and morbidity end points (outcomes) were reported among
studies, making comparisons difficult. In addition,
various definitions of length of RBC storage were
used to define “fresher” versus “older.” This issue is
particularly problematic when multiple units of various durations of storage are transfused. For example,
some used less than 7 days, less than 10 days, or less
than 14 days as “fresher,” and more than 14 days,
more than 21 days, or longer as “older” RBCs. Other
January 2015, Vol. 22, No. 1
studies used the mean age, oldest unit, or oldest of
multiple units.
It is worth emphasizing that no clinical evidence
supports these “fresh” and “old” definitions. Investigators have inferred that the kinetics of in vitro changes
during storage correlate with the in vivo effectiveness
of RBCs when defining the age of RBC storage. This
approach does not account for the fact that the kinetics
of the in vitro changes are variable depending on the
parameter, and none has been shown to be clinically relevant. Variable preparations of RBCs, including
differing storage media or modifications (eg, leukoreduction), have been used in studies over the years.
Leukocytes in the blood products have been reported
to affect clinical outcomes via immunomodulation.7
Rather than replicate a recent systematic review
on the subject,4 in this article we will summarize and
contrast key results from previous studies, describe
the results of recent publications, and discuss the
available data from recently completed RCTs.
In Vitro Changes
In the United States, the FDA has indicated that the
maximum “shelf-life” for a unit of RBCs is 42 days
when stored in additive solution (eg, AS-1, AS-3,
AS-5). The limit on RBC storage duration is primarily based on degree of hemolysis (< 1%) at the end
of storage and the percent (minimum, 75%) of the
RBCs remaining in the circulation 24 hours following
transfusion.8,9 The many changes encompassed by
the storage lesion occur in a time-dependent manner
with kinetics that vary depending on the parameter.8,9 There is a progressive decrease in intracellular
2,3-diphosphoglycerate (DPG) and adenosine triphosphate with a concomitant accumulation of extracellular free hemoglobin and free iron. A decrease in
2,3-DPG reduces oxygen delivery to tissue, although
this change is reversible after transfusion. Irreversible
changes to the RBC membrane, including the release
of microvesicles, reduce deformability and may increase the likelihood of occluding microvasculature.
Extracellular hemoglobin that is free or contained
in microvesicles may scavenge nitric oxide, and iron
may increase circulating, nontransferrin-bound iron
and, thus, could promote inflammation.8-10 There is a
progressive accumulation of lactic acid and potassium
and a steady decrease in pH during storage. In addition, the accumulation of other biological by-products,
including cytokines, lipids, histamines, and enzymes,
may induce febrile transfusion reactions, increase oxidative membrane damage, and activate or suppress
the immune system.10
Although the in vitro changes are clear and demonstrable (eg, loss of 2,3-DPG by day 14 of storage),
no data exist on the in vivo clinical significance of
these changes nor a cutoff point of storage duration
Cancer Control 27
to define “older” RBCs. Therefore, defining “older”
RBCs (or the age of multiple transfused units) for
clinical study is arbitrary, and a fact that, in part, may
explain the varied storage duration cutoffs used in
many published studies.
Cardiac Surgery
Clinical studies of the duration of RBC storage in
patients who underwent cardiac surgery are shown
in Table 1.2,3,11-22 The most well-known of these studies is that of Koch et al,3 which is a single center,
retrospective study of 6,002 patients who underwent
cardiac surgery and received transfusions with RBCs
between 1998 and 2006. A total of 2,872 patients received 8,802 units of blood stored for 14 days or less
(“fresher”), and 3,130 patients received 10,782 units
of blood stored for more than 14 days (“older”). Re-
cipients of older RBCs (median, 20 days) had higher
rates of hospital mortality compared with those who
received fresher RBCs (median, 11 days; 2.8% vs 1.7%;
P = .004). Compared with those who received fresher RBCs, recipients of older RBCs also had a higher
rate of 1-year mortality (7.4% vs 11.0%; P < .001),
were more likely to require prolonged support on
mechanical ventilation (MV) beyond 72 hours (9.7% vs
5.6%; P < .001), and more likely to have renal failure
(2.7% vs 1.6%; P = .003), sepsis or septicemia (4.0%
vs 2.8%; P = .01), or multisystem organ failure (0.7%
vs 0.2%; P = .007).3 Of note, the conclusions of this
study have been debated and challenged primarily
because of the observational nature of the study and
the presentation of unadjusted analyses.23
Several studies of patients who underwent cardiac surgery were unable to find similar associations.
Table 1. — Effects of the Duration of RBC Storage Among Patients Undergoing Cardiac Surgery
Study
Design
Definition of Storage
Duration
Clinical Setting
No. of
Patients
Increased Risk for Adverse Events
With Longer Storage?
Andreasen19
Retrospective
multicenter
< 14 vs ≥ 14 days
Cardiac surgery
1,748
Yes for postoperative wound infection and
septicemia
Baltsvias22
Retrospective
single center
≤ 7 vs > 14 days
Cardiac surgery
(pediatric)
570
No for mortality
No for other end points
Koch3
Retrospective
single center
≤ 14 vs > 14 days
Cardiac surgery
6,002
Yes for mortality and composite of
17 clinical outcomes
Leal-Noval17
Retrospective
single center
Mean age
Cardiac surgery
585
Yes for pneumonia;
No for ICU LOS and other end points
McKenny14
Retrospective
single center
≤ 14 vs > 14 days
Cardiac surgery
1,153
No for mortality
No for ICU LOS
Redlin21
Retrospective
single center
≤ 3 vs 4–14 days
Cardiac surgery
(pediatric)
139
Yes for transfusion requirements
Sanders20
Retrospective
single center
< 14 vs > 14 days
Cardiac surgery
444
Yes for LOS and renal failure
Vamvakas16
Retrospective
single center
Mean age
Cardiac surgery
256
Yes for postoperative infections
Vamvakas18
Retrospective
single center
Mean age, oldest,
mean of 2 oldest units
Cardiac surgery
268
No for postoperative ICU and hospital LOS
van de Watering11
Retrospective
single center
Mean age, youngest,
oldest, < 18 vs > 18 days
CABG
2,732
No for mortality and ICU LOS in
multivariate analysis
van Straten13
Retrospective
single center
< 14 vs > 14 days
CABG
3,597
No for early or late postoperative mortality
Voorhuis15
Retrospective
single center
≤ 14 vs > 14 days
Cardiac surgery
821
No for mortality
No for other end points
Wasser2
Randomized
single center
< 12 hours vs 2–5 days
Cardiac surgery
237
No for coagulation rests, postoperative
bleeding, or transfusion requirements
Yap12
Retrospective
single center
Median age, oldest,
< 30 vs ≥ 30 days
Cardiac surgery
670
No for postoperative mortality, renal failure,
pneumonia, duration of MV, or ICU LOS
CABG = coronary artery bypass graft, ICU = intensive care unit, LOS = length of stay, MV = mechanical ventilation, RBC = red blood cell.
28 Cancer Control
January 2015, Vol. 22, No. 1
In a multivariate analysis of 2,732 patients who received
coronary artery bypass graft (CABG), van de Watering
et al11 showed that patients who exclusively received older RBCs (mean storage, 24.3 ± 3.5 days) had similar rates
of 30-day survival or length of stay (LOS) in the intensive
care unit (ICU) as patients who received fresher RBCs
(mean storage, 12.7 ± 2.8 days). Yap et al12 found no
association between the duration of storage of RBCs and
any of the study end points, such as early postoperative
mortality, renal failure, pneumonia, LOS in the ICU, and
hours of MV support, in 670 consecutive patients who
had nonemergency CABG, aortic valve replacement, or
both. In a retrospective analysis of 3,597 patients who underwent CABG, van Straten et al13 did not find length of
RBC storage (cutoff, 14 days) to be a risk factor for
early or late mortality. McKenny et al14 analyzed
1,153 patients who underwent cardiac surgery and
found no association between duration of storage (cutoff,
14 days) and postoperative mortality rates in multivariate analyses. Voorhuis et al15 analyzed the data of
821 patients who underwent cardiac surgery and found
that the transfusion of RBCs stored for more than 14 days
was not associated with adverse outcomes. The incidences of the primary outcome (composite end point of death,
myocardial infarction, and stroke) were 8.6% and 4.5%
in the “any older” group (RBC age, 21 ± 5 days) and the
“fresher” group (RBC age, 13 ± 2 days), respectively (adjusted OR, 1.68; 95% CI: 0.65–4.34).15 Rates of prolonged
ICU stays were 12.3% and 6.3% in the “any older” and
“fresher” groups, respectively (adjusted OR, 1.58; 95%
CI: 0.69–3.66).15
In addition to the reports on mortality outcomes,
several investigators assessed the possible association
between length of RBC storage and other clinical parameters, such as occurrence of infections, ICU and
hospital LOS, as well as organ failure in transfused
patients. Vamvakas et al16 reported on an independent
relationship between the storage duration of RBCs
and postoperative pneumonia or wound infections
among 256 patients who received transfusions and
underwent CABG surgery, discovering that the risk of
pneumonia increases by 1% for every additional day
of mean storage length of RBCs (P < .005). Leal-Noval
et al17 found that the oldest unit transfused (> 28 days),
but not the mean age of all transfused units, correlated
with the development of postoperative pneumonia
(OR, 1.06; 95% CI: 1.01–1.11). However, they did not
find a correlation between the mean duration of storage with prolonged ICU LOS (> 4 days), prolonged
length of MV support (> 24 hours), or perioperative
infarction, mediastinitis, or sepsis.17 A subsequent
study by Vamvakas et al18 reported no association
between duration of RBC storage and postoperative
ICU and hospital LOS. Andreasen et al19 investigated
1,748 patients receiving CABG and found that, compared with patients not receiving transfusions, the
January 2015, Vol. 22, No. 1
adjusted ORs for severe infection among all transfusion recipients and recipients of fresher (< 14 days;
n = 953) or older (≥ 14 days; n = 548) RBCs were
1.6 (95% CI: 0.9–2.8), 1.1 (95% CI: 0.6–2.1), and 2.3
(95% CI: 1.2–4.2), respectively. In a retrospective study
of 444 patients undergoing cardiac surgery, Sanders
et al20 found that patients who exclusively received
older RBCs (> 14 days) or any older blood (older
blood, fresher blood, or a mixture of both) had a
longer postoperative LOS and a higher incidence of
new renal complications than patients who received
transfusions with fresher RBCs.
Two recent retrospective studies reviewed data
from pediatric patients who underwent cardiac surgery.21,22 Redlin et al21 evaluated 139 pediatric patients
undergoing cardiac surgery, and, of those patients,
26 received RBC units stored for no more than 3 days,
and 113 received RBCs stored for between 4 and
14 days. The latter group required additional transfusions of RBCs and fresh frozen plasma than the former
group (19 vs 25 mL/kg [P = .003] and 73% vs 35%
[P = .0006], respectively). In another retrospective review of 570 patients receiving transfusion with 1 or
2 units of blood, Baltsavias et al22 found no difference
in mortality, length of ICU stay, MV duration, postoperative infection, and major organ dysfunction between
the fresher group (median [interquartile range] storage
duration, 6 days [range, 5–7 days]) and the older group
(storage duration, 14 days [range, 11–19 days]).
Trauma
Studies on the effects of RBC storage among
patients with trauma have generated conflicting results
(Table 2).24-37 Zallen et al24 performed a retrospective review of a prospectively collected database and
found that the mean age of blood or number of units
for more than 14 or 21 days was an independent risk
for multiorgan failure among the 63 patients studied. Keller et al25 reported that the number of units
older than 14 days was associated with an increased
hospital LOS, but not the duration of MV support in
86 patients with trauma. Offner et al26 found the
number of transfused units that had been stored for
14 or 21 days was associated with an increased risk
for infection. Weinberg et al27 reported that transfusion
of large (but not small) volumes of older blood was
associated with increased rates of mortality among
1,813 patients with severe trauma (mean injury severity score [ISS], 26]. In a report of patients with
less severe traumatic injury (mean ISS, 14.4), Weinberg et al28 found that the transfusion of older blood
(> 14 days old) was associated with a slightly increased rate of mortality (OR, 1.12; 95% CI: 1.02–1.23).
The same authors later reported that a higher mortality rate occurred in patients receiving transfusions with
at least 3 units of older blood (≥ 14 days) compared
Cancer Control 29
with those who received at least 3 units of fresher
RBCs (adjusted RR, 1.57; 95% CI: 1.14–2.15).29 In a
retrospective analysis of 202 patients with trauma who
received at least 5 units of RBCs, Spinella et al30 found
higher rates of mortality among patients transfused
with older RBCs (maximum storage age, ≥ 28 days)
than with fresher RBCs (maximum storage age,
≤ 27 days; 26.7% vs 13.9%; P = .02). They also found an
association between the maximum age of transfused
RBCs (> 21 or 28 days) and deep venous thrombosis.30
Vandromme et al31 retrospectively analyzed the data
of 1,183 patients with trauma who received transfusions and found that transfusions of exclusively older
RBCs (≥ 14 days) significantly increased the risk of
pneumonia (adjusted RR, 1.42; CI: 1.01–2.02), whereas
transfusions of exclusively fresher RBCs (adjusted RR,
1.02; CI: 0.62–1.67) or mixed RBCs (adjusted RR, 1.35;
95% CI: 0.98–1.87) did not.
In a prospective, observational study, Leal-Noval
et al32 assessed the effects of RBC transfusion on
cerebral tissue oxygenation (PtiO2) in 66 patients with
traumatic brain injury. The duration of RBC storage
was divided into 4 groups: less than 10 days (n = 18),
10 to 14 days (n = 15), 15 to 19 days (n = 17), and
more than 19 days (n = 16). They observed a significant increase in PtiO2 after the transfusion of RBCs
stored for less than 19 days, but they saw no significant changes in PtiO2 after the transfusion of RBCs
stored for more than 19 days. Kiraly et al33 performed
a prospective, nonrandomized study in 32 trauma patients in the ICU who were hemodynamically stable
and nonseptic. Seventeen of those patients transfused
with older blood (≥ 21 days) demonstrated a significant decline in the area under the curve for tissue
oxygen saturation (StO2) as measured by near-infrared
spectroscopy.33 Patients transfused with fresher blood
(< 21 days old) and a control group not receiving
transfusions had no similar rate of decline in the area
Table 2. — Effects of the Duration of RBC Storage Among Patients Undergoing Trauma
Study
Design
Definition of Storage Duration
No. of
Patients
Hassan36
Retrospective single center
< 14 vs ≥ 14 days
Juffermans37
Retrospective single center
> 14 days
196
Yes for occurrence of new infection
Keller25
Retrospective single center
Mean age, oldest unit,
2 oldest units > 7, 14, 21, 28 days
86
Yes for hospital LOS for RBCs > 14 days
No for MV
Prospective single center
< 21 vs ≥ 21 days
32
Yes for decrease in tissue oxygenation
Leal-Noval
Prospective, observational
single center
< 10 days
10–14 days
15–19 days
> 19 days
66
Yes for failure to increase cerebral tissue
oxygenation (>19 days in the RBC group)
Murrell35
Retrospective single center
Weighted mean age
275
Yes for ICU LOS
No for hospital mortality
Offner26
Retrospective single center
> 14 days
> 21 days
61
Yes for infection
Spinella30
Retrospective single center
Max age ≥ 14, 21, 28 days
202
Yes for hospital mortality and deep
venous thrombosis
Vandromme31
Retrospective single center
< 14 vs ≥ 14 days
1,183
Yes for pneumonia
27
Weinberg
Retrospective single center
< 14 vs ≥ 14 days
1,813
Yes for mortality rate
(for a large volume of older RBCs)
Weinberg28
Retrospective single center
< 14 vs ≥ 14 days
430
Yes for mortality
Weinberg
Retrospective single center
< 14 vs ≥ 14 days
1,647
Yes for mortality (> 3 units transfused)
Weinberg34
Prospective single center
Range: 7–42 days
93
Yes for decline in tissue oxygenation
with RBC age
Zallen24
Retrospective single center
Mean age
63
Yes for multiorgan failure
Kiraly33
32
29
820
Increased Risk for Adverse Events
With Longer Storage?
Yes for complicated sepsis
No for mortality
ICU, intensive care unit, LOS = length of stay, MV = mechanical ventilation, RBC = red blood cell.
30 Cancer Control
January 2015, Vol. 22, No. 1
under the curve for StO2. They found a moderate
correlation between increasing the duration of RBC
storage and decreasing the oxygenation (r = 0.5).33
Weinberg et al34 evaluated microvascular perfusion in
93 stable patients with trauma (mean ISS, 26.4) during
RBC transfusion and found that the transfusion of
relatively older RBCs was associated with a decline
in both StO2 and perfused capillary density.
Other studies have produced mixed results (see
Table 2). Murrell et al35 studied 275 patients and
found that older blood was associated with longer
stays in the ICU (RR, 1.15; 95% CI: 1.11–1.20) but
not higher rates of hospital mortality (OR, 1.21; 95%
CI: 0.87–1.69). In a cohort of 820 patients with trauma,
Hassan et al36 found that the total number of RBC units
but not the number of older (> 14 days old) RBC units
transfused was associated with an increased rate of
mortality. However, the number of older units was a
significant risk factor for severe sepsis or septic shock,
particularly when more than 7 units were transfused
(OR, 1.9; 95% CI: 1.1–3.4; P = .03).36 In a retrospective
study of 196 patients with trauma who received transfusions, Juffermans et al37 found a modest correlation between transfused RBCs stored for longer than
14 days and the occurrence of new infections (OR,
1.04; 95% CI: 1.01–1.07).
Critical Care
Regarding the adverse effects of prolonged RBC storage on clinical outcomes, conflicting analyses have
also been reported among patients who are critically
ill (Table 3).38-53 Purdy et al38 reported that, of the
31 patients they studied who were admitted to the
ICU with severe sepsis, the median age of RBC units
Table 3. — Effects of the Duration of RBC Storage Among Patients in Critical Care
Study
Design
Aubron43
Definition of Storage
Duration
Clinical
Setting
No. of
Patients
Increased Risk for Adverse Events
With Longer Storage?
Retrospective 2 centers
Mean, maximum,
minimum age
ICU
8,416
Prospective single center
Median
ICU
44
No for tissue oxygen saturation
Dessertaine
Retrospective single center
Median of max age
ICU
534
No for mortality
No for infections
Fernandes49
Prospectively randomized,
single center
Continuous variable
ICU (sepsis)
15
No for gastric mucosal pH
Gajic44
Retrospective single center
< 15 days
15–20 days
> 20 days
ICU
181
No for acute lung injury
Janz46
Retrospective single center
Median
ICU (sepsis)
97
Yes for acute lung injury/ARDS
Juffermans41
Retrospective single center
≤ 14 vs > 14 days
ICU (sepsis)
67
Storage time as a confounder
Katsios
Prospective single center
> 7, > 14, and > 21 days
as cutoff
ICU
261
No for occurrence of deep
venous thrombosis
Kopterides53
Prospective single center
< 14 vs > 14 days
ICU (sepsis)
37
No for change in
lactate:pyruvate ratio
Kor45
Randomized single center
≤ 5 days vs standard issue
RBCs (median, 21 days)
ICU
100
No difference in pulmonary
function
Marik48
Prospective single center
< 15 vs ≥ 15 days
ICU (sepsis)
23
Yes for gastric mucosal pH
Pettila
Prospective multicenter
Quartile of max age
ICU
757
Higher hospital mortality with
older RBCs
Purdy38
Retrospective single center
Median age
ICU (sepsis)
31
Yes for mortality
Sakr51
Prospective single center
Continuous variable
ICU (sepsis)
35
No for microvascular flow
Taylor
Prospective single center
Maximum age
ICU
449
No for nosocomial infections
Walsh50
Prospectively randomized,
single center
≤ 5 vs ≥ 20 days
ICU
22
No for gastric mucosal pH
Creteur52
39
47
42
40
No for mortality
No for ICU or hospital LOS
ARDS = acute respiratory distress syndrome, ICU = intensive care unit, LOS = length of state, RBC = red blood cell.
January 2015, Vol. 22, No. 1
Cancer Control 31
transfused to survivors was 17 days (range, 5–35 days)
compared with 25 days (range, 9–36 days) for nonsurvivors (P < .0001). In another study of 534 patients
in the ICU, Dessertaine et al39 found no association
between the storage duration of transfused RBCs (defined as the maximum age of 23 days [median]) and
rate of mortality or nosocomial infection. Furthermore, in a prospective study of 449 patients in the
ICU, Taylor et al40 found that the maximum age of
transfused RBCs was not associated with an increased
risk for nosocomial infection. Juffermans et al41 retrospectively reviewed 67 patients in the ICU with sepsis
and found that the total amount of transfused RBCs
was associated with secondary infection (OR, 1.18;
95% CI: 1.01–1.37), and the duration of RBC storage
was identified as a confounder of the effects of the
amount of RBCs on infection.
Pettila et al42 performed a prospective, multicenter, observational study of 757 patients who were
critically ill (mixture of medical/surgical patients) in
47 ICUs in Australia and New Zealand and found
that patients who received older blood (average age,
17.6 days) had higher rates of hospital mortality compared with those who received fresher blood (average age, 7.5 days; OR, 2.01; 95% CI: 1.07–3.77) after
adjusting for disease severity and number of RBCs
transfused. Aubron et al43 evaluated 8,416 patients
who received a median of 4 RBC units (interquartile
range, 2–7) in the ICU at 2 hospitals. After a multivariate analysis, the duration of RBC storage was
not independently associated with rate of mortality.
Furthermore, no clinically relevant relationship was
seen between the mean age of transfused RBCs and
length of ICU stay.43
Several investigators have assessed the relationship between duration of RBC storage and pulmonary function or the risk of acute lung injury (ALI)
in patients in the ICU. In a retrospective analysis of
181 patients in the ICU, Gajic et al44 found no association between mean age or age of the oldest unit transfused and occurrence of ALI. Kor et al45 performed
a small, double-blind, randomized, single-center
trial of 100 patients in the ICU on MV support to
compare the effects of fresher RBCs (median age,
4 days) with standard RBCs (median age, 26.5 days).
They found no significant difference in the primary outcome of pulmonary function assessed by the
partial pressure of arterial oxygen to the fraction of
inspired oxygen concentration ratio as well as the
immunological and coagulation status between the
2 groups. A similar rate of mortality was seen among
the fresher and standard-issue RBC groups, but the
study was not powered for this outcome.45 Janz et al46
assessed whether the duration of RBC storage was
associated with the risk of developing ALI in a cohort
of 96 patients in the ICU who were septic and had
32 Cancer Control
received transfusions. They found that the median
storage duration of transfused RBCs in patients with
ALI/acute respiratory distress syndrome (ARDS) was
longer (24.5 days; interquartile range, 20–31 days)
compared with patients without ALI/ARDS (21 days;
interquartile range, 15–27 days; P = .018). The same
association was not seen in the 176 trauma patients in
the ICU who received transfusions or in 125 patients
in the ICU who were not septic, had no trauma, and
had received transfusions.46
In a prospective study of 261 patients in the
ICU, Katsios et al47 reported no association between
the storage duration of transfused RBCs and the development of deep venous thrombosis. A previous
study of patients with trauma found an association between the maximum age of transfused RBCs (> 21 or
28 days) and the occurrence of deep venous thrombisis, but no multivariate analysis was performed.30
Several studies have addressed whether older
RBCs adversely affect microcirculation or tissue oxygenation (see Table 3).38-53 Marik et al48 found an
inverse relationship between the duration of RBC
storage and the maximal changes in gastric mucosal
pH (pHi) in 23 patients in the ICU who were septic
(r = –0.71; P < .001). However, later studies did not
confirm this finding. In a small, randomized study of
15 septic patients, Fernandes et al49 compared the transfusion of either 1 RBC unit (mean age, 12.8 ± 8.1 days)
or 500 mL of albumin solution and found no correlation between the storage duration of transfused RBCs
and pHi. In another double-blind, randomized study of
22 patients in the ICU, Walsh et al50 compared the
effects of transfusing 2 units of leukoreduced RBCs,
which were stored for either no more than 5 days (median, 2 days) or for at least 20 days (median, 28 days)
and found no difference in pHi or gastric-to-arterial
PCO2 gap. Sakr et al51 assessed transfusion-induced
changes in the sublingual microcirculation of 35 patients in the ICU with sepsis following the administration of either 1 or 2 units of leukoreduced RBCs (mean
storage, 24 days; interquartile range, 12–28 days) and
found no effect of the duration of RBC storage on the
changes of microvascular flow. Creteur et al52 evaluated
44 patients in the ICU for oxygenation and microvascular reactivity using near-infrared spectroscopy
and found no association between the duration of
RBC storage and oxygen variables. Kopterides et al53
reviewed the data from 37 patients in the ICU with
sepsis and found no relationship between the duration
of RBC storage and change in the lactate:pyruvate
ratio (microdialysis).
Cancer and Other Patient Populations
Several studies have addressed the effects of RBC
storage among patients with cancer, those undergoing
liver transplantation, those receiving transfusions, and
January 2015, Vol. 22, No. 1
mixed patient populations, among others (Table 4).54-69
Several earlier studies reported on the effects of
RBC storage duration on postoperative infections in
patients undergoing surgery for colorectal cancer.54-56
In a retrospective study of 466 consecutive patients
who underwent resection for colorectal cancer be-
tween the years 1980 and 1992 in Norway, Edna et
al54 analyzed 290 patients who received a transfusion
of nonfiltered blood and found that infections were
more likely to occur in the patients who received
transfusions (31%) than in patients who did not
receive transfusions (13%; P < 0.001). However,
Table 4. — Effects of the Duration of RBC Storage Among Oncology and Other Patient Populations
Study
Design
Definition of
Storage Duration
Basora67
Retrospective single
center
Median, oldest unit
Cata57
Retrospective single
center
< 13 days
13–18 days
> 18 days
Cywinski62
Retrospective single
center
Dunn61
Retrospective single
center
Edgren63
Retrospective multicenter
Edna54
Clinical Setting
No. of
Patients
Increased Risk for Adverse
Events With Longer Storage?
Knee arthroplasty
335
No for postoperative wound
infection
Prostate cancer
316
No for 5-year cancer recurrence
≤ 15 vs > 15 days
Liver transplantation
637
Yes for mortality and graft failure
Median
Liver transplantation
509
No for 2-year mortality
No for postoperative infection
or organ rejection
0–9 days
10–19 days
20–29 days
30–42 days
Mix
364,037
Yes for 5% increased mortality
for RBCs stored > 30 days
(2-year follow-up)
Retrospective single
center
Median age
Colorectal cancer
240
No for postoperative infections
Eikelboom64
Retrospective single
center
Continuous variable;
quartile; 10-day
interval
Cardiovascular disease
4,933
Yes for hospital mortality for
highest age quartile of RBCs
Kekre58
Retrospective single
center
< 14 vs ≥ 15 days
Cancer
1,929
No for overall survival
Kekre59
Retrospective single
center
Mean age, ≥ 15 days
HSCT
555
No for nonrelapse mortality
No for LOS or ICU admission
Lee68
Retrospective single
center
≤ 14 vs > 14 days
Breast reconstruction
74
Yes for postoperative
complications
Middelberg69
Retrospective single
center
≤ 17 vs > 17 days
Mix (inpatients and
outpatients)
8,971
No for increased mortality with
fresh (compared with old) RBCs
Mynster55
Retrospective multicenter
Max age
Colorectal cancer
225
Yes for infection
(for RBCs > 20 days)
Mynster56
Retrospective multicenter
< 21 vs ≥ 21 days
Colorectal cancer
740
No for mortality
No for cancer recurrence
(recipients of ≥ 21 days
had less recurrence)
Robinson65
Retrospective single
center
Mean age
Percutaneous coronary
intervention
909
Yes for 30-day morality
Saager66
Retrospective single
center
≤ 14 days
14–28 days
> 28 days
Noncardiac surgery
6,994
No for mortality
Yuruk60
Prospectively randomized,
single center
< 1 vs 3–4 weeks
Hematology patients
20
Same increase in perfused
vessel density in both groups
HSCT = hematopoietic stem cell transplantation, ICU = intensive care unit, LOS = length of stay, RBC = red blood cell.
January 2015, Vol. 22, No. 1
Cancer Control 33
the median storage time of blood transfused to patients with infectious complications (18 days; range,
2–35 days) was no different from those without infections (20 days; range, 1–37 days; P = .10).54 Mynster
et al55 retrospectively analyzed transfusion data from
a prospectively acquired database of 303 patients
who underwent resection of colorectal carcinoma in
Denmark; 225 of these patients received transfusions.
The overall infection rate was higher in patients who
received a transfusion (40%) compared with those
who had not received a transfusion (24%; P = .011).
A multivariate analysis showed that the transfusion
of blood stored for at least 21 days correlated with
the rate of postoperative infection (intra-abdominal
abscess, anastomotic leakage, wound infection, pneumonia, and septicemia). The OR was 2.35 (95% CI:
1.27–4.37; P = .007).55 The same investigators published another analysis of 740 patients from the same
prospectively acquired database and discovered a
higher rate of cancer recurrence in patients who received blood exclusively stored for less than 21 days
(hazard ratio [HR]: 1.5; 95% CI: 1.1–2.2) than patients
who received blood stored for at least 21 days.56
One decade later, Cata et al57 studied 316 patients who underwent surgery for prostate cancer and
did not find an association between the duration of
RBC storage and the 5-year biomedical (defined by
prostate-specific antigen level) recurrence of cancer following radical prostatectomy. At 5 years, the
recurrence-free survival rates were 74%, 71%, and
76% for patients who received younger (≤ 13 days),
middle (13–18 days), and older (≥ 18 days) aged
RBCs, respectively (P = .82; Wald test).57 A retrospective study by Kekre et al58 analyzed the data from
1,929 patients with cancer who received a transfusion
within 1 year of a diagnosis of cancer and found that
the overall survival rates were not associated with the
storage duration of transfused RBCs. Median survival rates were 1.2, 1.7, and 1.1 years for the patients
who received exclusively fresher (< 14 days), intermediate
(14–28 days), or older (> 28 days) units of RBCs,
respectively (P = .36).58 The same authors had also
studied the data of 555 patients who received transfusions during hematopoietic stem cell transplantation
and found that the proportion of older units (≥ 15 days)
and the mean age of the transfused RBCs did not correlate with rates of 100-day nonrelapse mortality, LOS,
or ICU admission (P > .05).59 Yuruk et al60 performed
a small randomized trial of 20 hematology patients
and found that changes in microcirculatory density
and hemorheologic properties were similar between
the fresher RBC group (median, 7 days [interquartile
range, 5–7 days]) and older RBC groups (median,
23 days [interquartile range, 22–28 days]).
Two studies of patients receiving liver transplantation also generated conflicting conclusions. Dunn
34 Cancer Control
et al61 retrospectively analyzed 509 patients receiving
liver transplantations and reported that no independent
association existed between the duration of RBC storage
and postoperative infections, organ rejection, or death.
Patients who received more blood had an increased
risk for death.61 However, Cywinski et al62 analyzed
637 patients receiving liver transplantations and found
that the risk for graft failure and mortality was significantly higher in recipients of older RBC units (> 15 days
old) compared with recipients of fresher RBC units
(HR, 1.65; 95% CI: 1.18–2.31). The authors concluded
that patients who intraoperatively received older RBCs
had an increased risk for adverse outcomes.62
Several large studies have reported outcomes on
mixed patient populations. Edgren et al63 reported
on a large data set of 404,959 transfusion episodes
in more than 300,000 patients (mostly trauma and
surgical) derived from the Swedish and Denmark
Scandinavian Donations and Transfusions’ database
from 1995 to 2002.63 During a 2-year follow-up, an
increased mortality rate of 5% was seen among patients transfused with RBCs that were stored for 30 to
42 days compared with patients who received RBCs
that were stored for 10 to 19 days (HR, 1.05; 95%
CI: 0.97–1.12).63 No dose effect, no pattern for cause of
mortality, and no change in mortality over time were
seen, leading the authors to state that the small excess
risk was most consistent with weak confounding.63
Two studies examined patients with cardiovascular
disease.64,65 Eikelboom et al64 studied 4,933 patients
with cardiovascular disease and found a higher risk
of mortality (RR, 1.48; 95% CI: 1.07–2.05) in recipients of the highest quartile of transfused storage
duration (31–42 days). Robinson et al65 analyzed
909 patients receiving transfusions following a percutaneous coronary intervention and found that
the duration of RBC storage was associated with a
slightly higher rate of 30-day mortality (HR, 1.02; 95%
CI: 1.01–1.04; P = .002), and recipients of only older
RBCs (> 28 days old) had an even a greater risk of
mortality (HR, 2.49; 95% CI: 1.45–4.25; P = .001).
In a retrospective analysis of nearly 7,000 patients
who received transfusions for general (noncardiac)
surgery, Saager et al66 found no association between
the median duration of storage and risk of postoperative mortality (HR, 0.99; 95% CI: 0.94–1.04; P = .64). In
a retrospective analysis of 335 patients who underwent
knee arthroplasty, Basora et al67 found no independent
association between the age of transfused RBCs and
postoperative wound infection. However, Lee et al68
analyzed 261 patients who underwent surgery for
breast reconstruction and found that postoperative
complications (vascular thrombosis, hematoma, and
flap congestion) were higher in patients who received
older blood (44.1%; RBC age > 14 days) compared with
those who received fresher blood (20.0%, RBC age
January 2015, Vol. 22, No. 1
≤ 14 days) or no transfusion (12.8%; P < .05).
In a retrospective analysis of 8,971 patients who
received transfusions, including both inpatients and
outpatients, Middelburg et al69 found an almost 2-fold
increase in mortality rate for recipients of fresher
RBCs compared with older RBCs (HR, 0.56; 95%
CI: 0.32–0.97 for RBC stored > 24 days compared with
< 10 days). A similar report of the adverse events of
fresher blood was previously published by Mynster
et al.56 They found a higher rate of cancer recurrence
in patients who received RBCs stored for less than
21 days (HR, 1.5; 95% CI: 1.04–2.18).56 These 2 studies
suggest that fresher RBCs may have potentially detrimental effects in some patient populations.
The results from observational studies and small
RCTs, both of which represent the body of literature
on the subject, are mixed, and these studies have
substantial methodological limitations. The strong correlation between the decision to transfuse and the
severity of the underlying illness limits the interpretations from observational studies.
Randomized Controlled Trials
More than 25 years ago, the first prospective RCT of
RBC storage was conducted and involved 237 patients who were randomized to receive 2 units of
either fresh whole blood (< 12 hours) or stored blood
(2–5 days) at the end of the extracorporeal circulation in a primary coronary bypass operation.2
No differences were seen in postoperative bleeding, coagulation tests, or transfusion requirements
between the 2 groups.2 Since then, several small,
prospective RCTs have been conducted; however, these
trials are limited by their low numbers of participants
(Table 5).2,45,49,50,60,70-72
Given the inconclusive findings from retrospective studies and the small number of study participants from the historical RCTs, 2 large, properly
powered, multicenter RCTs have been reported. One
study evaluated 377 infants born premature with
very-low birth weight (< 1250 g) in a neonatal ICU
who required at least 1 RBC transfusion.70 A total of
188 patients received fresh RBCs (median storage,
5.1 days; standard deviation [SD], 2.0), and 189 patients received RBCs stored according to standard of
care (median storage, 14.6 days; SD, 8.3).70 The RR
was 1.00 (95% CI: 0.82–1.21) for the primary outcome
of the study, a composite measure of necrotizing enterocolitis, retinopathy of prematurity, intraventricular
hemorrhage, bronchopulmonary dysplasia, and death.
The rates of clinically suspected infection were 77.7%
and 77.2% for the fresher RBC and standard-care RBC
groups, respectively (RR, 1.01; 95% CI: 0.90–1.12).70
Rates of positive cultures were 67.5% and 64.0% for
Table 5. — Randomized Controlled Trials of RBC Storage Duration
Study
Design
Definition of
Storage Duration
Clinical Setting
No. of Patients
Increased Risk for Adverse Events
With Longer Storage?
Fergusson70
Prospectively
randomized
multicenter
< 7 days vs standard
of care
Premature infants
377
No for mortality
No for rate of complications
Fernandes49
Prospectively
randomized,
single-center
Continuous variable
ICU (sepsis)
15
(10 transfused,
5 received albumin)
No for gastric mucosal pH
Kor45
Randomized
single center
≤ 5 days vs
standard-issue RBCs
(median, 21 days)
ICU
100
No difference in pulmonary function
Steiner72
Prospectively
randomized,
multicenter
≤ 10 vs ≥ 21 days
Cardiac surgery
1,098
No for changes in MODS, adverse
events, or 28-day mortality rate
Yuruk60
Prospectively
randomized,
single center
< 1 week vs 3–4 weeks
Hematology
patients
20
Same increase in perfused vessel
density in both group
Walsh50
Prospectively
randomized,
single center
≤ 5 days vs ≥ 20 days
ICU (on MV)
22
No for gastric mucosal pH
Wasser2
Randomized
single center
< 12 hours vs 2–5 days
Cardiac surgery
237
No for coagulation rests, postoperative
bleeding, or transfusion requirements
Weiskopf71
Randomized
single center
< 2 hours vs 3–4 weeks
Healthy volunteers
35
No in pulmonary gas exchange
variables
ICU = intensive care unit, MODS = multiorgan dysfunction score, MV = mechanical ventilation, RBC = red blood cell.
January 2015, Vol. 22, No. 1
Cancer Control 35
the fresher RBC and standard RBC groups, respectively (RR: 1.06; 95%: 0.91–1.22).70 Hence, this RCT
demonstrated that the use of fresher RBCs compared
with standard care did not decrease or increase the
rate of complications or death in this population of
premature, very-low birth weight neonates.70
A study conducted by Steiner et al72 enrolled
1,613 patients undergoing cardiac surgery, 1,418 of
whom were randomized to receive leukoreduced
RBCs stored for either no more than 10 days (fresher) or 21 days or longer (older). A total of 1,096 patients receiving transfusions within 96 hours following
surgery were evaluable and analyzed for changes in
multiorgan dysfunction score from prior to surgery
to the highest composite change in multiorgan dysfunction score through day 7 (or death or discharge,
if earlier), adverse events, and 28-day mortality. A total
of 538 patients received a median of 4 units of fresh
RBCs (median storage age, 7 days), and 560 patients
received a median of 3 units of older RBCs (median
storage age, 28 days). No difference was seen in the
median composite change in multiorgan dysfunction
score at day 7 (8.48 in the fresh RBC group vs 8.66
in the older RBC group; P = .42).72 A total of 53%
and 51% of the patients in the fresh and old groups,
respectively, developed a serious adverse event.
All-cause mortality rates at day 28 were 4% in patients
who received fresh RBCs and 5% in patients who
received old RBCs.72 The study concluded that RBC
storage duration was not significantly associated with
7-day changes in multiorgan dysfunction score, serious adverse events, or 28-day mortality rates among
patients undergoing cardiac surgery.72
Another recent trial, the Age of Blood Evaluation (ABLE) study, is a multicenter RCT of critically ill
Canadian patients and was funded by the Canadian
Institute of Health Research (MCT-90648). This study
involved 2,420 patients in the ICU randomized to receive
RBCs less than 7 days old or standard-issue RBCs. The
primary end point was 90-day mortality. The preliminary results of this study were presented at a recent
critical care meeting in Toronto, Canada.73 The average
age of the RBCs in the fresh group was 6.1 ± 4.9 days
compared with 22.0 ± 8.5 days in the standard-issue
group. The 90-day mortality rate in the intent-to-treat
patients was not different between the groups (absolute
risk reduction, 1.57% [95% CI: –2.25–5.40]). Thus, the
preliminary results from this study are consistent with
the other large randomized trials showing no difference
in clinical outcomes associated with longer compared
with shorter stored RBCs.
Conclusions
Observational studies of the clinical effects of the
storage duration of red blood cells are conflicting and
have methodological limitations; in addition, they are
36 Cancer Control
confounded by indication. These limitations are best
addressed by randomized controlled trials. A number of published and reported randomized controlled
trials — 1 in adults, 1 in pediatrics, and 1 recently
reported — provide strong evidence that the storage
duration of red blood cells does not have measur­able
adverse effects on the clinical outcomes in select transfused patient populations. Additional randomized
controlled trials are underway in the critically ill and
medical/surgical patient populations. Together, these
random­ized controlled trials will define whether the
storage duration of red blood cells has clinical relevance.
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dysfunction score or mortality in transfused cardiac surgery patients [Abstract].
Transfusion. 2014;54(suppl):15A.
73. Hébert P. Age of BLood Evaluation (ABLE) trial in the resuscitation of critically ill patients. Paper presented at: Critical Care Canada Forum 2014; Toronto,
Ontario, Canada; October 29–November 1, 2014. http://www.criticalcarecanada.
com/presentations/2014/age_of_blood_evaluation_able_trial_in_the_resuscitation_of_critically_ill_patients.pdf. Accessed November 13, 2014.
Cancer Control 37
Indications for RBC transfusions have
been revised because patients can now
be maintained at lower hemoglobin levels.
Ray Paul. Blue Marble, 2007. Acrylic, latex, enamel on wood, 49" × 64". Private
collection.
Transfusion Indications for Patients With Cancer
Thomas Watkins, DO, PhD, Maria Katarzyna Surowiecka, MD, and Jeffrey McCullough, MD
Background: During the last few years, considerable focus has been given to the management of anemia
and coagulopathies. This article provides current concepts of red blood cell (RBC) and plasma coagulation
factor replacements.
Methods: The literature was reviewed for clinical studies relevant to RBC transfusion indications and outcomes
as well as for the uses of coagulation factor replacement products for coagulopathies most likely encountered in
patients with cancer.
Results: Most patients without complications can be treated with a hemoglobin level of 7 g/dL as an indication
for RBC transfusion. However, the effects of disease among patients with cancer may cause fatigue, so transfusions at higher hemoglobin levels may be clinically helpful. Leukoreduced RBCs are recommended as standard therapy for all patients with cancer, most of whom do not develop coagulopathy. Transfusions to correct
mild abnormalities are not indicated in this patient population. Data are inconclusive regarding the value of
coagulation factor replacement for invasive procedures when the international normalized ratio is below 2.
Conclusions: Indications for RBC transfusion have become more conservative as data and experience have
shown that patients can be safely and effectively maintained at lower hemoglobin levels. Coagulation factor
replacement is unnecessary for most modest coagulopathies.
Introduction
Transfusion is an important part of cancer therapy.
Red blood cells (RBCs) may be needed because of
myelosuppression for chemotherapy or anemia in
the setting of chronic disease. Because of myelosuppression, platelets are often part of the continuum
of care for patients with cancer. Typically, plasma is
From the Department of Laboratory Medicine and Pathology,
University of Minnesota Medical School, Minneapolis, Minnesota.
Address correspondence to Jeffrey McCullough, MD, Department
of Laboratory Medicine and Pathology, University of Minnesota
Medical School, Mayo Mail Code 609, 420 Delaware Street South East,
Minneapolis, MN 55455. E-mail: [email protected]
Submitted June 26, 2014; accepted October 31, 2014.
No significant relationships exist between the authors and the
companies/organizations whose products or services may be
referenced in this article.
38 Cancer Control
not needed because coagulopathy is not a major aspect of cancer or its therapy. However, in infrequent
situations in which coagulation factor replacement
is needed, plasma can be vital to the treatment of
patients with cancer. Most infections can be managed
with antimicrobials; however, granulocyte transfusions may sometimes be considered for recalcitrant
infections in patients with neutropenia. The uses and
indications for all of these blood components have
undergone changes over the last few years. This report is a summary of those changes and the current clinical indications and uses of RBCs, plasma,
and granulocytes.
Transfusions
RBC transfusion is common in the treatment of patients
with cancer.1-4 Overall, patients with oncological and
January 2015, Vol. 22, No. 1
hematological malignancies use around 34% of the RBC
supply.1 In patients with cancer, as is similar with any
other patient population, the indication for RBC transfusion is to alleviate symptomatic anemia. The decision
to transfuse should not be driven by the hemoglobin
concentration, and no single criterion can be used as
an indication for RBC transfusion. Thus, the patient’s
clinical status should be of utmost consideration.5
Anemia may occur in 90% of patients during chemotherapy and, furthermore, cancer treatments often
cause the loss, destruction, and decreased production
of RBCs — all of which lead to anemia.6 In particular, lung and gynecological cancers are associated
with anemia because the treatments for such cancers
include platinum-based therapies.7 Anemia in cancer
may decrease quality of life and increase cancer-induced fatigue. Cancer-associated anemia may also
be an indicator of poor clinical outcomes.8 If urgent
correction of anemia is unnecessary, then erythropoietin treatment may be a valid alternative to RBC
transfusion and can decrease RBC transfusion rates.9
In general, RBC transfusions are used to treat
(1) tissue hypoxia due to inadequate RBC mass,
(2) acute anemia due to trauma or surgical blood
loss, (3) anemia in patients receiving chemotherapy,
and (4) cardiovascular decompensation of chronic anemia. They are also used to ensure the optimal tissue
oxygenation in patients with anemia undergoing radiation therapy. RBC transfusion is not indicated for the
correction of anemia due to iron deficiency, as a source
of nutritional supplementation, or in volume expansion.
Dynamic physiological changes in patients with
anemia help allow the decreased RBC mass to continue
to oxygenate tissue. In brief, these changes include increased blood flow (as blood viscosity decreases) and
increased oxygen offloading in hypoxic tissues (as the
concentration of 2,3-diphosphoglycerate increases in
the RBCs). In the setting of anemia, the overall blood
volume is maintained with increased plasma volume.
Compensatory cardiac output changes maintain adequate perfusion. As a result of these dynamic physiological changes, symptoms of anemia rarely manifest
until hemoglobin values significantly dip. Animal studies indicate that extreme hemodilution can be tolerated in healthy animals.10 One study showed that 6 of
7 baboons survived hematocrit levels down to 4% and
that they maintained adequate cardiac compensation at
hematocrit levels as low as 10%.11 In addition, humans
can tolerate very low levels of hemoglobin.12,13
RBC transfusions have been used for decades;
recently, the effectiveness of RBC transfusions has
been evaluated in randomized trials so that the best
evidence can be ascertained to guide transfusion decisions. In some patient populations, nontransfused
patients have better outcomes than transfused patients
and patients who receive fewer units do better than
January 2015, Vol. 22, No. 1
those who receive more RBC units.14-16 The following
clinical trials described below illustrate this concept.
Results from a trial by Hébert et al17 changed the
practice of transfusion. This study was a randomized
controlled trial that compared a “liberal” transfusion
strategy (defined as a post-transfusion goal of a hemoglobin concentration between 10 and 12 g/dL with a
transfusion indication of a hemoglobin concentration
of 10 g/dL) with a “restrictive” transfusion strategy
(defined as a post-transfusion hemoglobin concentration between 7 and 9 g/dL with a transfusion indication of a hemoglobin concentration of 7 g/dL). The
trial included 838 volunteers and demonstrated an
overall in-hospital mortality rate significantly lower in
the participants who received the restrictive transfusion. The 30-day mortality rates were not significantly
different between 2 groups.17 However, clinically “less
ill” volunteers (Acute Physiology and Chronic Health
Evaluation score < 20) or those who were younger
(< 55 years of age) had significantly lower 30-day
mortality rates than those who were “more severely ill”
or older following the restrictive transfusion strategy.17
Thus, the study results demonstrated that a restrictive
transfusion strategy is at least equivalent to a liberal
transfusion strategy in all groups, except among those
with severe ischemic heart disease, and the restrictive
transfusion strategy was potentially better in “less ill”
and younger people.17 This was the first well-structured clinical trial of RBC transfusion suggesting that
maintaining patients at lower hemoglobin levels might
be beneficial.17
Vincent et al18 evaluated the 28-day mortality rate
of 3,534 patients from 146 western European intensive
care units (ICUs). The mortality rates among study
volunteers were 22.7% and 17.1% among those receiving transfusions and those not receiving transfusions,
respectively.18 The study controlled for patients with
a similar degree of organ dysfunction. The receipt of
an RBC transfusion in the ICU increased a patient’s
odds of dying by a factor of 1.37.18
Corwin et al19 analyzed anemia and blood transfusions among 4,892 study volunteers who were critically ill in US ICUs. The study results showed that
the number of RBC transfusions was an independent
predictor of longer ICU stay, longer length of hospital
stay, and increased mortality rates.
In another trial, Carson et al20 compared the
effect of a transfusion threshold of 10 g/dL with
8 g/dL in cardiovascular patients undergoing surgical
hip fracture repair. The trial involved 2,016 patients
older than 50 years of age, and the primary outcome
was death or the inability to walk across a room
without human assistance on 60-day follow-up. Rates
of death or an inability to independently walk after
60 days, in-hospital morbidity rates, and in-hospital
complications were similar in the 2 groups. Thus, the
Cancer Control 39
liberal transfusion strategy did provide clinical benefit
over the restrictive (9 g/dL) strategy.
Evidence does not support a benefit to a
post-transfusion hemoglobin concentration above
10 g/dL.17,21 However, this level may be helpful in
pediatric patients with cancer who have acute blood
loss or cyanotic heart disease due to the additional
challenges of this patient population.22
Despite well-performed clinical trials, no universal
RBC transfusion criterion exists. A restrictive transfusion strategy is at least equivalent to a liberal transfusion strategy in the majority of clinical scenarios.
However, in clinical practice, the underlying condition
of the patient and his or her transfusion goals and
desired outcomes should be considered. RBC transfusion may be indicated in a patient with symptoms of
anemia and a hemoglobin level below 7 g/dL. Transfusion with hemoglobin concentrations between 7 and
10 g/dL may be indicated when significant underlying
comorbidities exist, such as cardiac disease, respiratory disease, bone marrow failure, or other hematological diseases; this is because anemia may not be well
tolerated in these patients.23,24 Traditionally, single unit
transfusions were not recommended; however, as the
hemoglobin indication has decreased and transfusion
has become more conservative, it has become clear
that the transfusion of 1 unit can be effective and
sufficient. Single unit vs 2-unit transfusions can reduce blood use as much as 25% with no adverse clinical consequences.25 Specifically, the AABB (formerly
American Association of Blood Banks) recommends
transfusion at a hemoglobin concentration of 7 to
8 g/dL for hospitalized patients who are stable,
8 g/dL for those with cardiovascular disease, and
higher hemoglobin (unspecified) concentrations for
patients with acute coronary syndromes.26
Reactions or adverse events due to RBC transfusion are uncommon and may occur in 1% to 3%
of transfusions.27 The most common adverse event
is febrile nonhemolytic transfusion reaction, which
typically is due to human leukocyte antigen (HLA)
antibodies in the recipient or an allergic reaction to
plasma proteins. The most severe yet rare reaction is
acute hemolysis, usually due to ABO incompatibility
due to administration error. Because the changes that
occur during RBC storage have become better understood, concern has developed as to whether RBCs
nearing the end of the routine 42-day storage might
have undergone changes, thus making them risky for
certain patients. The focus of research has been on
patients with cardiovascular disease or those undergoing surgery; presently, however, no data suggest
this is a concern for patients with malignancy.28 For
more information, please refer to the article by Drs
Qu and Triulzi in this issue.
RBC transfusion has an immune-modulating ef40 Cancer Control
fect.29 RBC transfusion may be associated with increased risks of postoperative infections, longer durations of hospital stay, and longer stays in the ICU.28,30,31
RBC transfusion has also been linked to longer durations of mechanical ventilation, increased incidences
of multiple organ failures, and an overall increase in
health care costs.28,30-33 However, these issues have not
been resolved. In the previous few years, concerns
have been raised that RBC transfusions might exacerbate cancer; however, no consensus has yet to be
made on this issue. For more information about this
topic, please read the article by Drs Dasararaju and
Marques in this issue.
The rationale for the transfusion of RBCs is to
increase the delivery of oxygen to the tissues, but
physiological changes with RBC storage may limit this
goal. In addition, the ability of transfused RBCs to deliver oxygen to areas most in need of oxygenation may
be decreased.33 The physiological changes that occur
in stored RBCs (collectively called the RBC storage
lesion) may limit, to some degree, the ability of the
transfused RBCs to enter the microcirculation and may
decrease vasodilation by altering the bioavailability of
nitric oxide. During storage, RBCs undergo changes
that result in their removal from the circulation within
24 hours of transfusion. However, some RBCs recover
biochemical normalcy and survive normally.34 Other
changes to stored RBCs include microparticle formation, changes in shape, decreased concentration of
RBC 2,3-diphosphoglycerate, decreased pH, and the
decreased availability of adenosine triphosphate and
glucose. In combination, the physiological changes
resulting from the RBC storage lesion may limit the
delivery of oxygen by the transfused RBCs. However,
no consensus exists on whether RBCs stored for long
periods of time are deleterious to any patient group;
thus, RBCs of any storage age can be used for patients
with cancer. Leukoreduced RBCs have decreased rates
of transfusion reactions, HLA alloimmunization, and
have the potential benefit of modifying the transfusion-related immune modulation (TRIM) effect (if it
exists). Thus, leukoreduced RBCs are recommended
as the standard blood product for routine use in patients with cancer.
Frequent transfusions for cancer and chemotherapy treatments over an extended period of time
may result in iron overload. Treatment regimens for
many solid organ cancers avoid this complication
because the transfusion-dependent period is shorter in duration due to chemotherapy and irradiation
regimens.34,35 As transfusion dependence increases
during treatment, the risk of transfusion-transmitted
infection, allergic response, and severe transfusion
reactions increase with each unit transfused. Health
care professionals must weigh any benefit from RBC
transfusions against these risks.
January 2015, Vol. 22, No. 1
Special Red Blood Cell Products
Patients with cancer may require specially prepared
RBC products due to frequent comorbidities.
Leukoreduced Blood Components
The leukocyte content of different blood products
widely varies (as high as 1 × 109 in whole blood to
< 0.6 × 106 in fresh frozen plasma [FFP]). Leukoreduced
blood products are blood products produced by
filtration or apheresis to decrease the number of
leukocytes remaining in the product to below 5 × 106
leukocytes/component.36 Leukoreduced blood components are beneficial in 3 ways: (1) decreased frequency of febrile nonhemolytic transfusion reactions,
(2) decreased HLA sensitization of recipients, and
(3) decreased likelihood of cytomegalovirus (CMV)
transmission via transfusion.37
Leukoreduction may significantly reduce febrile
nonhemolytic transfusion reactions and may decrease
cardiopulmonary transfusion reactions (transfusion-related acute lung injury and transfusion-associated circulatory overload).38,39 Presumably, this occurs
through reduced levels of bioactive lipids and soluble
CD40L in leukoreduced RBCs, which would have been
produced by leukocytes had they remained in the
blood product.40 As the RBCs age in storage media,
they develop well-established changes that include
decreased deformability and decreased levels of adenosine triphosphate and 2,3 diphosphoglycerate. Donor leukocytes release cytokines and lipid mediators
capable of affecting neutrophils in a time-dependent
course during RBC storage.41 Prestorage leukoreduction decreases the release of metabolites and cellular
components into the RBC product.
Leukoreduction may also be effective in decreasing
alloimmunization and platelet transfusion refractoriness.
This is especially relevant to patients with cancer as
they may receive numerous RBC and platelet transfusions during their treatment cycle. A study published
in 1997 examined 1,047 patients with acute myeloid
leukemia.42 Those who received leukoreduced platelets had decreased levels of lymphocytotoxic antibodies
and lower rates of refractoriness to platelet transfusion
when compared with the study controls who received
unmodified pooled platelet concentrates.42
Leukoreduction may decrease the TRIM effect of
blood transfusion that may lead to possible increased
cancer recurrence. Evidence suggesting that blood
transfusion may decrease immune function was established more than 30 years ago, showing that survival
rates were increased following renal transplantation.29
Other, more controversial data exist regarding RBC
transfusion and tumor recurrence perioperatively.
Vamvakas and Carven31 showed that patients with colorectal cancer who received RBC transfusion perioperatively had longer lengths of hospital stays when
January 2015, Vol. 22, No. 1
adjusted for multiple confounding factors related to
the severity of their illness, difficulty of operation, and
risks for postoperative infections. In addition, Blajchman32 reported adverse effects on tumor recurrence in
50% of nonrandomized trials. Further data suggest that
an immunomodulatory role in transfusion is related
to a dose-dependent association (ie, increased RBC
transfusion) with postoperative bacterial infections
and RBC transfusion.30
Cytomegalovirus Infection and
Safe Blood Components
Transfusion-transmitted CMV is a possible risk for
severe infectious complications in severely immunosuppressed patients with cancer who have not
been previously infected with CMV. Donor screening questionnaires cannot exclude CMV seropositive
volunteers, and CMV has a high seroprevalence; 40%
to 50% of adults have CMV antibodies. Furthermore,
regional blood centers may have difficulty obtaining
CMV negative products locally because the majority
of adults in these areas may be CMV seropositive.
An additional issue with CMV seronegative donors is
that some may still carry CMV in their leukocytes or
plasma. For transfusion recipients who are immunologically competent, CMV infection is not life threatening. However, CMV infection in immunocompromised
patients with cancer can result in potentially fatal
sequelae, including delayed hematopoietic stem cell
engraftment, pneumonia, and severe gastrointestinal
inflammation. However, even in these patients the
risk is low. By using CMV-safe leukocyte blood cells,
one study found that CMV infection was reduced from
2.4% to 1.3% and CMV disease was reduced from
2.4% to 0%.43
CMV is leukotropic and is not present in the RBCs,
platelets, or plasma of healthy donors. Leukoreduction decreases the likelihood of CMV transmission,
and leukoreduced products are generally regarded
as being safe from CMV infection and equivalent to
CMV antibody negative blood.43-46
Irradiated Blood Components
A serious and typically fatal complication of blood
transfusion is transfusion-associated graft-vs-host
disease (TA-GVHD). The transfusion of viable allogeneic T-lymphocytes in blood products to an
immunosuppressed individual has the potential for
TA-GVHD, a complication that can be prevented
by irradiating the blood components. The actual
incidence of TA-GVHD is low in most patients with
cancer, and the irradiation of blood products is indicated in few, small, but well-defined populations of
patients at risk. The types of patients who require
irradiated cellular blood products include neonates, patients with congenital immune deficiencies
Cancer Control 41
(eg, severe combined immunodeficiency syndrome,
Wiskott–Aldrich syndrome), those with a hematological malignancy who are undergoing chemotherapy, and recipients of allogeneic and autologous
bone marrow transplantations, partial HLA-matched
products (often directed donations from genetic relatives), and all granulocyte products. Patients with
HIV/AIDS and patients with solid organ tumors do
not require irradiated RBCs.47
Leukoreduction does not prevent TA-GVHD. Although patients with suppressed immune systems are
at the most risk for TA-GVHD than any other patient
group, rare instances exist in which transfusion between similar HLA-type individuals has resulted in
TA-GVHD in immune-competent individuals. These
include situations in which the donor and recipient
share an HLA haplotype such that the patient does
not recognize the donor cells as foreign and, thus,
does not eliminate them, creating the potential for
TA-GVHD.48,49
Washed Red Blood Cells
The indications for washed RBC products in patients
with cancer are largely in line with the requirements
for washed products in general medical settings.
Overall, the goal for washing RBC products is to
decrease plasma elements, including antibodies, plasma proteins, and electrolytes, that may have adverse
effects on the recipient. Patients with severe immunoglobulin A deficiency have the potential to have
anaphylactic transfusion reactions. Washing RBCs
removes immunoglobulin A from the unit. Rarely,
patients who experience recurrent febrile nonhemolytic and urticarial transfusion reactions may also
benefit from washed RBCs. Additional indications
for washed RBCs may include rapid or large volume
(> 25 mL/kg) transfusions in small volume or in patients with small stature.
Washed products may be indicated for transfused
products following irradiation, because some patients
with cancer and poor renal function may have difficulty with the increased extracellular potassium in
RBCs after the irradiation.
Some patients with cancer may also require volume-reduced RBC products. If a patient with cancer has
a compromised renal or circulatory system that cannot
accommodate the increased volume of the transfused
RBC unit, then volume reduction may be indicated.
Fresh Frozen Plasma
FFP is plasma that has been separated from whole
blood or obtained by plasmapheresis and frozen at
–0.4°F (–18°C) or below within 8 hours of collection. At this temperature, FFP can be stored for up to
12 months after donation. A unit of FFP has a volume
of about 200 to 250 mL and contains all of the coagu42 Cancer Control
lation proteins present in whole blood. FFP does not
contain RBCs and, thus, can be administered without
regard for the Rhesus (Rh) type of the patient. However, because plasma contains antibodies, it should be
ABO matched to avoid possible hemolysis. Additional
plasma preparations used clinically include plasma
frozen within 24 hours of collection (FP24), which
contains reduced levels of labile coagulation factors
V and VIII. FP24 is frequently used by blood blanks
interchangeably with FFP when a clinical need exists
for fibrinogen replacement.
FFP transfusions are typically undertaken in the
setting of bleeding or in preparation for an invasive
procedure when laboratory coagulation screening test
results are abnormal.50,51 These are typically defined as
prothrombin and partial thromboplastin times greater
than 1.5 times the normal limit. The usual dose of FFP is
10 to 15 mL/kg body weight, but the dose may be higher
in the setting of massive blood loss. This dose would be
3 to 4 units of FFP; however, in practice most health care
professionals use 2 units and, thus, patients are often underdosed. A dose should be given at least every 6 hours
until hemostasis is achieved or coagulation parameters
are stabilized.51 The need for additional FFP is based
on the repletion of factor VII, which has the shortest
half-life of all the coagulation factors. If FFP is given
for bleeding, then its effectiveness can be best assessed
by monitoring the clinical response of the patient. If it
is given to correct abnormal coagulation parameters,
then the parameters may be followed as an indication
of hemostasis response.50
If the patient is also receiving platelets, then it is
important to remember that when platelets are stored
in plasma, every plateletpheresis unit contains the
equivalent of 1 bag of FFP. In this situation, either
smaller doses or no additional doses of FFP may be
required. In Europe and the United States, platelets
may be stored in an additive solution of electrolytes
instead of plasma.52 Because the additive solutions
replace plasma, those platelet products cannot be
considered a source of coagulation factors.
National guidelines for the use of FFP exist both
in the United States and abroad.50,51 The clinical indications for the therapeutic use of FFP include active
bleeding before an invasive procedure in the presence
of an inherited or acquired clotting factor deficiency,
active bleeding in the setting of a consumptive coagulopathy or disseminated intravascular coagulation,
massive transfusion, immediate reversal of warfarin
effect in an actively bleeding patient, and thrombotic thrombocytopenic purpura.53 Patients with cancer
may be at risk for abnormalities of hemostasis due to
tumor pathology and evolution of the disease as well
as treatment effect. Coagulation factor abnormalities
may occur as a result of vitamin K deficiency from
malnutrition, diarrhea, liver disease, biliary obstrucJanuary 2015, Vol. 22, No. 1
tion, use of vitamin K antagonists, and antibiotic therapy.54 In the setting of abnormal coagulation screening
test results, invasive procedures such as surgery, line
placement, indwelling catheter placement, among
others, may result in significant blood loss. The use
of FFP along with vitamin K and cryoprecipitate for
additional fibrinogen replacement may be considered
in these situations.
However, the effectiveness of FFP used prophylactically in the nonbleeding patient prior to an invasive procedure or surgery in the setting of abnormal
coagulation values has not been proven.55 A paucity
of good randomized controlled trials have compared
the use of FFP with no FFP. Two well-conducted randomized controlled trials reported a lack of evidence
for the prophylactic use of FFP.55
Several issues exist when considering the use of
FFP. Reversing a coagulopathy with FFP generally
requires a large volume of transfused product. This
could be a significant concern, particularly for patients
who have blood volume status issues prior to transfusion and who are at risk for transfusion-associated
volume overload. In addition, due to the relatively
low concentration of clotting factors in a unit of FFP,
the increase in factor activity after more than 1 L of
transfused FFP may be modest. If immediate correction of coagulopathy is needed, then a product containing factors II, VII, IX, and X and proteins C and S
and more concentrated forms of coagulation factors
should be considered.
The transfusion of plasma carries significant risk
that should be weighed against its perceived benefit,
especially when FFP is prophylactically used. Potential serious complications include transfusion-associated lung injury and volume overload as well as
transfusion-transmitted infection. Allergic reactions
to plasma are common and may, in rare cases, be life
threatening.
Pathogen inactivation is a process by which blood
components are treated in a manner that damages
nucleic acids, thus rendering the components free of
infectious pathogens.56 One of these plasma components, Octaplas (Octapharma USA, Hoboken, New
Jersey), is available for use in the United States. Octaplas is prepared from pools of about 1,000 donor
units and then subjected to solvent detergent treatment for pathogen inactivation and reallocated into
units of about 200 mL, which is similar to a standard
unit of FFP.57 The solvent detergent treatment spares
coagulation factors so that the product is considered
to be similar to FFP.
Granulocyte Transfusion
Infections — particularly fungal infections — continue
to be a source of morbidity and mortality in patients
with neutropenia because of aggressive chemotherapy
January 2015, Vol. 22, No. 1
or hematopoietic stem cell transplantation. With a
granulocyte count below 1,000, the risk of infection is
increased, and this risk is even further increased based
on the duration of neutropenia. During the 1970s, several studies established that granulocyte transfusion
was associated with improved survival rates in patients
with gram-negative sepsis and granulocytopenia for
at least 10 days.58-60 No carefully controlled studies of
granulocyte transfusion exist in other clinical settings.
However, as our ability to manage neutropenia and to
treat gram-positive and gram-negative sepsis has improved with the use of newer antibiotics, the value of
granulocyte transfusions has become questionable.61,62
Granulocyte transfusions in the 1970s up to the present contained about 1 × 1010 granulocytes and were
obtained from donors, most of whom were stimulated
with dexamethasone. The advent of granulocyte colony-stimulating factor (G-CSF) and its resultant use
in patients to increase granulocyte counts and mobilize hematopoietic stem cells led to the possibility of
using G-CSF stimulation of blood donors in order to
obtain larger numbers of granulocytes for transfusion.
When it is combined with dexamethasone, G-CSF can
result in granulocyte counts of up to 40,000/µL with
a yield of up to 8 × 1010 granulocytes.63,64 Small studies of these transfusions have suggested efficacy.65,66
However, no studies adequately establish the clinical
value of granulocyte transfusions. A multicenter trial
managed by the National Marrow Donor Program in
5 US centers studied 40 patients with infection and
neutropenia.67 Survival rates with complete or partial response rates 4 weeks after initiating transfusions were 38% for invasive mold infection, 40% for
bacteremia/candidemia, and 60% for severe bacterial
infection.67 Thus, evidence suggests that granulocyte
transfusion therapy is feasible and may be clinically effective. A recently completed large, multicenter
clinical trial did not show benefit from granulocyte
transfusions except in a small subgroup of patients
who received very high doses of granulocytes.68
These result suggest it is possible that granulocyte
transfusions may be clinically beneficial if very high
doses of cells are given.68 Currently, if granulocyte
transfusions are to be used, then cells obtained from
dexamethasone and G-CSF–stimulated donors are recommended to obtain a substantial number of cells.
These transfusions can provide an increased granulocyte count to more than 5,000/µL in many patients,66
and subsequent transfusions can maintain counts in
this range.67 Indications for considering granulocyte
transfusion include bacterial of fungal infections of
the blood or proven tissue infections of bacteria of
fungi unresponsive to antibiotics. Response to transfusion should not be evaluated on a daily basis, but
granulocyte transfusions should be considered as a
course of therapy similar to antibiotics. Therefore,
Cancer Control 43
transfusions should be continued for a minimum of
5 days or until the infection has been resolved.
Granulocytes should be transfused as soon as
possible after collection because storage time is limited.69-71 Transfusion of a unit of granulocytes should
not take more than 2 hours. Reactions to granulocyte
transfusions are relatively common and generally similar to a febrile nonhemolytic transfusion reaction.
Severe pulmonary reactions have been reported when
granulocytes were infused in close proximity to amphotericin, but whether this represents a major risk
or applies to other antifungals is not clear. It is best
to separate the transfusion of granulocytes from amphotericin infusion by at least 2 hours.
Outpatient Transfusion
With improvements in medical treatments and longer
survival rates among patients with cancer, the management of anemia and thrombocytopenia on an outpatient basis has become an important consideration.
In patients with acute myeloid leukemia or high-risk
myelodysplastic syndromes, the availability of highly
effective antimicrobials and transfusion support has
allowed a shift in care from inpatient to outpatient
settings.72 In these patient populations, outpatient
management of cytopenias has been shown to be
safe and effective in both the postconsolidation and
postinduction therapy periods.73,74
Outpatient treatment has several potential benefits, including reduced cost and resource utilization,
improved quality of life, and decreased incidence of
nosocomial infections.75 Important factors involved
in outpatient management include establishing therapy guidelines, determining the location where the
therapy takes place, and patient education. Communication with the local blood bank is also important,
particularly with regard to special products.
Indications and guidelines for inpatient transfusion are well established. However, it is not clear
whether these should be applied or modified for outpatient transfusion. Thus, because no national guidelines exist for outpatient transfusions, each institution
must determine its own indications.
On one hand, the rational and physiology of the
management of anemia or thrombocytopenia are the
same for inpatients or outpatients, and, thus, possibly the guidelines and indications for transfusion
should be the same. By contrast, patients are living
in a different environment as outpatients. They are
less acutely ill, less fragile, and more stable and thus
should be more resilient. However, they are more
removed from easy and quick access to medical care.
Their care is provided by intermittent outpatient clinic
visits that may involve travel and inconvenience. Thus,
it is appropriate to manage transfusion to provide
the stability and continuity that enables the patient
44 Cancer Control
to function in the outpatient setting. It might also be
appropriate to transfuse larger-than-usual inpatient
doses of the component if doing so extends the time
to the next clinic visit. For example, larger doses of
platelets extend the time to the next transfusion,76,77
and, if the sole reason for a patient to return for a
clinic visit is for a platelet count to determine the need
for the next transfusion, then a larger dose can extend
the time for the next clinic visit. Doing so provides a
better quality of life for the patient and may also be
more cost effective, although no such studies have
been done to determine whether this is true.
Another consideration is the laboratory value as
the indication for the transfusion. For instance, if the
hemoglobin level is slightly above 7 g/dL and the
hospital’s guideline for RBC transfusion is 7 g/dL, then
the transfusion might be considered to be inappropriate in the quality system monitoring. By contrast,
if a return clinic visit is not needed for 1 or 2 weeks,
then it would be inappropriate to have the patient
return sooner simply to repeat the hemoglobin level
to determine when the hemoglobin concentration is
less than 7 g/dL so the transfusion would meet the
hospital guideline. It seems that more appropriate
care would be to transfuse the patient at that visit
despite a hemoglobin concentration above the level recommended by the guideline. Thus, transfusing
2 units of RBCs or transfusing at a hemoglobin concentration of 8 g/dL or even 9 g/dL could be considered appropriate in the outpatient setting.
The topic of indications for outpatient transfusions is not established and deserves considerable
analysis and discussion because of different patient
life situations. We also need to determine ways in
which to offer the most cost-effective methods for
providing care in the outpatient setting.
Conclusions
A hemoglobin level of 7 g/dL is a suitable indication
for red blood cell transfusion in stable patients without complications. However, patients with cardiovascular disease or acute coronary syndrome should be
transfused at a hemoglobin level of 8 g/dL. Indications
for transfusion in patients with other types of complications have not been established. Patients with
cancer have reported an increased feeling of wellbeing
and stamina when maintained at hemoglobin levels
at about 7 g/dL, but no structured studies have determined the optimal hemoglobin levels for patients
with advanced cancer.
Although coagulopathy is uncommon in patients
with cancer, fresh frozen plasma is used as replacement therapy for moderate to severe coagulopathy.
Fresh frozen plasma may also be used for increases in
the international normalized ratio in preparation for
invasive procedures, although no structured studies
January 2015, Vol. 22, No. 1
have established the exact value.
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46 Cancer Control
January 2015, Vol. 22, No. 1
Platelet transfusion has
a well-defined role in treating
patients with cancer.
Ray Paul. Flowers for Phoebe, 2010. Acrylic, latex, enamel on canvas, 48" × 48".
Private collection.
Platelet Transfusion for Patients With Cancer
Craig H. Fletcher, MD, Melkon G. DomBourian, MD, and Peter A. Millward, MD
Background: Platelet transfusion is a critical and often necessary aspect of managing cancer. Low platelet
counts frequently lead to bleeding complications; however, the drugs used to combat malignancy commonly
lead to decreased production and destruction of the very cell whose function is essential to stop bleeding.
The transfusion of allogeneic platelet products helps to promote hemostasis, but alloimmunization may make
it difficult to manage other complications associated with cancer.
Methods: The literature relating to platelet transfusion in patients with cancer was reviewed.
Results: Platelet storage, dosing, transfusion indications, and transfusion response are essential topics
for health care professionals to understand because many patients with cancer will require platelet transfusions during the course of treatment. The workup and differentiation of non–immune-mediated compared
with immune-mediated platelet refractoriness are vital because platelet management is different between types
of refractoriness.
Conclusions: A combination of appropriate utilization of platelet inventory and laboratory testing coupled
with communication between those caring for patients with cancer and those providing blood products is
essential for effective patient care.
Introduction
Platelets are discoid anucleate cells that measure
3 to 5 µm at their greatest diameter. They are derived
from megakaryocytes in the bone marrow and contain ABO antigens on their surface. Platelets are an
essential component of hemostasis because they are
From the Department of Clinical Pathology, Blood Bank and
Transfusion Medicine, Beaumont Health, Royal Oak, Michigan.
Address correspondence to Craig H. Fletcher, MD, Beaumont Health,
3601 West 13 Mile Road, Royal Oak, MI 48073. E-mail: Craig.Fletcher@
Beaumont.edu
Submitted November 7, 2014; accepted November 14, 2014.
No significant relationships exist between the authors and the
companies/organizations whose products or services may be
referenced in this article.
The authors would like to thank the staff and their clinical colleagues
at Beaumont Health for their ongoing support and teamwork.
January 2015, Vol. 22, No. 1
responsible for forming a platelet plug, providing a
framework for the formation of fibrin clots, and secreting cytokines and growth factors.1 Platelets express
A and B red blood cell antigens, class I human leukocyte antigen (HLA), and platelet-specific antigens
(eg, human platelet antigen [HPA]) on their surface.2,3
Platelets are available from 2 sources based on
the method in which they are collected: apheresis
platelets and whole blood–derived platelets. Apheresis platelets are obtained via an apheresis collection device from a single donor. Oftentimes, 2 or
3 apheresis platelet units can be acquired during this
single collection event; each of these units is considered 1 adult dose. Whole blood–derived platelets are
acquired from the platelet concentrate portion of a
whole blood donation. Routinely, 4 to 6 platelet concentrates are pooled together to obtain a typical dose.4
Cancer Control 47
Both apheresis platelet and pooled whole blood–
derived platelet units must contain a minimum of
3 × 1011 platelets per bag. These 2 products have similar clinical effects and can be interchangeably used.2,5
The leukoreduction of platelets provides several
benefits, including the reduction of (1) the platelet
alloimmunization rate, (2) cytomegalovirus transmission due to transfusion, and (3) febrile nonhemolytic
transfusion reactions.2
Storage and Dosing
Platelets are stored in the blood bank at room temperature (68–75°F [20–24°C]) on a platelet rotator
to facilitate the exchange of oxygen. Primarily due
to their risk of bacterial contamination (approximate risk: 1 per 1,000 units), platelets have a shelf
life of 5 days; the day of collection is considered
day 0.6 Volunteers who donate blood are tested for
HIV, hepatitis B and C, and West Nile virus infections,
and blood collection facilities must also screen all
platelet products for bacteria,7,8 either via bacterial
cultures or assessing bacterial growth by oxygen consumption measurement.1
One dose of platelets should increase the platelet count of an average-sized adult by 35,000 to
40,000/µL,9 and this increment can be measured with
a post-transfusion platelet count or complete blood
count. In adult patients, platelets are dosed in units.
Dosing of platelets for pediatric patients may be
done based on body weight (typical pediatric platelet
dose, 5–10 mL/kg).5
Indications for Transfusion
A platelet transfusion may be indicated for either a
quantitative defect (thrombocytopenia) or a qualitative defect (dysfunctional platelets). The normal
range for a platelet count is approximately 150,000
to 450,000/µL; however, the platelet count is but one
aspect in determining a patient’s risk for bleeding.
Many etiologies of thrombocytopenia exist in patients with cancer. The patient’s disease may directly
cause thrombocytopenia via tumor involvement of the
bone marrow, spleen, or both. Although myeloablative chemotherapeutic regimens may cause prolonged
thrombocytopenias, nonmyeloablative chemotherapy produces variable degrees of thrombocytopenia
based on drug selection, drug dosage, and number of
cycles administered. Patients with cancer can develop
microangiopathic conditions that may lead to platelet destruction, including disseminated intravascular
coagulation, thrombotic thrombocytopenic purpura,
hemolytic uremic syndrome, and vasculitis. Immune
thrombocytopenia has been associated with patients
with lymphoproliferative malignancies.10 Commonly
used antibiotics, such as penicillins and cephalosporins, may also cause thrombocytopenia via an im48 Cancer Control
mune-mediated, drug-induced mechanism known as
hapten-dependent antibody formation.11
The AABB (formerly American Association of Blood
Banks) recommends the following prophylactic platelet
transfusion triggers: less than 10,000/µL in adult inpatients with therapy-induced hypoproliferative thrombocytopenia, less than 20,000/µL for central venous
catheter placement, and less than 50,000/µL for either
diagnostic lumbar puncture or major elective non-neuraxial surgery.12 Other common platelet transfusion triggers include less than 10,000/µL for stable, nonbleeding
patients and less than 20,000/µL for febrile patients.
A trigger of 100,000/µL is often used for neurosurgical
patients or those patients experiencing ophthalmological bleeding.2,9 Despite these AABB recommendations,
debate continues about the rationale, efficacy, and
threshold of prophylactic platelet transfusions in patients
with cancer. For example, Stanworth et al13 suggested
that the effectiveness of prophylactic platelet transfusions may vary between specific groups of patients with
cancer. When comparing chemotherapy and allogeneic
hematopoietic stem cell transplantation among patients
receiving prophylactic platelet transfusion versus not
receiving prophylactic dosing, they reported decreased
bleeding events in the prophylactic platelet transfusion
group. However, when comparing patients who received
autologous hematopoietic stem cell transplantation,
the researchers saw no difference in bleeding events
between the prophylactic and nonprophylactic platelet
transfusion groups.13 Moreover, Schiffer14 emphasized
the need for studies to evaluate platelet prophylaxis in
patients with acute leukemia and protracted thrombocytopenia due to induction chemotherapy.
Platelet Dysfunction
Platelets become dysfunctional for many causes,
including medication and herbal supplement use,
renal failure (uremia), and genetic abnormalities
(eg, Glanzmann thrombasthenia, Bernard–Soulier
syndrome). In addition, the membranes used in
cardiopulmonary bypass circuits and extracorporeal
membrane oxygenation circuits can also cause platelet
dysfunction.15
The most common medication to cause platelet
dysfunction is aspirin, which irreversibly inhibits the
enzyme cyclooxygenase I.15 A myriad of other medications inhibit platelet function, including nonspecific nonsteroidal anti-inflammatory drugs, adenosine
diphosphate receptor inhibitors, adenosine reuptake
inhibitors, glycoprotein IIB/IIIA inhibitors, thromboxane inhibitors, and β-lactam antibiotics.15
Response to Platelet Transfusion
Several aspects of the platelet product can affect a
patient’s response to transfusion, including dose of
platelets received, type of product (apheresis or whole
January 2015, Vol. 22, No. 1
blood–derived), ABO compatibility, and storage duration of the product. An analysis of the data collected
by Triulzi et al16 demonstrated that post-transfusion
platelet increments were higher in hematology/oncology patients who received (1) apheresis platelets,
(2) ABO-identical platelets, and (3) fresher platelets
(stored 3 days compared with 4 or 5 days).16 However,
despite the differences in these 3 categories, none of
these factors were predictive of World Health Organization grade 2 or higher bleeding.16
Many patient-specific factors also play a role in
the response to platelet transfusion. In an analysis of
data obtained from the Trial to Reduce Alloimmunization to Platelets (TRAP), Slichter et al17 concluded
that the status of a patient’s spleen had the greatest
impact on the post-transfusion platelet increment.
Splenectomized patients had the highest increments,
whereas patients with a palpable spleen had both
lower platelet increments and a shorter time to their
next platelet transfusion. Other factors that led to a
lower platelet increment included increased weight
and height, administration of amphotericin or heparin,
bleeding, fever, and infection.17
One unit of platelets should increase the platelet
count by 35,000 to 40,000/µL as measured within
1 hour following the transfusion. Two calculations
exist to quantify the patient’s response to platelet
transfusion: the corrected count increment (CCI) and
the percent platelet recovery (PPR). The CCI incorporates the patient’s body surface area to evaluate
response to platelet transfusion. An acceptable CCI
is generally higher than 5,000/µL.18 The mathematical
formula for calculating the CCI is:
By contrast to the CCI calculation, the PPR utilizes the patient’s total blood volume instead of body
(post-transfusion platelet count/µL – pretransfusion platelet count/µL)
× body surface area (m2)
CCI = –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
No. of platelets transfused × 1011
surface area to evaluate a patient’s response to platelet
transfusion. An acceptable PPR is generally higher
than 20%.19 The mathematical formula for calculating
the PPR is:
Platelet Refractoriness
(post-transfusion platelet count/µL – pretransfusion platelet count/µL)
× total blood volume × 100%
PPR = ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
No. of platelets transfused × 1011
Platelet refractoriness can be defined as the failure
to achieve a 1-hour post-transfusion platelet increment of 11,000/µL on 2 consecutive transfusions.17
Because transfusing ABO-incompatible platelets may
also negatively impact the post-transfusion platelet
January 2015, Vol. 22, No. 1
increment, many institutions require this failure to
be with ABO-identical or ABO-compatible platelets.
Platelet refractoriness can be broken down into
2 broad categories: non–immune-mediated and immune-mediated. Non–immune-mediated platelet refractoriness can be due to splenomegaly, sepsis, fever,
medications, and active bleeding. Two-thirds of cases
of platelet refractoriness are estimated to be nonimmune in nature and another one-fifth comprise both
nonimmune and immune causes.20 Immune-mediated
platelet refractoriness is due to alloantibody formation
against the HLA system, the HPA system, or both. Risk
factors for alloimmunization to these systems include
prior transfusion, pregnancy, and transplantation.20
The 1-hour post-transfusion platelet increment
helps to identify patients with platelet refractoriness,
and it is also a key differentiating factor between the
majority of nonimmune and immune causes. Although
patients with nonimmune causes of refractoriness will
typically show some platelet increment within 1 hour
following the transfusion (likely a minimum increment
of < 35,000/µL seen in nonrefractory patients), patients with immune-mediated refractoriness often do
not demonstrate such an increment. One caveat to this
differentiating factor is in patients with splenomegaly;
in these patients, up to 90% of the total body platelet
mass may be sequestered by the spleen.21 Nevertheless, an appropriate platelet transfusion strategy can
still be pursued. For a nonimmune refractory patient,
the underlying disease processes should be treated
and more platelets should be transfused; by contrast,
in an immune refractory patient, more appropriate
platelets should be obtained.
HLA-Matched and Crossmatched Platelets
Transfusing patients who are refractory to platelets
with anti-HLA or anti-HPA antibodies centers on
identifying the antibody specificity and procuring
antigen-negative platelets. If a screening test for
anti-HLA antibodies is positive, then the first step
in providing HLA-matched platelets is to determine
the HLA type of the patient. The specificity of the
anti-HLA antibodies may also be determined at this
stage in the evaluation. The blood bank will then
communicate with the blood supplier to obtain
HLA-matched platelets (matching the HLA class I
antigens, specifically the A and B loci). Some blood
suppliers have databases of the HLA class I antigen
types of apheresis platelet donors to facilitate the
identification of potential donor–patient matches.22
Two strategies exist for the procurement of
HLA-matched platelets. The first method involves
identifying donors who are a high-grade match
(grade A or B) with the HLA type of the patient.
The second method, known as antibody specificity
prediction, utilizes the antibody specificity to obCancer Control 49
tain HLA antigen–negative platelets. These 2 strategies are specific to each blood supplier and, thus,
vary by region. The process to obtain HLA-matched
platelets may take several days or even weeks based
on the HLA type of the patient, the specificity of
antibodies, and donor availability.
The process to obtain HPA-matched platelets is
similar to the process used to obtain HLA-matched
platelets. If a screening test for anti-HPA antibodies
is positive, then both the patient’s HPA type and
the antibody specificity should be determined. The
process to obtain HPA-matched platelets follows the
same approach as obtaining HLA-matched platelets.
An alternative to obtaining either HLA- or
HPA-matched platelets for alloimmunized patients
involves the use of crossmatched platelets. Typically, platelet crossmatching is performed at blood
centers via solid-phase red cell adherence assay
to assess the compatibility between the serum of
the patient and the platelets of the donor (Wendy
Enting, LPN, oral communication, November 2014).
Crossmatch-compatible platelets are presumed to
lack the antigen(s) to which the patient has formed
antibodies. Benefits to platelet crossmatching include rapid turnaround time (hours), simultaneous
screening of multiple platelet units, and the ability to obtain platelets without having to perform
HLA/HPA typing on the patient and donor.23 In a
systematic literature review, Vassallo et al24 found
that while platelet crossmatching did not greatly
improve failure rates (typically 20%–30% using
HLA-matched platelets25) in alloimmunized refractory patients, platelet crossmatching did improve
the availability of platelets for these patients. In an
observational study of 114 patients who received
1,621 platelet transfusions, Petz et al26 concluded
that all 3 methods for the selection of platelets
for alloimmunized patients (HLA-matched, crossmatched, and antibody specificity prediction) were
equally effective as measured by the PPR.
Laboratory Assays
Many different assays may be utilized to identify the
presence and specificity of HLA and HPA antibodies.
The various methodologies include lymphocytotoxicity testing, platelet immunofluorescence testing,
lymphocyte immunofluorescence testing, enzyme-linked immunosorbent assays (ELISAs), antigen-capture ELISAs, monoclonal antibody-specific
immobilization of platelet antigens, and flow cytometric assays.20 Each methodology has a unique set
of benefits and drawbacks. In addition to variations
in sensitivity and specificity rates, other factors that
the health care professional must consider include
assay complexity, turnaround time for obtaining results, the reproducibility of results, and concordance
50 Cancer Control
rates across different platforms.27 The nuances and
selection of these assays are determined by blood
suppliers, reference laboratories, or both.
Mitigating Platelet Transfusions
The prevention of alloimmunization plays an important role in improving patient care and reducing the
number of platelets transfused. Both leukoreduction
and ultraviolet B irradiation were demonstrated in
the TRAP study to be equally effective in preventing antibody-mediated platelet refractoriness during
chemotherapy for acute myeloid leukemia.18 A total of
17% of study volunteers who received leukoreduced
platelets became alloimmunized compared with
45% of those who received nonleukoreduced platelets.18 All platelets for patients with cancer should be
leukoreduced; currently, nearly all platelets collected
today are leukoreduced by blood suppliers.
Many strategies have been proposed to mitigate
the need for platelet transfusions, particularly in
refractory patients.28 Medications such as antifibrinolytics (ε-aminocaproic acid), intravenous immunoglobulin, Rhesus immune globulin, and cyclosporine
A have been used with varied success in small studies,
as have other modalities such as plasma exchange,
immunoadsorption, and massive platelet transfusion.28
Thrombopoietin receptor agonists (eg, eltrombopag,
romiplostim) designed to increase platelet production
have shown some effectiveness for the treatment of
thrombocytopenia in patients with immune thrombocytopenia and chronic hepatitis C.29 Currently,
clinical trials to expand these indications to treat
thrombocytopenia in patients with cancer are ongoing (eltrombopag trials: NCT01656252, NCT02093325,
NCT01147809, NCT01488565; romiplostim trials:
NCT00299182, NCT02052882).
Conclusions
Platelet transfusion has a well-defined role in the
treatment of patients with cancer. By understanding
the requirements of storage, dosing, indications, and
responses to platelet transfusion, health care professionals can provide the most appropriate care for their
patients. Further knowledge of platelet refractoriness
and how to care for refractory patients will enhance
the proper utilization of laboratory testing and the
allocation of scarce resources.
References
1. American Association of Blood Banks (AABB). Circular of Information
For the Use of Human Blood and Blood Components. Bethesda, MD: AABB;
2013. http://www.aabb.org/tm/coi/Documents/coi1113.pdf. Accessed November
16, 2014.
2. Slichter SJ. Evidence-based platelet transfusion guidelines. ASH Education Book. 2007;2007(1):172-178.
3. Yankee RA, Grumet FC, Rogentine GN. The selection of compatible
platelet donors for refractory patients by lymphocyte HL-A typing. N Engl J
Med. 1969;281(22):1208-1212.
4. Dumont LJ, Papari M, Aronson CA, et al. Whole-blood collection and
January 2015, Vol. 22, No. 1
component processing. In: Fung MK, Grossman BJ, Hillyer CD, et al, eds.
Technical Manual. 18th ed. Bethesda, MD: AABB; 2014:156.
5. Millward PA, Brecher ME. Therapeutic use of blood products. In: Bope
ET, Rakel RE, Kellerman R, eds. Conn’s Current Therapy 2010. Philadelphia,
PA: Saunders Elsevier; 2010:486-487.
6. Corash L. Bacterial contamination of platelet components: potential solutions to prevent transfusion-related sepsis. Expert Rev Hematol.
2011;4(5):509-525.
7. US Food and Drug Administration. 21 C.F.R. § 610.40. http://www.
accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=610.40. Accessed November 16, 2014.
8. US Department of Health and Human Services; US Food and Drug Administration (FDA); Center for Biologics Evaluation and Research. Guidance for
Industry and FDA Review Staff: Collection of Platelets by Automated Methods.
Bethesda, MD: FDA. http://www.fda.gov/downloads/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm062946.
pdf. Accessed November 16, 2014.
9. McCullough J. Overview of platelet transfusion. Semin Hematol.
2010;47(3):235-242.
10. Liebman HA. Thrombocytopenia in cancer patients. Thromb Res.
2014;133(suppl 2):S63-S69.
11. Kenney B, Stack G. Drug-induced thrombocytopenia. Arch Pathol Lab
Med. 2009;133(2):309-314.
12. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2014.
[Epub ahead of print].
13. Stanworth SJ, Estcourt LJ, Llewelyn CA, et al. Impact of prophylactic platelet transfusions on bleeding events in patients with hematologic malignancies: a subgroup analysis of a randomized trial. Transfusion.
2014;54(10):2385-2393.
14. Schiffer CA. They took a mulligan and mostly got it right…the issue of
prophylactic platelet transfusion for patients receiving autologous stem cell
transplantation. Transfusion. 2014;54(10):2372-2374.
15. Konkle BA. Acquired disorders of platelet function. Hematology Am
Soc Hematol Educ Program. 2011;2011(1): 391-396.
16. Triulzi DJ, Assmann SF, Strauss RG, et al. The impact of platelet
transfusion characteristics on posttransfusion platelet increments and clinical bleeding in patients with hypoproliferative thrombocytopenia. Blood.
2012;119(23):5553-5562.
17. Slichter SJ, Davis K, Enright H, et al. Factors affecting posttransfusion
platelet increments, platelet refractoriness, and platelet transfusion intervals
in thrombocytopenic patients. Blood. 2005;105(10):4106-4114.
18. The Trial to Reduce Alloimmunization to Platelets Study Group.
Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med.
1997;337(26):1861-1869.
19. Davis KB, Slichter SJ, Corash L. Corrected count increment and percent
platelet recovery as measures of posttransfusion platelet response: problems
and a solution. Transfusion. 1999;39(6):586-592.
20. Hod E, Schwartz J. Platelet transfusion refractoriness. Br J Haematol.
2008;142(3):348-360.
21. Aster RH. Pooling of platelets in the spleen: role in the pathogenesis
of “hypersplenic” thrombocytopenia. J Clin Invest. 1966;45(5):645-657.
22. Bolgiano DC, Larson E, Slichter SJ. A model to determine required
pool size for HLA-typed community donor apheresis programs. Transfusion.
1989;29(4):306-310.
23. Salama OS, Aladl DA, El Ghannam DM, et al. Evaluation of platelet
cross-matching in the management of patients refractory to platelet transfusions. Blood Transfus. 2014;12(2):187-194.
24. Vassallo RR, Fung M, Rebulla P, et al; International Collaboration for
Guideline Development, Implementation and Evaluation for Transfusion Therapies. Utility of cross-matched platelet transfusions in patient with hypoproliferative thrombocytopenia: a systematic review. Transfusion. 2014;54(4):1180-1191.
25. Slichter SJ. Platelet crossmatch testing for donor selection. Prog Clin
Biol Res. 1982;88:153-164.
26. Petz LD, Garratty G, Calhoun L, et al. Selecting donors of platelets
for refractory patients on the basis of HLA antibody specificity. Transfusion.
2000;40(12):1446-1456.
27.Fontão-Wendel R, Silva LC, Saviolo CBR, et al. Incidence of transfusion-induced platelet-reactive antibodies evaluated by specific assays for the
detection of human leucocyte antigen and human platelet antigen antibodies.
Vox Sanguinis. 2007;93(3):241-249.
28. Delaflor-Weiss E, Mintz PD. The evaluation and management of platelet
refractoriness and alloimmunization. Transfus Med Rev. 2000;14(2):180-196.
29. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores
trilineage hematopoiesis in refractory severe aplastic anemia that can be
sustained on discontinuation of drug. Blood. 2014;123(12):1818-1825.
January 2015, Vol. 22, No. 1
Cancer Control 51
Knowledge of transfusion
complications related to HSCT
can help with the early detection
and treatment of patients before
and after transplantation.
Ray Paul. SP12-6796 × 40, 2013. Acrylic, latex, enamel on canvas printed with
an image of myxofibrosarcoma with metastases to the artist’s lung, 26" × 36".
Transfusion Support Issues
in Hematopoietic Stem Cell Transplantation
Claudia S. Cohn, MD, PhD
Background: Patients receiving hematopoietic stem cell transplantation require extensive transfusion
support until red blood cell and platelet engraftment occurs. Rare but predictable complications may arise
when the transplanted stem cells are incompatible with the native ABO type of the patient. Immediate and
delayed hemolysis is often seen.
Methods: A literature review was performed and the results from peer-reviewed papers that contained
reproducible findings were integrated.
Results: A strong body of clinical evidence has developed around the common complications experienced
with ABO-incompatible hematopoietic stem cell transplantation. These complications are discussed and the
underlying pathophysiology is explained. General treatment options and guidelines are enumerated.
Conclusions: ABO-incompatible hematopoietic stem cell transplantations are frequently performed.
Immune-related hemolysis is a commonly encountered complication; therefore, health care professionals
must recognize the signs of immune-mediated hemolysis and understand the various etiologies that may
drive the process.
Introduction
Hematopoietic stem cell transplantation (HSCT) is used
to treat a variety of hematological and congenital diseases. The duration and specificity of transfusion support
for patients receiving HSCT depends on the disease, the
source of the stem cells, the preparative regimen applied
prior to transplantation, and patient factors during the
post-transplantation recovery period. Human leukocyte
From the Department of Laboratory Medicine and Pathology,
University of Minnesota, Minneapolis, Minnesota.
Submitted March 27, 2014; accepted July 23, 2014.
Address correspondence to Claudia S. Cohn, MD, PhD, D242
Mayo Memorial Building, MMC 609, 420 Delaware Street,
South East, Minneapolis, MN 55455. E-mail: [email protected]
Dr Cohn has received grants or research support funds and
honorarium from Fenwal and Fresenius Kabi.
52 Cancer Control
antigen (HLA) matching remains an important predictor of success with HSCT; however, the ABO barrier is
often crossed when searching for the most appropriate
HLA match between donor and patient. Crossing the
ABO barrier has little or no effect on overall outcomes;
however, complications can arise due to antigenic incompatibility between the transplanted cells and the
patient.1 This review will discuss the transfusion support
of patients receiving HSCT, common transfusion-related
complications that health care professionals will likely
encounter, and the measures required to safely deliver
blood components.
HSCTs can be broadly divided into related allogeneic, unrelated allogeneic, and autologous transplantation. Hematopoietic progenitor cells (HPCs)
for allogeneic transplantation come from 3 sources:
apheresis-derived, mobilized peripheral blood proJanuary 2015, Vol. 22, No. 1
genitor cells (HPC-A), bone marrow (HPC-M), and
umbilical cord (HPC-C). HPC-A is commonly used for
autologous transplantation. Pediatric patients receive
more HPC-M, whereas adults receive more HPC-A. Use
of HPC-C is on the rise in both populations.2
Patients undergoing HSCT remain dependent on
red blood cell (RBC) and platelet transfusions until
engraftment of these cell lines occurs. The platelet line
is considered engrafted when a patient’s count is at
least 20,000/µL after 3 consecutive days without platelet transfusion.3 RBC engraftment is more difficult to
assess and may be defined by the appearance of 1%
reticulocytes in the peripheral blood,4 or, on the day of
the last RBC transfusion, with no transfusion given the
following 30 days.5 Typically, neutrophil engraftment
is defined as an absolute neutrophil count of more
than 500/µL across 3 consecutive days.3 Engraftment
is influenced by many factors, including the relationship of the donor to the patient, the stem cell source,
and the dose of CD34+ cells in the transplantation.3 In
general, engraftment time is shortest with HPC-A and
greatest when HPC-C is used6; however, considerable
patient-to-patient variability exists. One study that
compared HPC-C and HPC-A noted roughly equivalent
neutrophil recovery times but found a longer time
to platelet and RBC engraftment for HPC-C.5 These
prolonged engraftment times translated into higher
transfusion rates for RBCs and platelets.
Pretransplantation Support
Prior to HSCT, patients may be immunocompetent or
immunocompromised depending on their underlying
disease. A patient who is immunocompetent (eg, aplastic
anemia, hemoglobinopathies) is capable of mounting
an immune response to transfusions, leading to alloimmunization against platelet antigens, HLAs present on
the surface of leukocytes and platelets, or both. Antibodies against HLA contribute to delayed engraftment
and graft rejection in some patient populations.7,8 As a
result, pretransplantation transfusions in patients who
are immunocompetent should be avoided because they
are associated with increased graft failure rates.9,10 For
patients who are stable, RBC transfusions can be minimized by using a hemoglobin trigger of 7 to 8 g/dL.
Multiple studies have shown that using this hemoglobin
threshold is at least as effective and results in similar
outcomes as higher triggers unless a patient is symptomatically anemic.11,12
Platelet transfusions may also be minimized by
adhering to evidence-based guidelines. Using a platelet count of 10,000/µL as a threshold for administering platelets to a nonbleeding patient has been well
established.13
When transfusion is required, using leukoreduced
components reduces the risk of alloimmunization.14
Patients who are immunocompromised, either beJanuary 2015, Vol. 22, No. 1
cause of their disease or due to chemotherapy,
are less likely to become sensitized to foreign antigens. Nonetheless, using leukoreduced products to
minimize the risk of alloimmunization is recommended. Extra care must also be taken if the stem cell
donation comes from a blood relative. In this situation, family members should not give direct blood
donations because doing so may lead to alloimmunization against major and/or minor HLAs present in
the transplant.15
Post-Transplantation Support
Chemotherapy regimens may be fully myeloablative or
use reduced intensity conditioning to partially ablate
the patient’s marrow. Either regimen will cause the
patient to be dependent on RBC and platelet transfusions until engraftment of those cell lines occurs.
Although granulocyte progenitor cells are also destroyed, granulocyte-colony stimulating factor may be
given because granulocyte transfusions are reserved
for specific scenarios. The need for plasma and cryoprecipitate transfusions is less frequent because HSCT
does not typically interfere with the production of
coagulation factors. Refer to the article by McCullough
and colleagues in this issue for more detailed information on this topic.
Although the frequency and extent of RBC
and platelet transfusions are increased during the
post-transplantation period, the indications for these
transfusions do not change. Because no large prospective study specifically targets RBC transfusion
triggers in patients undergoing HSCT, the more general guidelines from the AABB (formerly American
Association of Blood Banks) may be used, which recommend adhering to a restrictive transfusion strategy
(7.0–8.0 g/dL) in a stable patient who is hospitalized
unless the patient is symptomatically anemic.16 Special care must be taken to transfuse irradiated RBC
units alone, because the risk for transfusion-associated
graft-vs-host-disease (TA-GVHD) is high in patients
receiving HSCT.17 Because transplants often cross the
ABO barrier, ABO compatibility may be complex in
patients receiving HSCT. When the transplant creates
an incompatibility issue (eg, group B transplantation
into a group A patient), transfusing group O RBCs
and AB plasma will be necessary (Table). The decision to switch a patient’s blood type is highly variable
across institutions. At my institution, if a patient is
independent of RBC transfusion for 100 days and
no incompatible isohemagglutinins against the new
RBC phenotype can be detected in 2 consecutive
blood samples, then the patient’s native blood type
is switched to the donor type for future transfusions.
Patients receiving HSCT undergo a period of hypoproliferative thrombocytopenia that ends when the
platelet line engrafts. To support patients through this
Cancer Control 53
Table. — Component Type Selection for Hematopoietic
Stem Cell Transplantation Crossing the ABO Barrier
Type of
Mismatch
Major
Minor
Bidirectional
Transplantation
Donor
Type
Transfusion
Recipient
Type
Red Blood
Cell
Plateletsa
/Plasma
A
O
O
A
AB
B
O
O
B
AB
AB
O
O
AB
AB
A
A
O
AB
AB
B
B
O
AB
O
A
O
A
AB
O
B
O
B
AB
O
AB
O
AB
A
AB
A
O
AB
B
AB
B
O
AB
A
B
O
AB
B
A
O
AB
Platelets stored in additive solution reduce the volume of incompatible
plasma transfused.
a
aplasia, the general triggers for platelet transfusions
apply. Because the patient is a chimera of donor and
native blood types, ABO-incompatibility issues may
arise. Because ABO antigens are present on the surface of platelets, one must consider the ABO type
of the platelets and the anti-A and anti-B antibodies
present in the donor plasma in which the platelets are
stored. Choosing platelet units based on plasma compatible with both the donor and patient is necessary
(see Table).18 However, if a group O patient is making
high-titer ABO antibodies (> 512–1024), then attention
must be paid to the ABO type of the platelet unit
and care must be taken to avoid group A1 platelets.
Using platelet additive solution (PAS), which removes
65% of donor plasma, is an option available when
the isohemagglutinin titer is a concern.19 Washing the
platelet unit will also reduce or eliminate problems
with lysis. However, the procedure is labor intensive
and may damage the platelets. Washing can also be
logistically challenging because washed platelet units
become outdated after 4 hours. Refer to the article in
this issue by Fletcher and colleagues for more details
on this topic.
Recent studies have addressed questions of platelet dose and the comparative merits of therapeutic
54 Cancer Control
compared with prophylactic platelet transfusions. One
such study evaluated the effect of platelet dose on
bleeding in patients with hypoproliferative thrombocytopenia.20 In this study, patients were randomly assigned to receive either low-dose (1.1 × 1011
platelets), medium-dose (2.2 × 1011), or high-dose
(4.4 × 1011) prophylactic platelet transfusions when
their first morning counts were 10,000/µL or lower.
Overall, no significant difference was seen in World
Health Organization grade 2 or higher bleeding events
in the 3 groups.20 The low-dose group received significantly fewer platelets; however, this group also
received transfusions more often. The authors concluded that using these different doses for prophylactic transfusion had no effect on the incidence of
bleeding.20 However, a subgroup analysis of the study
data showed that pediatric patients (range, 0–18 years
of age) had a significantly higher risk of grade 2 or
higher bleeding than adults across all platelet dose
groups.21 This finding was most pronounced in the
pediatric autologous transplant population.21
Two studies examined the efficacy and safety of
prophylactic compared with therapeutic platelet transfusions.22,23 The Trial of Prophylactic Platelet Study
(TOPPS) randomly assigned patients undergoing chemotherapy or stem cell transplantation into either
a therapeutic or prophylactic arm.22 Patients in the
prophylactic arm received a platelet transfusion in
response to a first morning platelet count of less than
10,000/µL, whereas the therapeutic group received
platelet transfusion when clinically indicated. Results
showed that the therapeutic arm used significantly
fewer platelets when compared with the prophylactic
group; however, patients in the therapeutic arm had
higher bleeding rates, more days with bleeding, and
a shorter time to the initial bleeding episode than patients in the prophylactic cohort.22 It should be noted
that 70% of the patients in this study were recipients
of autologous stem cell transplants, which represents
a group of people who have a lower risk of bleeding than those receiving allogeneic transplantation.20
When recipients of autologous transplantation were
compared, the rate of bleeding was similar for both
therapeutic and prophylactic groups.22
The second large prospective trial conducted by
Wandt et al23 was performed under similar conditions as TOPPS. The researchers studied recipients
of autologous stem cell transplantation and patients
with acute myeloid leukemia undergoing chemotherapy. In this trial, higher rates of bleeding were seen
in all patient groups receiving therapeutic platelet
transfusions. In addition, the therapeutic group had
6 patients with head bleeds (2 of the 6 were fatal),
whereas the prophylactic group had none.23 As with
the TOPPS trial, a significant reduction in platelet
transfusions was seen in the therapeutic arm. Of note,
January 2015, Vol. 22, No. 1
the similar data in the 2 studies led to different conclusions. The TOPPS group concluded that the benefit
of reduced bleeding made prophylactic transfusions
a preferred practice for all patients,22 whereas Wandt
et al23 made a distinction, stating that patients with
acute myeloid leukemia undergoing chemotherapy
should still receive prophylactic platelet transfusions
but that the therapeutic strategy should become the
new standard of care for patients receiving autologous
stem cell transplantation.
Complications
Transfusion-related complications exist that are specific to, or more frequently seen in, the patient population receiving HSCT. Some of these complications
arise when lymphocytes within the transplant are
activated against the recipient, leading to TA-GVHD
and passenger lymphocyte syndrome (PLS). Another
complication, pure red cell aplasia (PRCA), occurs
when a patient’s residual antibodies attack the transplant. Standard transfusion reactions, such as allergic
or febrile nonhemolytic reactions, are frequently seen
in this heavily transfused patient population. Refer to
the article by Marques and colleagues in this issue
for a more detailed discussion of standard transfusion
reactions.
Transfusion-Associated Graft-vs-Host Disease
Graft-vs-host disease is seen in patients who are
severely immunocompromised and have been exposed
to immunocompetent lymphocytes that recognize the
body as foreign due to differences in HLAs. TA-GVHD
occurs when a susceptible patient is exposed to viable
lymphocytes introduced via blood transfusion. The
immunocompromised recipient is incapable of rejecting or mounting an attack against the lymphocytes
in the graft. Although the basic underlying etiology
is similar, TA-GVHD has a different presentation and
natural history when compared with conventional
graft-vs-host disease. Typically, TA-GVHD presents
with a maculopapular rash, enterocolitis, and pancytopenia that begin 8 to 10 days following transfusion.17
As the attacking lymphocytes target the stem cells
engrafting within the bone marrow, irreversible and
complete bone marrow aplasia will result. TA-GVHD
develops within 21 days of transfusion and is almost
always fatal.24,25
Cellular blood components isolated from whole
blood or collected by apheresis all contain some lymphocytes. RBC, platelet, and granulocyte units all carry
risk for TA-GVHD; however, plasma and cryoprecipitate are acellular and do not pose a risk. To prevent
TA-GVHD, lymphocytes within a blood component
must be eliminated or disabled. Leukoreduction is
not considered sufficient because the process reduces but does not completely eliminate white blood
January 2015, Vol. 22, No. 1
cells.26,27 Frozen units may also carry risk because the
lymphocytes may survive. Treating components with
γ- or X-irradiation, or pathogen inactivation with UV
irradiation, has been shown to be effective prophylaxis for TA-GVHD.28 A dose of at least 2500 cGy
into the center of a cellular blood component and
1500 cGy throughout the unit leaves lymphocytes
intact but unable to proliferate.29 This simple precaution prevents TA-GVHD.
Irradiation at the indicated dose appears to damage the RBC membrane.30 The damage does not affect
the oxygen-carrying capacity of the erythrocyte but
does allow potassium to leak from the cell.31 The level
of extracellular potassium has been shown to increase
with storage time. As a result, RBCs may be stored
for 28 days following irradiation.29 Because platelets
are not affected by irradiation, their storage time of
5 days remains unchanged.32
All patients undergoing HSCT should receive irradiated components from the time of initiation of conditioning chemotherapy. The AABB suggests that HSCT
recipients receive irradiated components for at least
1 year following transplantation,33 although many centers continue to provide irradiated products for the life
of the patient.34 The British Committee for Standards in
Haematology (BCSH) also recommends that irradiation
begin with the initiation of conditioning chemotherapy;
however, separate recommendations exist for patients
receiving allogeneic compared with autologous HSCT.34
The BCSH recommends that patients receiving allogeneic HSCT should continue to receive irradiated components for 6 months following transplantation or until
the lymphocyte count is greater than 1 × 109/L; however,
if chronic graft vs host disease is present, then irradiated products should be indefinitely given.34 The BCSH
states that patients receiving autologous HSCT should
also receive irradiated components beginning from the
time of initiation of conditioning chemotherapy, but this
can revert to nonirradiated components 3 months after
transplantation.34 If patients receiving autologous HSCT
also received total body irradiation, then the BCSH recommends extending the use of irradiated products for
6 months following transplantation.34
Issues of ABO Compatibility
Crossing the ABO barrier is not considered a contraindication with HSCT. A meta-analysis found no
impact on overall survival rates when comparing ABO
matched and mismatched HSCTs.35 Nonetheless, some
complications may arise because of issues related to
ABO incompatibility. The nature of the complication is
often related to whether the incompatibility represents
a major or minor mismatch (see Table), with a major mismatch occurring when the transplant contains
RBCs incompatible with the plasma of the recipient.
Conversely, a minor mismatch is present when plasma
Cancer Control 55
from the donor contains isohemagglutinins against the
RBCs of the recipient. Bidirectional transplantation
(eg, group A transplant into group B recipient) carries
both major and minor mismatches.
Major ABO Mismatches
Immediate and Delayed Hemolysis: When a major
ABO mismatched transplantation is provided, immediate hemolysis may occur during the infusion. This
complication is commonly seen when the HSCT is
derived from bone marrow because more RBCs are
present36; however, RBC depletion techniques have
helped eliminate this complication.37 Because HSCTs
derived from peripheral blood typically contain a
minimal volume of RBCs (8–15 mL), clinically significant cases of immediate hemolysis have not been
identified.36 Most HPC-C units are RBC-depleted prior to cryopreservation, and the residual erythrocytes
lyse during cryopreservation; therefore, immediate
hemolysis does not occur with the transplantation
of cord blood.
Preformed antibodies against non-ABO RBC antigens may remain in a recipient’s peripheral circulation
for many weeks following transplantation. These antibodies may cause lysis when engrafted cells begin to
produce new RBCs.38,39 In addition, chimeric patients
may develop antibodies against ABO or non-ABO
RBC antigens, thus resulting in delayed hemolysis.40
Pure Red Cell Aplasia: When recipients have
isohemagglutinins specific for the ABO type of the
transplant, delayed erythrocyte engraftment and PRCA
may ensue. PRCA is seen frequently with group O
patients receiving a group A transplantation or with
bidirectional mismatches.41 The condition develops
when antibodies against newly engrafted RBCs destroy erythrocyte progenitor cells in the bone marrow. This intramedullary destruction leads to severe
anemia with no corresponding involvement of leukocyte or platelet cell lines. The incidence of PRCA is
increased when reduced intensity conditioning regimens are used,42,43 likely due to residual recipient B
lymphocytes, plasma cells, or both, thus producing
isohemagglutinins. An increase in post-transplantation
isohemagglutinin titers is also an important predisposing factor for PRCA.44-47
PRCA may spontaneously resolve,44,48 but treatment to reduce its duration is warranted to diminish
the risk of iron overload from multiple RBC transfusions.49 Therapy for PRCA includes bolstering the
graft-vs-host effect either through withdrawal of immunosuppression44 or with a donor infusion of leukocytes.42,50,51 Other treatments include erythropoietin,52
rituximab,53,54 bortezomib, or all 3 options in combination.43,55 Because PRCA is associated with high
levels of isohemagglutinins,44-47 a direct reduction of
titers by plasma exchange may be effective in some
56 Cancer Control
patients.47,56 Although the reduction of titers before
the transplantation has been attempted to prevent
PRCA,57,58 knowing the actual effect of this approach
is impossible. Some European centers use apheresis
as standard care for reducing pretransplantation isohemagglutinin titers to fewer than 1:32.59
Minor Mismatches
Passenger Lymphocyte Syndrome: If lymphocytes
within the HSCT recognize the recipient RBCs as foreign, then antibodies may be produced that are specific for ABO or minor RBC antigens. PLS is seen most
frequently in transplants that use a group O donor
with a group A recipient,60 and it typically presents 7
to 14 days following transplantation with an abrupt
onset of hemolysis. When the passenger lymphocytes
produce antibodies against the ABO system, the hemoglobin level may precipitously drop. The laboratory
signs of intravascular hemolysis (ie, hemoglobinemia,
hemoglobinuria, elevated level of lactate dehydrogenase) should be used to follow the course of disease.
In most cases, results on a direct antiglobulin test
will be positive unless all antibody-bound cells have
already lysed. Hemolysis can persist as long as incompatible RBCs are present, but it typically subsides
within 5 to 10 days.61 Antibodies against minor RBC
antigens have been less frequently reported. In these
cases, hemolysis ranges from mild to severe and may
be intravascular or extravascular depending on the
nature of the antibody involved.
The risk factors for PLS are similar to those seen
in PRCA. A non-myeloablative-conditioning regimen
carries greater risk than when full ablation is used.62
Because HPC-A preparations carry a greater lymphocyte load when compared with HPC-M and HPC-C
collections, recipients of peripheral blood stem cells
are at an increased risk for developing PLS.62-65 I am
not aware of a PLS case reported with umbilical cord
stem cell transplantation. Maintaining graft-vs-host
disease prophylaxis with a T-cell inhibitor alone, such
as cyclosporine A, without an accompanying B-cell
inhibitor is also considered a risk factor.66,67
Alloimmunization Against Minor Red Blood
Cell Antigens: The antibodies that cause PLS are temporary because they are derived from passenger lymphocytes that are not engrafted. When alloantibodies
against RBCs are produced by the post-transplantation
immune system, the antibodies may persist for several
years,68 and they may be produced by the engrafted
cells of the immune system of the donor69-71 or by
the residual cells of the immune system of the recipient.68,72,73 The antibodies produced may be against donor RBCs, residual recipient RBCs, or, in some cases,
both. The incidence of alloantibody formation against
minor RBC antigens ranges from 2.1% to 3.7% in the
published literature.74,75 These antibodies have not
January 2015, Vol. 22, No. 1
been linked with significant complications.70,72
Prevention of Transfusion-Transmitted
Cytomegalovirus Infection: Cytomegalovirus
(CMV) infection continues to be a serious complication following HSCT.76-78 Most CMV infections may
be due to a reactivation of the virus from a previous
infection rather than due to the acquisition of a new
strain.79 However, CMV antibody-negative persons are
at risk for developing a transfusion-transmitted de
novo CMV infection. To reduce this risk, one may
use CMV-antibody negative blood or leukoreduced
components. A large controlled trial and meta-analysis
showed that leukoreduced components are as effective
as antibody-negative components in the prevention
of transfusion-transmitted CMV infection.80,81 However, a survey of AABB physician members showed
wide variability in transfusion practice.82 Since then,
2 additional studies have been published with results
that support the safety of using leukoreduced blood
alone for the prevention of transfusion-transmitted
CMV infection.83,84 These studies focused on transfusion and transmission in patients receiving allogeneic
HSCT. A total of 123 patients who were CMV negative and who had received nearly 8,000 leukoreduced
but unscreened blood products were analyzed. Both
studies found no risk for transfusion-transmitted CMV
infection. Anti-CMV immunoglobulin G was detected
in some patients in both of the studies,83,84 but this
effect was likely due to the passive transfer of antibodies during transfusions.84 Nonetheless, the overall
risk of transfusion-transmitted CMV infection in leukoreduced components is not zero. A study of blood
donors in Germany found CMV DNA in 44% of newly
seropositive donors and the overall prevalence of CMV
DNA was 0.13% in nearly 32,000 donations.85 The
small risk of CMV-seronegative blood donors presenting in the window period of a new CMV infection has
led to the suggestion that blood products for vulnerable patient groups be obtained from donors with a
longstanding history of CMV-positive serology.86 An
alternative suggestion may be to screen donated blood
for CMV DNA or immunoglobulin M antibodies.86
Conclusions
Transfusion support for patients receiving stem cell
transplantation depends on many factors. The source
of the transplant, the conditioning regimen, and the
clinical status of the patient all must enter into the
decision-making process regarding the safest component. Despite advances in knowledge, technology,
and screening methodologies, complications may still
occur and can lead to prolonged transfusion dependence. Knowledge of these complications can help
with early detection and treatment, thus reducing the
number of transfusions necessary in these patients.
January 2015, Vol. 22, No. 1
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January 2015, Vol. 22, No. 1
Cancer Control 59
Therapeutic apheresis is an important
treatment modality frequently used to
manage specific complications in patients
with underlying malignant disease.
Ray Paul. Dark Shadows, 2010. Acrylic, latex, enamel on canvas, 30" × 30".
Therapeutic Apheresis for Patients With Cancer
Laura S. Connelly-Smith, MBBCh, DM, and Michael L. Linenberger, MD
Background: Disease complications associated with certain malignancies may be mediated by cells or
soluble molecules that traffic in the bloodstream. Because of this, therapeutic apheresis (TA) methodologies have
been used to selectively remove or manipulate specific molecules, antibodies, or cellular elements to treat the
underlying pathological process. For some disorders, TA is utilized as a rapid-acting and short-term adjunct
to conventional chemotherapy or immunotherapy. For others, a series of scheduled treatments is recommended
for optimal management. In all cases, the risks, benefits, and costs must be strongly considered.
Methods: The current literature and published guidelines were reviewed to summarize the use of TA in the
management of certain complications of cancer.
Results: Although TA is relatively safe and useful as a first-line or salvage modality for some disorders, few
prospective, randomized clinical trials exist and the majority of evidence is derived from observational studies.
Expert-based, clinical practice guidelines have been developed to inform hematology/oncology professionals
and apheresis physicians about the efficacy and limitations of TA for malignancy-related indications.
Conclusions: Certain oncological conditions respond to TA and consensus guidelines are available to support
clinical decision-making. However, well-designed, prospective intervention trials are needed to better define
the role of TA for a variety of disorders.
Introduction
Therapeutic apheresis (TA) is used to treat certain
disease complications in patients with cancer with
the intention of removing or manipulating a specific
molecule, antibody, or cellular element thought to be
contributing to the underlying pathological process.
From the Seattle Cancer Care Alliance (LSC-S, MLL), the Division of
Hematology (LSC-S, MLL) of the School of Medicine at the University
of Washington, and the Fred Hutchinson Cancer Research Center
(MLL), Seattle, Washington.
Address correspondence to Laura S. Connelly-Smith, MBBCh, DM,
Seattle Cancer Care Alliance, 825 East Eastlake Avenue, Seattle, WA,
98109. E-mail: [email protected]
Submitted June 15, 2014; accepted October 8, 2014.
No significant relationships exist between the authors and the
companies/organizations whose products or services may be
referenced in this article.
60 Cancer Control
In general, TA is a relatively safe procedure; however,
insufficient clinical evidence to support the economic cost of TA can be a limitation to its use for some
conditions. Evidence-based clinical practice guidelines
have been developed and periodically updated by the
American Society for Apheresis (ASFA) to help support the decision making of health care professionals
regarding the use of TA.1
In this article, we provide a brief overview of TA
and discuss considerations for its use as a treatment
option. The apheresis modalities most commonly
used to treat patients with cancer include the therapeutic plasma exchange (TPE), leukocytapheresis,
extracorporeal photopheresis (ECP), thrombocytapheresis, and erythrocytapheresis. Herein, we review
the known oncological diseases or associations for
which specific TA modalities have been successfully
January 2015, Vol. 22, No. 1
Table 1. — Indications for Therapeutic Apheresis in Patients With Cancer
Therapeutic
Apheresis Modality
Therapeutic plasma
exchange (TPE)
Indication
Hyperviscosity in
monoclonal gammopathies
Disease Condition
Categorya
Gradeb
Symptomatic
I
1B
Prophylaxis for rituximab
I
1C
Myeloma kidney/myeloma cast nephropathy
II
2B
Paraneoplastic neurological syndromes
(see also Table 4)
Lambert Eaton myasthenic syndrome
II
2C
Other paraneoplastic
neurological syndromes
III
2C
Hematopoietic stem cell transplantation–
associated thrombotic microangiopathy
Refractory
III
2C
Therapeutic
leukocytapheresis
Hyperleukocytosis
With leukostasis clinical signs
and symptoms
I
1B
Prophylaxis (asymptomatic)
III
2C
Extracorporeal
photopheresis
Cutaneous T-cell lymphoma,
mycosis fungoides, Sézary syndrome
Erythrodermic
I
1B
Nonerythrodermic
III
2C
GVHD
Skin chronic GVHD
II
1B
Skin acute GVHD
II
1C
Non–skin acute and chronic GVHD
III
2B
Symptomatic
II
2C
Prophylactic
III
2C
I
1B
Thrombocytapheresis
Thrombocytosis with
myeloproliferative neoplasm
Erythrocytapheresis
Polycythemia vera/primary erythrocytosis
Denotes American Society for Apheresis category.
Denotes American Society for Apheresis grade.
For more information, refer to Tables 2 and 3.
GVHD = graft-vs-host disease.
Data from reference 1.
a
b
employed. Table 1 summarizes these modalities, clinical conditions, and the most recent ASFA guideline
recommendations.1 However, well-designed, prospective intervention trials are still required to fully define
the role of TA for many of these disorders.
TA plays an important role in the management
of various oncological diseases. It is a procedure in
which blood is separated from a patient, a portion
of which is then removed or otherwise manipulated
and the remainder is then returned to the patient. TA
procedures include TPE (in which plasma is replaced
with a colloid or crystalloid solution) and modalities
that selectively remove and dispose of plasma solutes
(plasmapheresis), white blood cells (WBCs; leukocytapheresis), or platelets (thrombocytapheresis). ECP
is a type of leukocytapheresis procedure whereby the
removed white cells are manipulated prior to being
reinfused into the patient.
Apheresis procedures can utilize centrifugation to
separate blood components into layers within a rapidly rotating separation chamber based on their relative
density — with red blood cells (RBCs) being the most
dense, plasma the least dense — and intermediate
layers, moving from the axis of rotation outward and
consisting of platelet-rich plasma, lymphocytes, and
granulocytes.1 Specific kits are designed to remove
RBCs or plasma or cells of intermediate density from
January 2015, Vol. 22, No. 1
anticoagulated blood during the procedure. The fluid
returned back to the patient contains the undesired
blood components along with anticoagulant, crystalloid, and/or colloid solutions. Membrane filtration
systems separate and collect plasma on a principle
similar to hemodialysis and ultrafiltration, namely
using membranes permeable to high-molecular-weight
proteins but not cellular elements. The predominant
instruments and methodologies used for TA procedures in the United States utilize centrifugation.2
Clinical Adverse Events
TA can be associated with minimal to potentially fatal adverse events, although the overall incidence is
relatively low (5%–12%).3 Hypersensitivity reactions
due to plasma or blood product replacement fluid can
range from urticarial to anaphylactoid-type reactions.
Hypocalcemia secondary to citrate anticoagulant can
manifest as paresthesia, nausea, vomiting, lightheadedness, and twitching. Hypovolemia due to fluid shifts
or vasovagal reaction may manifest as hypotension,
muscle cramps, and headache. Rare, serious adverse
events requiring the procedure to be interrupted or
abandoned (0.8% incidence) or resulting in fatality
(≤ 0.5%) due to cardiovascular events can include
arrhythmia or ischemia, pulmonary edema, pulmonary embolism, and respiratory arrest; neurological
Cancer Control 61
complications can also occur and may include tetany,
seizures, and cerebrovascular accident.3 Hemorrhage,
thrombosis, and infection are uncommon. The causes
of death have included respiratory arrest, anaphylaxis,
and catheter-associated sepsis.3
Vascular Access
The majority of apheresis procedures are centrifugation based; therefore, they require withdrawal blood
flow rates of 50 to 150 mL/minute.4-7 Peripheral antecubital veins that can be cannulated using 16- to
18-gauge polytetrafluoroethylene- or silicone-coated, dialysis-type steel needles will accommodate
blood flow rates of 80 mL/minute and is adequate
for centrifugation techniques. By contrast, filtration
therapies require a blood flow rate of at least 150 to
200 mL/minute, which is unsuitable for antecubital
veins.4-7 Other considerations specific to TA include
whether the treatment relies on discontinuous, sequential blood exchange cycles (1 lumen is sufficient)
or continuous processing (2 lumens are needed).4-6
When a central venous catheter (CVC) is necessary
for a limited (< 2 weeks) course of TA, a nontunneled,
semi-rigid polyethylene catheter should be considered.8 For a longer duration (> 2 weeks) of TA, a tunneled CVC is preferred over a nontunneled CVC due
to less risk of infection.9 Typically, tunneled catheters
designed for long-term use (weeks to months) are
made of silicone and are more biocompatible, flexible,
and have the least thrombogenicity. The preferred venous site of CVC insertion is the internal jugular vein,
and both ultrasonographic guidance and fluoroscopy
have been shown to be associated with a lower rate
of complications during insertion.10
Central venous access is not always required.11-13
The Canadian Apheresis Study Group found that 67%
of 5,234 TPE procedures could be completed with
peripheral venous access alone.11 The frequency of
complications due to CVC placement exceeds the frequency of complications directly related to the procedure.14 Central venous access has been identified as
a major risk factor for complications of TPE in other
studies.10,14-16 CVCs are associated with a higher total
complication rate. These include infection (2%–28%),
thrombosis (0.2%–11%), hemorrhage (2%–14%), and
venous stenosis (10%–26%) with internal jugular catheters and up to 42% with subclavian vein catheters.17
In most series, the incidence of total adverse events associated with all vascular access is
low at 1% to 2%.6,18,19 Data from the International Apheresis Registry 2007 report that peripheral
veins are commonly used in Europe and Australia
(66%–70% of apheresis treatments),7 whereas CVCs
are the most common vascular access type used for
TA procedures in North America, South America, and
Asia (84%–98%).7 This regional difference in the use
62 Cancer Control
of peripheral veins compared with CVCs has not been
explained by differences in patient age, sex, the median number of treatments per patient, or the type
of apheresis procedure.13 Nevertheless, peripheral
venous access is underutilized in TA procedures and
is the access of choice because it is associated with a
lower risk of infection relative to CVCs and placement
can be done immediately with a low risk of other
serious complications.10 Complications of peripheral
cannulation include risk of infection, venous infiltration, patient discomfort, thrombosis and sclerosis of
veins, and the loss of future venous access. Peripheral
vein access for TA is not a viable option in children
due to their small venous caliber.
Peripherally inserted central catheters are too
small in caliber (4–5 Fr) to accommodate the negative pressure and blood flow rates required for TA
procedures.10 Arteriovenous fistulas and grafts are viable options for long-term access when the treatment
duration is expected to be over a period of several
months or years.13
Evidence and Decision Making
Hematologists and oncologists who may have incomplete knowledge of the indications, limitations, risks,
and relative efficacy of the procedure might request TA.
Because many procedures are for uncommon and infrequent indications, few randomized clinical trials or other
high-level evidence studies are available to guide clinical
decision-making. Therefore, the ASFA has undertaken a
critical evaluation of published studies and observations,
publishing periodic, evidence-based systematic reviews
of TA applications since 2007. The ASFA clinical practice
guidelines use the GRADE system, adopted from Guyatt
et al,20 whereby each disease, including specific clinical presentations, is categorized for the role of TA and
graded for the strength of recommendation and quality
based on the published evidence (Tables 2 and 3).1,20
Table 2. — American Society for Apheresis Categories
Category
Description
I
Disorders for which apheresis is accepted as a first-line
therapy, either primary stand-alone treatment or in
conjunction with another mode of treatment.
II
Disorders for which apheresis is accepted as a
second-line therapy, either as a stand-alone treatment
or in conjunction with other modes of treatment.
III
Optimum role of therapeutic apheresis is not established.
Decision making should be individualized.
IV
Disorders for which published evidence demonstrates or
suggests apheresis to be ineffective or harmful. Institutional
Review Board approval is desired if apheresis treatment is
undertaken in these circumstances.
From Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of
therapeutic apheresis in clinical practice-evidence-based approach from the
Writing Committee of the American Society for Apheresis: the sixth special issue.
J Clin Apher. 2013;28(3):145-284. Reprinted with permission from the American
Society for Apheresis.
January 2015, Vol. 22, No. 1
Table 3. — American Society for Apheresis Grading Recommendations
Recommendation
Description
Quality of Evidence
Application
Grade IA
Strong recommendation; highquality evidence
RCTs without important limitations or
overwhelming evidence from observational
studies
Strong recommendation; can apply to most
patients in most circumstances without
reservation
Grade IB
Strong recommendation;
moderate quality evidence
RCTs with important limitations (inconsistent
results, methodological flaws, indirect, or
imprecise) or exceptionally strong evidence
from observational studies
Strong recommendation; can apply to most
patients in most circumstances without
reservation
Grade IC
Strong recommendation; lowquality or very-low-quality
evidence
Observational studies or case series
Strong recommendation; may change when
higher-quality evidence becomes available
Grade 2A
Weak recommendation;
high-quality evidence
RCTs without important limitations or
overwhelming evidence from observational
studies
Weak recommendation; best action may
differ depending on circumstances or
patient or societal values
Grade 2B
Weak recommendation;
moderate-quality evidence
RCTs with important limitations (inconsistent
results, methodologic flaws, indirect, or
imprecise) or exceptionally strong evidence
from observational studies
Weak recommendation; best action may
differ depending on circumstances or
patient or societal values
Grade 2C
Weak recommendation; lowquality or very-low-quality
evidence
Observational studies or case series
Very weak recommendations; other alternatives may be equally reasonable
RCT = randomized controlled trial.
Adapted from Guyatt GH, Cook DJ, Jaeschke R, et al. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):123S-31S. Reprinted with permission from the American College of Chest Physicians.
ASFA category I and II indications are those for which
TA is considered first-line or second-line therapy, respectively. Category III indications acknowledge the lack of
high-level evidence to recommend the TA procedure
as primary or second line; however, the treatment may
be beneficial and, thus, individualized decision-making
should be used to guide inclusion of TA in the treatment
plan. Category IV reflects ineffectiveness or harm by TA
with the risks outweighing benefits.21
The 6th edition published in 2013 is a compilation
of 78 diseases or medical conditions assigned ASFA
categories I to IV.1 All TA procedures discussed within
this review are referenced according to the category
and recommended grade per the ASFA 2013 guidelines with further updates as indicated.1
Therapeutic Plasma Exchange
TPE involves the removal of a large volume of plasma
and replacement with plasma, albumin, or both. The
major mechanism of action of TPE is the removal of a
pathological solute, such as autoantibodies, immune
complexes, cryoglobulins, myeloma light chains, or
cytokines. Of note, TPE may also have an immunomodulatory effect, including the modulation of the
Th1/Th2 T-cell balance toward Th2,22 the suppression
of interleukin 2 and interferon γ production,23,24 and
an increase in suppressor T-cell function.
A standard TPE procedure exchanges 1 to
1.5 plasma volumes resulting in the removal of 60%
to 70% of intravascular large molecular weight solutes.25 Some large molecules (eg, immunoglobulin
[Ig] G) distribute in both the intravascular and the
January 2015, Vol. 22, No. 1
extravascular spaces; during TPE, the extravascular
molecules can move into the intravascular space.
Therefore, TPE may remove more total solute than
might be predicted based on the pretreatment concentration because of re-equilibration occurring
from the extravascular to the intravascular compartment.
Because TPE removes normal plasma coagulation factors, the activities of factors V, VII, VIII, IX,
and X, as well as von Willebrand factor (vWF), may
significantly decline.26,27 Activities of factor VIII, factor IX, and vWF return to normal within 4 hours
after TPE, whereas the remaining coagulation factors
achieve pre-TPE activity levels within 24 hours.26 The
exception to this is fibrinogen, which reaches 66% of
preapheresis levels within 72 hours.28 TPE may also
remove medications, especially those highly protein
bound. The clinical impact of this effect is understood
for relatively few drugs.29,30
Albumin is the most commonly used replacement fluid for TPE procedures. Normal plasma has
the same oncotic pressure as 5% albumin.31,32 Thus,
replacing plasma with 4% to 5% human serum albumin will maintain plasma volume and avoid hypotension. However, because albumin is expensive,33 some
health care professionals may prefer to use albumin
and saline, with the majority of the albumin being
given at the end of the procedure. The combination
of albumin and saline is hypo-oncotic and has been
associated with a greater frequency of hypovolemic
reactions and edema compared with using albumin
alone.16 Another disadvantage is that albumin does
Cancer Control 63
not replace coagulation factors, which may lead to
significant post-treatment coagulopathy.
Plasma is used as replacement fluid with TPE in a
limited number of disorders. It avoids postprocedure
coagulopathy and immunoglobulin depletion. Its disadvantages include transfusion reactions, citrate toxicity, and the potential for viral transmission. Plasma is
indicated as replacement fluid to replace ADAMTS13
when treating thrombotic thrombocytopenic purpura
(TTP) or when coagulopathy must be corrected.34
Neither cryosupernatant plasma nor solvent/
detergent–treated plasma has been shown to offer any
advantage over standard plasma for any indication.34
A meta-analysis of 3 trials comparing fresh frozen plasma
and cryosupernatant plasma for the initial treatment of
TTP did not reveal any benefit for patients receiving
cryosupernatant plasma.35 Similarly, controlled studies
failed to establish superiority of solvent/detergent–treated plasma over fresh frozen plasma.34 The only cohort
of patients with TTP who may benefit from the use of
solvent/detergent–treated plasma are those with severe
allergies to standard plasma.36
Hyperviscosity in Monoclonal Gammopathies
Hyperviscosity syndrome (HVS) refers to the clinical
sequelae caused by the altered physiology related to
plasma hyperviscous states, most typically seen in
Waldenström macroglobulinemia (WM; also known
as lymphoplasmacytic lymphoma) associated with
monoclonal IgM or, less frequently, with multiple myeloma associated with monoclonal IgA or IgG3. Specific signs and symptoms include mucosal bleeding,
visual impairment with retinal hemorrhage or retinal
detachment, headache, dizziness, vertigo, nystagmus,
hearing loss, somnolence, coma, and seizure. Other
manifestations include congestive heart failure (related to plasma volume overexpansion), respiratory
compromise, coagulation abnormalities, anemia, fatigue, peripheral polyneuropathy (depending on the
specific Ig properties), and anorexia.
WM represents approximately 2% of all cases of
non-Hodgkin lymphoma.37 When the IgM protein associated with WM exceeds a concentration of 4 g/dL,
the relative plasma viscosity can exceed 4 centipoise
(cp; relative to water: normal range, 1.4–1.8 cp) and
HVS can occur.38 Unlike the situation with IgG, IgM
is predominantly intravascular (> 80%) and increased
viscosity with IgM can become exponential above a
concentration of 3 g/dL. In turn, a small reduction
in IgM concentration can have a significant effect on
lowering serum viscosity.
TPE is an effective, short-term treatment for complications of HVS.39-41 Because bleeding is the most
common sign of HVS and retinal examination findings
correlate with the symptomatic threshold for HVS in
patients with WM, urgent TPE should be carried out
64 Cancer Control
to reduce the likelihood of blindness from retinal
hemorrhages or retinal detachment.42,43 TPE is a safe
and well-tolerated procedure in this setting.44 It is
not typically necessary to reduce the plasma viscosity to normal levels to relieve symptoms. However,
some evidence suggests that patients with monoclonal
IgM antibodies that produce neuropathy or other
target organ dysfunction may benefit from a more
aggressive effort to maintain serum viscosity near
normal levels.45,46
Hyperviscosity with WM is an ASFA category I
indication for TPE (grade 1B recommendation).1 Generally, 1 to 1.5 plasma volumes are exchanged per session, and fluid replacement usually consists of albumin
and saline in various proportions. Plasma exchange reduces plasma viscosity by approximately 20% to 30%
per session.47 Thus, 1 or 2 procedures can return the
plasma viscosity to near normal levels and reduce the
IgM concentration for several weeks. Concurrent chemotherapy is required to treat underlying disease and
prevent rebound HVS.
For asymptomatic patients with a serum viscosity
level above 3 to 3.5 cp, an IgM concentration greater
than 3 to 4 g/dL, or both, some experts suggest that
TPE can be prophylactically used prior to starting
rituximab therapy because significant transient increases in IgM levels can occur following single-agent
rituximab therapy (considered a “flare”) in 30% to
70% of patients.38,48,49 Based on this concern, the ASFA
guidelines have recommended TPE as prophylaxis
treatment prior to rituximab to lower IgM concentrations of less than 5 g/dL (grade 1C recommendation).1
The flare phenomenon may be less with regimens that
use chemotherapy prior to rituximab or regiments that
omit rituximab for the first 1 or 2 cycles.
Patients with myeloma and IgG3 subclass monoclonal paraproteinemia are more likely to develop
HVS than other patients with myeloma.50,51 This usually occurs at higher than 4 g/dL of monoclonal IgG3
in the plasma. In cases of IgG-associated HVS, the
increase in serum viscosity is approximately proportional to the concentration of the paraprotein.52 HVS
may also occasionally occur in IgA and light-chain
myeloma because of the formation of polymers; in
the majority of these cases, it occurs when the concentration of monoclonal IgG exceeds 6 to 7 g/dL.
Myeloma Cast Nephropathy
Nearly 50% of patients with multiple myeloma develop renal disease.53,54 Acute kidney injury from cast
nephropathy, also known as “myeloma kidney,” is the
most common type and accounts for 30% to 80% of
cases.55,56 The development of acute kidney injury
is associated with worse 1-year survival rates and
reduces the overall therapeutic options available to
patients.53,54 Cast nephropathy is due to the interaction
January 2015, Vol. 22, No. 1
and aggregation of filtered free light chains (FLCs)
and Tamm–Horsfall protein, thus causing intratubular
obstruction and damage. When the light chain production overcomes the capacity of the tubular cells
to endocytose and catabolize the FLCs, the increased
light chains in the tubular fluid of the distal tubule and
thick ascending loop of Henle form tubular casts with
the Tamm–Horsfall protein.57,58 As tubular obstruction
progresses, the decline in renal function becomes
irreversible. Other factors, such as dehydration, diuretics, hypercalcemia, hyperuricemia, and intravenous
contrast media, may all potentiate cast formation and
acute kidney injury.
The key to treating cast nephropathy is the rapid
lowering of FLCs. In addition to hydration and aggressive supportive care, antimyeloma chemotherapy
is necessary, whether it be with an alkylating agent
and prednisone therapy or one of the recent immune
modulators (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib). These latter agents have
emerged as effective therapy and have been referred
to as “renoprotective.”59 Supportive care with hemodialysis or peritoneal dialysis may also be needed.
TPE has been used in hopes of reducing the
delivery of plasma FLCs to the renal glomerulus for
filtration. Two studies suggested that TPE was beneficial.60,61 In addition, a small prospective comparison of forced diuresis, melphalan, and prednisone
(10 patients) vs forced diuresis, melphalan, prednisone, and TPE (11 patients) found a trend in favor of
TPE, and a subgroup analysis of patients dependent
on dialysis revealed that renal function recovered
in 43% of the TPE group compared with 0% in the
control group.62 These studies led to an endorsement
of TPE for myeloma kidney by the Scientific Advisors
of the International Myeloma Foundation.63 Subsequently, a large randomized trial of bortezomib-containing chemotherapy and supportive care, with or
without TPE, failed to demonstrate a benefit for 5 to
7 TPE procedures over 10 days.64 However, this study
has been criticized for the lack of FLC measurements,
the lack of histological evidence of cast nephropathy,
and the failure to consider early end points more specific to the recovery of renal function. In a report from
the Mayo Clinic, plasma exchange in combination
with bortezomib-based chemotherapy in 7 patients
was associated with 6 patients (86%) having at least
a partial response.65
Collectively, these observations suggest that a subgroup of patients with cast nephropathy might benefit from TPE, particularly those in nonoliguric renal
failure who do not require dialysis.56,60 The severity
of myeloma cast formation, including the need for
dialysis, has been identified as the major factor associated with nonreversible renal failure, even in patients
undergoing TPE.60,63,66,67 Moreover, biopsy findings that
January 2015, Vol. 22, No. 1
indicate potential reversibility (eg, absence of fibrosis
of all affected glomeruli) may be important predictors
of success.60,62
The ASFA evidence-based guidelines lists TPE as
a category II indication for myeloma kidney due to
light-chain cast nephropathy.1 After initial management, especially in the case of nonoliguric patients,
focus should be on fluid resuscitation (2.5–4 L/day),
alkalinization of the urine, and chemotherapy. If serum creatinine remains elevated after several days,
then renal biopsy should be considered to assess for
cast nephropathy. If cast nephropathy is highly suspected or confirmed, then TPE can be initiated by
processing 1 to 1.5 total plasma volumes every 1 to 2
days and using 5% albumin in saline as replacement
fluid. Some studies support a course of 10 to 12 TPE
procedures over 2 to 3 weeks and repeating this depending on patient response and clinical course.1 For
patients who are oliguric, excrete at least 10 g of light
chains per 24 hours, or whose serum creatinine level
is at least 6 mg/dL, TPE may be included as adjunct
therapy to initial chemotherapy and hemodialysis. If
TPE and hemodialysis are to be performed on the
same day, then the procedures can be performed in
tandem without compromising the efficiency of the
hemodialysis.
Paraneoplastic Neurological Syndromes
Paraneoplastic neurological syndromes (PNS) are
symptoms or signs resulting from damage to the
central or peripheral nervous system, including the
neuromuscular junction and muscle, removed from
the site of the malignancy or its metastases, and not
due to remote effects caused by infection, ischemia,
or metabolic disruptions.68 PNS can affect up to 1% of
patients with cancer but may occur more frequently
in those with non-Hodgkin lymphoma, small-cell lung
cancer, and thymomas.69-72 In the majority of patients,
PNS develop prior to the cancer diagnosis.
The pathogenesis of PNS is thought to be immune-mediated as a result of a cross-reaction against
antigens shared by the tumor and nervous system
cells.68,73 Many antibodies are associated with paraneoplastic syndromes (Table 4).68,73,74 Their role in
neuronal dysfunction is unclear and they can occur
in fewer than 50% of patients with PNS.75 No studies
have proven that these antibodies are pathogenic;
however, these antibodies have become useful diagnostic markers, particularly in monitoring for relapse.
The severity of the majority of PNS cases is due to the
early and nonreversible destruction of neural structures by the inflammatory process; in many cases,
the patient is severely debilitated within weeks to
months.76,77 Prompt initiation of therapy following the
diagnosis of PNS may stabilize symptoms and prevent
PNS spreading to further areas in syndromes with
Cancer Control 65
Table 4. — Paraneoplastic Neurological Syndromes and Their Associated Tumor Types, Symptoms, and Antibodies
Syndrome
Frequency of
Paraneoplastic
Origin (%)
Major Symptoms
Lambert–Eaton
myasthenic syndrome
60
Muscle weakness, autonomic dysfunction
SCLC
VGCC antibodiesa
Paraneoplastic
cerebellar degeneration
50
Truncal, limb ataxia, dysarthria, saccadic
gaze pursuit, nystagmus
Ovary
Breast
SCLC
Hodgkin lymphoma
Anti-Yo
Anti-Hu
Anti-VGCC
Anti-CV2/CRMP5
Paraneoplastic opsoclonus/
myoclonus
20
Saccades, ataxia, other cerebellar signs,
generalized myoclonus, altered mental
state, stupor, coma
Neuroblastoma
Breast
SCLC
Anti-Ri (ANNA-2)
Sensory neuronopathy
20
Pain, paresthesias (arms > legs),
numbness, ataxia
SCLC
Anti-Hu
Anti-CV2/CRMP5
Anti-amphiphysin
Limbic encephalitis
20
Seizures, short-term memory deficits,
behavioral and psychiatric disturbances
SCLC
Testicular
Anti-Hu
ANNA-1
Paraneoplastic
encephalomyelitis
10
Seizures, subacute dementia, personality
changes (limbic encephalitis), subacute
cerebellar signs, autonomic nervous
system dysfunction
SCLC
ANNA-1
Anti-Hu
Subacute visual loss, photosensitivity,
night blindness, impaired color vision
SCLC
Cervical
Melanoma
Recoverin antibodies
Stiffness predominantly upper limbs,
painful spasms precipitated by sensory
stimuli
Breast
Colon
Lung
Hodgkin lymphoma
Malignant thymoma
Antiamphiphysin
Weight loss, constipation, abdominal
distension, esophageal dysmotility,
gastroparesis
SCLC
Anti-Hu
Anti-CV2/CRMP5
Proximal myopathy, heliotrope rash,
scaly plaques on dorsal hands
Ovarian
Lung
Pancreatic
Stomach
Colorectal
Non-Hodgkin lymphoma
Cancer-associated
retinopathy
Paraneoplastic
stiff-person syndrome
5–20
Chronic intestinal
pseudo-obstruction
Dermatomyositis
30
Associated Tumor
Types
Frequently Associated
Paraneoplastic
Antibodies
Present in nearly all patients with the paraneoplastic and nonparaneoplastic form of Lambert–Eaton myasthenic syndrome.
Data from references 68, 73, and 74.
ANNA = antineuronal nuclear antibody, SCLC = small cell lung cancer, VGCC = voltage-gated calcium channel.
a
onconeural antibodies.78 For patients with an identified tumor, antitumor therapy should be rapidly instituted for stabilization or symptom improvement. The
use of immunomodulatory therapy does not substantially modify the neurological outcome of patients
whose tumors are successfully treated.76,79 For many
paraneoplastic syndromes, removal of the tumor is
the only effective treatment.80,81
The role and timing of immunotherapy for PNS
is not well defined; however, many reports indicate
its apparent benefit.82,83 No systematic studies exist
concerning the type of immunosuppressive therapy,
and no RCTs or quasi-RCTs exist on which to base
treatment or practice.84 In patients without detectable
tumor but with a prior history of malignancy and clinicopathological findings consistent with progressive
PNS, it is appropriate to empirically start immunosuppressive therapy with or without antitumor treatment.
66 Cancer Control
Initial therapies often include corticosteroids, TPE,
intravenous immunoglobin (IVIG), immune adsorption, and/or rituximab. More aggressive second-line
immunosuppression with cyclophosphamide, tacrolimus, mycophenolate, or cyclosporine may be used
when no response to initial treatments is seen and the
patient continues to lose neurological functions. More
severe neurological deficits associated with antibodies
against Yo, Hu, and CRMP5 are also the most refractory to immunosuppressive treatment. Survival from
time of diagnosis is significantly worse in patients
with anti-Yo (median, 13 months) or anti-Hu (median, 7 months) than in patients with anti-Tr (median,
> 113 months) or anti-Ri (median, > 69 months).85
However, patients who receive antitumor treatment,
with or without immunotherapy, live significantly longer than those who do not.76,84
The rationale for TPE with PNS is that plasma
January 2015, Vol. 22, No. 1
antibody levels can be reduced and thereby ameliorate the damage to the peripheral nervous system in
tissues. Plasma exchange can also reduce circulating
levels of cytokines and other mediators of inflammation that may contribute to the effectiveness of TPE
as immunomodulatory therapy. By comparison, PNS
involving the central nervous system do not typically
respond to TPE, a fact likely due to the inability of
plasma therapy to decrease intrathecal antibody titers.
Patients with acquired neuromyotonia and antibodies directed against voltage-gated potassium channels or paraneoplastic cerebellar degeneration with
anti-Tr antibodies may be more likely to respond to
TPE; however, many do not have malignancy. In 50%
of cases, encephalitis associated with anti–N-methyl
D-aspartate receptor antibodies responds to first-line
treatment with corticosteroids, IVIG, or TPE. Although
immunosuppression with corticosteroids, TPE, and/or
IVIG may benefit those with LGI1- and CASPR2-antibody associated syndromes, residual memory impairment is common. However, large case series on
long-term outcomes are currently lacking. Even less
is known about the treatment and prognosis of other neuronal cell-surface antibody syndromes (eg,
γ-aminobutyric acid [B], α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid receptor). Typically, they
are treated similar to anti–N-methyl D-aspartate receptor encephalitis. Disorders such as paraneoplastic cerebellar degeneration are generally associated
with neuronal loss; because they subacutely evolve
and treatment is often delayed, the neurons die, thus
making recovery impossible.85 Some central nervous
system disorders, such as opsoclonus–myoclonus
syndrome, may not involve cellular loss and, in fact,
may have no identifiable pathological features. Thus,
patients with these disorders, like those with the Lambert–Eaton myasthenic syndrome (LEMS), have the
potential for recovery.
LEMS is a syndrome that involves the neuromuscular junction and can typically respond well to immunosuppression and, subsequently, to treatment of the
underlying tumor. TPE may be useful adjunct therapy
for patients whose neurological deficit is severe or
rapidly developing or among those who cannot tolerate treatment with IVIG (ASFA category II; grade 2C
recommendation).1 Reports of benefit are tempered
by the observation that responses can be slow and
symptoms can worsen following the completion of
TPE if additional immunosuppressive therapy is not
employed.
The reported TPE regimens for LEMS vary from
5 to 15 regiments of daily TPE over 5 to 19 days to
8 to 10 regimens of TPE carried out at 5- to 7-day
intervals. Most reports employed 1.25 plasma volume exchanges.1 However, the peak effect is usually
demonstrated after 2 weeks and largely subsides after
January 2015, Vol. 22, No. 1
6 weeks.86 This may be due to the slower turnover of
the presynaptic voltage-gated calcium channel compared with the postsynaptic acetylcholine receptor.
The effectiveness of immunosuppressive therapy in non-LEMS PNS with onconeural antibodies
is not supported by higher level evidence.84,87 Few
studies prove efficacy, although several retrospective
and small prospective studies support the benefit
of immunosuppression for some patients and select
syndromes.88-91 The ASFA guidelines have assigned
a grade 2C recommendation for this category III indication.1 Procedures are performed daily or every
other day for a total of 5 to 6 exchanges over 2 weeks,
although the exact number of exchanges should be
adjusted for each patient. Some patients will require
maintenance therapy on a monthly or less frequent
basis. TPE cannot be considered as standard therapy
for PNS. Most patients treated with TPE have also received immunosuppressive drugs as well as specific
anticancer therapy.
Hematopoietic Stem Cell Transplantation–
Associated Thrombotic Microangiopathy
Thrombotic microangiopathy (TMA) refers to a histopathological appearance, describing arteriolar thrombi associated with intimal swelling and fibrinoid necrosis of the vessel wall.92 The microscopic injury
results from a variety of insults that can cause the
activation of intravascular platelets with the subsequent formation of platelet-rich thrombi within the
microcirculation. TMA following allogeneic hematopoietic stem cell transplantation (HSCT), also called
transplant-associated TMA, appears to be primarily
triggered by mechanisms of endothelial cell injury,
including conditioning chemotherapy,93-95 irradiation,96
immunosuppressive agents (eg, mammalian target
of rapamycin, calcineurin inhibitor drugs),97-100 graftvs-host disease (GVHD),101-103 and opportunistic infections.104,105 The damaged endothelial cells release
microparticles and vWF, which induce platelet adhesion/aggregation and a procoagulant state.106-108 This
process consumes platelets and induces mechanical
damage to RBCs as they impact microthrombi or fibrin
strands obstructing the microcirculation.
The clinical hallmarks of TMA include microangiopathic hemolytic anemia and thrombocytopenia, and the associated laboratory findings include
schistocytes, increased serum lactate dehydrogenase,
decreased serum haptoglobin, and indirect hyperbilirubinemia. Hemoglobinuria, either frank or microscopic, is frequent. Kidneys are the major target
organs of transplant-associated TMA; thus, renal function abnormalities are common. Unlike idiopathic
TTP, in which severe deficiency of the vWF-cleaving
protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin-1-like domains), leads to
Cancer Control 67
the presence of ultra-large multimers of vWF and
systemic platelet agglutination, multiple studies in
post-transplantation TMA have failed to document a
severe deficiency of ADAMTS13.109-111
TMA can occur within the first few weeks following transplantation or as a late complication, particularly in association with GVHD. One-year cumulative
incidences of 13% and 15% were reported in patients
undergoing nonmyeloablative conditioning and
high-dose conditioning, respectively.112 Most large,
retrospective studies report a prevalence of 10% to
25%.113 Transplant-associated TMA carries a poor
prognosis. In a literature review of 35 published
articles involving more than 5,423 allogeneic HSCT
recipients, 447 study volunteers (8.2%) developed
transplant-associated TMA and had a median mortality rate of 75% within 3 months of the diagnosis.114
Clinical risk factors associated with transplant-associated TMA include high-dose conditioning regimens,
acute GVHD, female sex, older age, active infections,
receiving transplantations from unrelated donors, and
the combination of mammalian target of rapamycin
and calcineurin inhibitor drugs.115
Currently, no consensus exists regarding the approach to treatment of transplant-associated TMA, and
no randomized clinical trial data exist. Initial management involves the reduction or discontinuation of
the mammalian target of rapamycin and calcineurin
inhibitor drugs (especially if used in combination)
along with aggressive treatment of underlying GVHD
and infections. A role for TPE in this disorder remains
unclear. Response rates of transplant-associated TMA
to TPE are significantly lower (< 50%)116 than the high
responses in idiopathic TTP (≤ 85%).117-119 A systematic
review published in 2004 noted an 82% mortality rate
among 176 study volunteers with transplant-associated TMA who underwent TPE compared with a 50%
mortality rate among 101 study volunteers not treated
with TPE, suggesting that the toxicity of the procedure
outweighs the potential benefits.114 Similarly high cumulative mortality rates were cited by the Blood and
Marrow Transplant Clinical Trials Network Toxicity
Committee in a consensus statement recommending
that TPE not be considered as standard of care for
transplant-associated TMA.120 The difference seen in
mortality rates may partly reflect the significant comorbidity of the post-transplantation state; however,
it also supports the available data that indicate that
transplant-associated TMA results from mechanisms
distinct from those involved in idiopathic TTP.
Because some patients with transplant-associated TMA appear to respond to treatment, a trial of
TPE could be considered as salvage therapy for select patients with persistent, progressive, end-organ
complications despite a resolution of infections and
GVHD (ASFA category III; grade 2C recommenda68 Cancer Control
tion).1 TPE for transplant-associated TMA is usually
performed daily until a response is seen and is then
either discontinued or tapered off, a process similar to treatment for idiopathic TTP. The therapeutic
end point may be difficult to determine because the
platelet count, schistocytes, and lactate dehydrogenase
levels could be affected by incomplete engraftment
and other post-transplantation complications.
Based on the data from anecdotal reports, other
salvage treatment options for transplant-associated
TMA might include daclizumab, defibrotide, and rituximab.121-123 Such anecdotal reports of clinical response
to eculizumab suggest that transplant-associated TMA
could involve aberrant and autonomous complement
activation and include some patients who may have
an inherent defect in complement regulation.124,125
Therapeutic Leukocytapheresis
The majority of leukocytapheresis procedures are carried out to treat hyperleukocytosis and complications
of leukostasis associated with acute leukemias.
Leukocytapheresis for Acute Leukemia
and Leukostasis With Hyperleukocytosis
Hyperleukocytosis is variably defined as a WBC or leukemic blast cell count above 50,000/μL or 100,000/μL.
The incidence of hyperleukocytosis ranges between
5% and 13% in adult acute myeloid leukemia (AML)
and between 10% and 30% in acute lymphoblastic leukemia (ALL).126 Although hyperleukocytosis does not appear to have a major impact in early
mortality in ALL unless the WBC count is more than
250,000/μL, it is associated with an increased likelihood
of induction death and reduced likelihood of achieving
complete remission in cases of AML.127,128
Hyperleukocytosis with AML and ALL may be
associated with disseminated intravascular coagulopathy, tumor lysis syndrome, and leukostasis. Leukostasis refers to end-organ complications due to microvascular leukoaggregates, hyperviscosity, tissue
ischemia, infarction, and hemorrhage as a result of
high numbers of leukocytes. The pathophysiology of
leukostasis is based on the rheological properties of
the blasts, which is a function of the deformability of
the blasts (rigidity) and the volume of the blasts (cell
fraction) in the blood,129 and the cytoadhesive interactions between the blasts and the endothelium.130
This second mechanism is based on the activation of
the endothelium by blasts to secrete cytokines that
in turn mediate the expression of specific receptors
such as intercellular adhesion molecule 1, vascular cell
adhesion protein 1, selectins, and others that promote
blast adhesion.130 Leukostasis in ALL usually occurs
with WBC counts higher than 400,000/μL.131 Compared with lymphoid blasts, myeloid blasts are larger,
less deformable, and their cytokine products are more
January 2015, Vol. 22, No. 1
prone to activate inflammation and the molecular expression of endothelial cell adhesion. A blast count
above 100,000/μL is a good predictor of leukostasis
in the myeloid phenotype AML (FAB M1, M2, M3v).
The blast count is less reliable in monocytic lineage
AML (FAB M4, M5) in which severe leukostasis can
occur with WBC counts above 50,000/μL.132
Central nervous system manifestations of leukostasis can include confusion, somnolence, dizziness,
headache, delirium, coma, and parenchymal hemorrhage, and pulmonary complications can include hypoxemia, diffuse alveolar hemorrhage, and respiratory
failure with interstitial infiltrates, alveolar infiltrates,
or both. Both pulmonary and neurological manifestations are associated with increased rates of mortality
in adults and children. In cases of hyperleukocytosis
in AML, the mortality rate has been reported to be
between 5% and 30%.133
Definitive treatments for hyperleukocytosis in the
setting of AML or ALL involve induction chemotherapy
with aggressive supportive care. Hydroxyurea, cytarabine, or both are useful in temporizing cytoreductive
agents for AML. Hyperuricemia and tumor lysis syndrome are treated with intravenous fluids, electrolyte
replacement, allopurinol or rasburicase, alkalinization of the urine, and dialysis. Bleeding and coagulopathy are managed with plasma, cryoprecipitate,
and/or platelet transfusions. However, RBC transfusions should be deferred to avoid augmenting hyperviscosity and promoting leukostasis.
Leukocytapheresis allows for the rapid reduction
of the intravascular leukemic cellular burden, thereby
resolving leukostatic microvascular occlusion and improving tissue perfusion. No randomized prospective
studies of leukocytapheresis for hyperleukocytosis
or leukostasis have been published. Published data
regarding the clinical value of therapeutic leukocytapheresis are limited, observational, and conflicting. This is partly due to different WBC thresholds
prompting leukocytapheresis, patient selection, and
therapeutic end points.
Previous multiple retrospective cohort studies
of AML demonstrate reduced early mortality; however, leukocytapheresis offers no benefit to overall
outcome.134,135 Recently, a systematic review and meta-analysis using an intent-to-treat approach evaluated
leukapheresis and low-dose chemotherapy interventions in patients with AML and WBC counts above
100,000/μL.136 Data were reviewed from 15 of the
studies in which leukocytapheresis was used. In the
analysis, the mean early mortality rate of 20.1% during
the first month of induction chemotherapy in patients
with hyperleukocytosis was not reduced by leukocytapheresis (or low-dose chemotherapy), suggesting
limited benefit.136 The authors noted limitations of the
primary studies: the studies were small, retrospective,
January 2015, Vol. 22, No. 1
observational, and all had a moderate to high risk of
confounding bias.136
Prophylactic leukocytapheresis remains a consideration for patients with AML and WBC counts above
100,000/μL without overt leukostasis manifestations
as a means to rapidly reduce blood viscosity and
facilitate safe RBC transfusion as well as to avoid
leukostasis that might occur following the start of chemotherapy, particularly with the M4 or M5 subtype.137
Among children and adults with ALL, clinical
symptoms of leukostasis develop in less than 3% at
WBC counts lower than 400,000/μL.131 Therefore,
prophylactic leukocytapheresis offers no advantage
over aggressive induction chemotherapy and supportive care, including among those with tumor lysis
syndrome. By comparison, pulmonary and central
nervous system complications develop in more than
50% of children with ALL and WBC counts above
400,000/μL, suggesting that prophylactic leukocytapheresis might be beneficial in that setting.131
For patients with ALL or AML and clinical leukostasis complications, ASFA category I (grade 1B
recommendation) has been assigned and is based on
numerous reports and retrospective case series that
describe the rapid reversal of pulmonary and central
nervous system manifestations following cytoreduction with leukocytapheresis.1 However, improvement
may not be observed if severe end-organ injury or
hemorrhage has already occurred. The ASFA category III (grade 2C recommendation) for prophylactic
leukocytapheresis probably reflects the limited and
conflicting data available in the literature to guide
treatment in patients who are asymptomatic.1
A single leukocytapheresis procedure can reduce
the WBC count by 30% to 60%.1 Daily — or, on occasion,
twice-daily — procedures for life-threatening cases can
be performed by processing 1.5 to 2 blood volumes and
using crystalloid or 5% albumin as the replacement fluid.
RBC priming may be employed for adults with severe
anemia; however, undiluted packed RBCs should be
avoided in small children with hyperviscosity. For patients with AML and leukostasis complications, apheresis
must be discontinued when the blast cell count is less
than 50,000 to 100,000/μL and clinical manifestations are
resolved or maximum benefit is achieved. Chemotherapy
should not be postponed and is required to prevent the
rapid reaccumulation of circulating blasts.
Leukocytapheresis for Chronic Myeloid Leukemia
With Hyperleukocytosis and Priapism
The incidence of leukostasis as a result of hyperleukocytosis in adults presenting with CML has been
estimated to be between approximately 12% and 60%
among children with CML.138,139 The most recognized
features of hyperleukocytosis in CML are constitutional (malaise and fever), cardiorespiratory, neurological,
Cancer Control 69
or vascular, including retinal hemorrhage, myocardial
ischemia, and priapism.
Priapism occurs in 1% to 2% of males presenting with chronic phase CML and WBC counts above
500,000/μL.140-142 It is characterized by a prolonged,
painful erection. Priapism in this setting is a urological emergency with a poor prognosis, and the risk of
impotence in adults is 50% despite appropriate management.143 The primary mechanism is the aggregation
of leukemic cells in the corpora cavernosa and the
dorsal vein of the penis.144 A contributing factor is the
venous congestion of the corpora cavernosa due to
mechanical pressure on the abdominal veins by the
enlarged spleen. Increased production of cytokines
and adhesion molecules by leukemic cells can also
be seen and will result in the activation of endothelial
cells and lead to the increased sequestration of cells
in the microvasculature.145
No standard treatment has been recommended
for leukemic priapism. Systemic therapies include cytoreductive agents, such as high-dose hydroxyurea
and tyrosine kinase inhibitors, with or without the
addition of leukocytapheresis to reduce hyperviscosity.138,146 A review of the published literature revealed
that 3 of 4 patients with ischemic priapism treated
by leukocytapheresis had a resolution of priapism
compared with 3 of 15 patients treated with chemotherapy alone.147 Some case series have reported on
the successful use of therapeutic leukocytapheresis
in combination with cytotoxic therapy to treat priapism.142,144,146,148,149 Although some of these studies indicated that a conservative approach may be successful
in preserving erectile function, a combined modality
approach is strongly recommended by the American
Urological Association so that systemic treatment for
the underlying disorder and intracavernous treatment
be concurrently administered.147
Leukocytapheresis for Other Chronic Leukemias
and Leukostasis With Hyperleukocytosis
Leukostasis complications with other leukemias are
rare but may occur with chronic myelomonocytic
leukemia150 and WBC counts higher than 100,000/μL
with a high level of lactate dehydrogenase. In cases
of chronic lymphocytic leukemia, leukostasis is rare
and is predominantly described in patients with WBC
counts above 1,000,000/μL.151
Extracorporeal Photopheresis
ECP is an immunomodulating cell therapy whereby a
patient’s circulating WBCs are collected via a leukocytapheresis procedure, exposed ex vivo to photo-activatable 8 methoxypsoralen, irradiated with ultraviolet
A light, and then reinfused into the patient. ECP was
originally introduced in 1987 by Edelson et al152 for
the treatment of Sézary syndrome, an aggressive form
70 Cancer Control
of advanced cutaneous T-cell lymphoma (CTCL). In
1988, ECP was approved by the US Food and Drug
Administration (FDA) for the treatment of advanced
forms of CTCL, and has since become a recommended
first-line therapy for selected patients with advanced
stage CTCL (ASFA category I).1,153,154
ECP is also currently utilized for patients with
acute and/or chronic skin and nonskin GVHD (ASFA
categories II and III, respectively) and for solid organ
transplant rejection (ASFA category II).1 Its use is also
expanding into the treatment of select autoimmune
diseases such as pemphigus vulgaris, scleroderma, inflammatory bowel disease, and nephrogenic systemic
fibrosis (ASFA category III).
The molecular mechanisms for the therapeutic
effects of ECP are not fully understood. The cytotoxic
effects and the role of other cell populations, including dendritic cells, T cells, and natural killer cells,
continue to be investigated. Detailed discussions of
all the cellular mediators in the process described
below are beyond the scope of this article but have
been reviewed elsewhere.155-158
Cell death by apoptosis appears to be a major
mechanism of action that occurs within 24 to 72 hours
of photoactivation; however, 5% to 15% of the total
lymphocyte population is exposed to treatment during
each procedure.159 Thus, additional and/or complementary mechanisms of action are also important.
Exposed monocytes undergo apoptosis later than
lymphocytes but a portion differentiate into immature dendritic cells.159 These dendritic cells have been
identified as key mediators of peripheral tolerance157
and are found in patients treated with ECP for chronic
GVHD.160 Together with macrophages, these immature
dendritic cells are the antigen-presenting cells that
recognize, engulf, and display cellular determinants
from the apoptotic lymphocytes. After engulfing apoptotic cells, the immature dendritic cells differentiate
into semi-mature dendritic cells, migrate to lymph
nodes, and present antigenic peptides to T lymphocytes. This brings about a shift from a Th1 to a Th2
immune response, an increase in anti-inflammatory
cytokines (eg, interleukin 10, transforming growth
factor β), a decrease in proinflammatory cytokines,
and the proliferation of T-regulatory cells. These T-regulatory cells down-regulate the GVHD process by
inactivating T-effector cells158,161-163 and encouraging
peripheral tolerance. In the treatment of CTCL, the
apoptotic tumor debris is thought to provide target
antigens for cytotoxic CD8+ lymphocytes.164
Cutaneous T-Cell Lymphoma
Cutaneous lymphomas are characterized by the localization of malignant lymphocytes in the skin.
Approximately two-thirds of these lymphomas are
of T-cell origin. The most common form of CTCL is
January 2015, Vol. 22, No. 1
mycosis fungoides, which makes up 60% of CTCL
cases.153 By contrast, Sézary syndrome, which is
an aggressive form of advanced CTCL, occurs in
about 5% of patients.165 In Sézary syndrome, the
prognosis is generally poor and has a median
survival rate of less than 3 years.166 A meta-analysis of
19 studies that utilized ECP for patients at all
stages of CTCL showed overall response rates
of 55.5% and 55.7% with ECP alone and ECP in
combination with other therapies, respectively.167
Scarisbrick et al 154 concluded that all patients
with erythrodermic CTCL (major criteria) are
candidates for ECP, and those with a peripheral
blood T-cell clone and/or circulating Sézary cells
comprising more than 10% of the lymphocytes
and/or have a CD4:CD8 ratio higher than 10 (minor criteria) may also benefit from ECP. Response
to ECP has been linked to a short duration of disease,
the absence of bulky lymphadenopathy or internal
organ involvement, a WBC count lower than
20,000/µL, fewer than 20% Sézary cells, normal or mildly abnormal natural killer cell activity, a level of CD8+
T cells above 15%, lack of prior intensive chemotherapy, and plaque-stage disease involving 10%
to 15% of the skin surface.154 Fewer patients with
nonerythrodermic CTCL have been treated with ECP
and 1 randomized crossover study alone suggested
no ECP benefit.168
Guidelines from the National Comprehensive Cancer Network recommend ECP as an option for advanced
mycosis fungoides and Sézary syndrome (stage 2B, 3,
or 4) when the disease is refractory to skin-directed
treatment.169 However, ECP is not expected to increase
survival; typically, the treatment delays the progression
of disease and improves pruritus.170
The standard schedule of ECP for the treatment
of CTCL consists of procedures performed on 2 consecutive days every 2 to 4 weeks and generally continued for up to 6 months to assess response.1,154 The
median time for a response to ECP is 5 to 6 months,
although response may take as long as 10 months in
some patients. Those who respond after 6 to 8 cycles
appear to have an improved long-term outcome. When
maximal response is achieved, ECP treatments can be
reduced to once every 6 to 12 weeks with the goal
of discontinuation if relapses do not occur. If CTCL
recurs in more than 25% of the skin, then ECP once
or twice monthly should be reinstituted. If evidence
exists of disease progression after 6 months of ECP
alone, combination therapy should be considered. If
minimal or no response is seen after 3 months of combination therapy, then ECP should be discontinued.1
Extracorporeal Cellular Therapy
in Graft-vs-Host Disease
GVHD remains a major complication of allogeneic
January 2015, Vol. 22, No. 1
HSCT. Despite an overall improvement in human leukocyte antigen typing, conditioning regimens, supportive care, and post-transplantation immunosuppression, the overall incidence of GVHD has increased
because an increasing number of older patients are
undergoing allogeneic HSCT and the use of haploidentical, double-cord blood and human leukocyte
antigen–mismatched donors are being used.171,172
GVHD following HSCT is classified as an acute,
chronic, or overlap syndrome. Despite prophylactic
therapy with immunosuppressive agents, 20% to 80%
of patients develop acute GVHD following allogeneic
HSCT. Acute GVHD results from the activation of donor T cells by host antigen–presenting cells, leading to
T-cell– and cytokine-mediated tissue injury.171 Chronic
GVHD is due to dysregulated allogeneic or autoreactive T cells, B cells, antigen-presenting cells, and natural killer cells, thus leading to fibrosis, inflammation,
sclerosis, and atrophy of affected tissues.163 Moderate-to-severe GVHD is the leading cause of impaired
immune function, compromised functional status,
and transplantation-related deaths. High-dose corticosteroids are first-line therapy for moderate-to-severe
acute and chronic GVHD with or without the use of
calcineurin inhibitors.173 Patients with chronic GVHD
require prolonged immunosuppressive treatment for
an average of 2 to 3 years from the initial diagnosis,
with 10% of those surviving for at least 7 years still
requiring immunosuppressive treatment at that time
or beyond.174 Severe GVHD unresponsive to treatment carries a high risk of death or severe morbidity
due to end-organ complications, infections, or both,
and the transplantation-related mortality rate exceeds
40%.175,176 To date, the US Food and Drug Administration has not approved a treatment option for GVHD.
Therapies for steroid-refractory acute GVHD
include mycophenolate mofetil, denileukin diftitox,
sirolimus, infliximab, etanercept, pentostatin, horse
vs rabbit antithymocyte globulin, and alemtuzumab.173,177,178 Evidence does not suggest that any one
second-line agent is superior to another.173 As a result, decisions on which agent to use at individual
treatment centers often vary according to the clinical experience of health care professionals, cost, and
treatment availability.
ASFA has reviewed the data available on the overall response rates to ECP for steroid-refractory acute
GVHD and found that overall response rates in pediatric and adult patients ranged from 52% to 100%,
with responses in cutaneous (66%–100%), gastrointestinal tract (40%–83%), and hepatic (27%–71%) acute
GVHD.1 Higher response rates have been reported
in early-onset GVHD179; however, the strongest predictor for response to ECP in a multivariate analysis
was GVHD severity (100% response in grade 2 disease vs 30% in grade 3/4).180 Complete responses and
Cancer Control 71
improved survival rates are often reported among
acute GVHD cohorts; however, the nonrandomized
and retrospective results for ECP are not superior to
results reported for alternative salvage approaches
for steroid-refractory acute GVHD.
Therapies for steroid-refractory/dependent chronic GVHD include sirolimus, mycophenolate mofetil,
azathioprine, thalidomide, ECP, total lymphoid irradiation, mesenchymal cells, imatinib, pentostatin, various monoclonal antibodies, and others.177,178 Approximately 30% to 65% of patients with chronic GVHD
and dependent on steroids improve with ECP, but
most experience partial responses alone.1 Skin, oral,
and ocular chronic GVHD manifestations respond in
30% to 100% of cases, whereas liver, joint, and gastrointestinal complications improve in 30% to 80%,
50%, and 0% to 50% of cases, respectively.1 A review
of 23 studies totaling 735 patients treated with ECP
for steroid-resistant, intolerant, or dependent chronic
GVHD noted that overall and complete response rates
were observed in 64% and 35% of cases with skin
involvement, in 56% and 27% cases of oral GVHD,
and in 47% to 57% with gastrointestinal tract chronic GVHD.181 ECP has also been reported to stabilize
lung function with bronchiolitis obliterans syndrome
related to chronic GVHD182; however, response rates
for lung involvement are typically lower, ranging from
0% to 66%.183,184 Patients responding to ECP also have
a better probability of survival, both in children (96%
vs 58% 5-year survival)185 and in adults (88% vs 18%
at 2 years; relative risk, 11.6; P = .022).186
Maximal responses for chronic GVHD usually require 2 to 6 months of treatment. The single,
randomized controlled trial using ECP for steroid-resistant skin chronic GVHD observed no statistically
significant difference in total skin score at 12 weeks
of ECP plus salvage GVHD therapy compared with
salvage therapy alone.187 However, unblinded assessments recorded 40% complete and partial responses at
12 weeks in the ECP-treated group compared with
10% in the non-ECP group (P < .001).187 More rapid
skin improvement was also observed at weeks 12 to
24 of ECP and corticosteroids could be more quickly
tapered. Among 29 control patients from this study
who crossed over to receive 24 weeks of ECP for
refractory disease, objective responses occurred in
the skin and extracutaneous tissue in 33% and up to
70%, respectively.187
No national consensus exists on the duration and
discontinuation of ECP procedures. For acute GVHD,
ECP is recommended on 2 consecutive days (1 cycle)
per week until disease response and then tapered to
alternate weeks before discontinuation.1 Some centers
have recommended a minimum of 8 weeks.188 For
chronic GVHD, 1 weekly cycle (or consider biweekly
if treating mucocutaneous chronic GVHD alone) until
72 Cancer Control
either a response or for 8 to 12 weeks, followed by a
taper to every 2 to 4 weeks until maximal response.1
One author has proposed 2 to 3 procedures per week
depending on disease severity for 4 weeks or more.189
Clinical response should be assessed weekly in acute
GVHD and every 8 to 12 weeks in chronic GVHD;
ECP should be discontinued in cases of no or minimal
response. Some studies indicate that approximately
10% of patients with chronic GVHD given ECP may
benefit from treatment longer than 12 to 24 months.181
Clinical practice guidelines and consensus statements addressing the use of ECP for GVHD collectively consider ECP as an established second-line therapy
option for steroid-refractory chronic GVHD, particularly involving the skin.1,190-192 ECP has also been
recommended as an adjunctive first-line modality for
bronchiolitis obliterans syndrome and select pediatric
patients with acute GVHD.1,190-192 More recently, a UK
group has provided its consensus statement and guidance on the use of ECP in adult and pediatric patients
with acute GVHD.188 The proven effectiveness of ECP
in both acute and chronic GVHD cases is mirrored
in the ASFA guidelines, which recommend ECP for
chronic (category II; grade 1B recommendation) and
acute (category II; grade 2C recommendation) GVHD.1
Thrombocytapheresis
Thrombocytosis Associated With Myeloproliferative
Neoplasms
Thrombocytosis is defined as a peripheral blood
platelet count above 350,000 to 400,000/μL. Reactive thrombocytosis is the most common cause of an
elevated platelet count and can be caused by iron
deficiency, inflammatory conditions, infections, malignancy, acute bleeding, hemolysis, and asplenia.
Because the platelets in these conditions are functionally normal, the increased platelet count does not
normally predispose to thrombosis or acute bleeding. However, functionally abnormal platelets are
associated with the elevated platelet counts seen in
patients with myeloproliferative neoplasms (eg, essential thrombocythemia, polycythemia vera, chronic
myelogenous leukemia, primary myelofibrosis) and
refractory anemia with ringed sideroblasts associated
with marked thrombocytosis. Functionally abnormal
thrombocytosis is associated with an increased incidence of thrombohemorrhagic events.193,194 Accurate
diagnoses of thrombocytosis are important for both
prognostication and treatment.195
Diagnoses of essential thrombocythemia and
polycythemia vera are currently in accordance with
criteria from the World Health Organization and are
based on a composite assessment of clinical and laboratory (hematological, morphological, and molecular) features.196 When evaluating thrombocytosis, the
detection of the clonal mutation JAK2 V617F confirms
January 2015, Vol. 22, No. 1
the presence of an underlying myeloproliferative neoplasm. However, the absence of this mutation does
not rule out the possibility. Up to 50% of patients
with essential thrombocythemia might be JAK2 V617F
negative; however, finding a mutation in a newly described genetic marker, CALR, or, less commonly, MPL,
can identify the majority of cases that are JAK2 mutation negative.197
Current risk stratification in essential thrombocythemia and polycythemia vera is designed to estimate the likelihood of thrombotic complications.
High risk is defined by age older than 60 years or
history of the presence of thrombosis, whereas low
risk is defined by the absence of both of these 2 risk
factors.198-200 Extreme thrombocytosis (platelet count
> 1,000,000/μL) can be associated with acquired von
Willebrand syndrome and, thus, a risk for bleeding.201
Risk factors for shortened survival rates in both polycythemia vera and essential thrombocythemia include
advanced age, leukocytosis, and a history of thrombosis.198,199,202
Major thrombotic complications with essential
thrombocythemia and polycythemia vera include
stroke, transient ischemic attacks, myocardial infarction, peripheral arterial thrombosis, lower extremity
deep venous thrombosis, pulmonary embolism, and
venous thrombosis in unusual sites such as hepatic (Budd Chiari syndrome), portal, and mesenteric
veins.203 The risk of thrombosis in essential thrombocythemia and polycythemia vera exceeds 20% and
a substantial portion of patients experience microcirculation disturbances.204 The most frequent bleeding events are hemorrhages from the gastrointestinal
tract followed by hematuria and other mucocutaneous hemorrhages. Hemarthrosis and large muscle
hematomas are uncommon.203 Patients with essential thrombocythemia and low risk of thrombosis are
given low-dose aspirin if microvascular symptoms
are present but do not require cytoreductive therapy. High-risk patients are treated with cytoreductive
therapy, such as hydroxyurea, interferon α, or, less
commonly, anagrelide in conjunction with low-dose
aspirin.
Thrombocytapheresis has been used to treat acute
thromboembolism or hemorrhage in select patients
with essential thrombocythemia or polycythemia vera
associated with uncontrolled thrombocytosis.205-207 The
current ASFA guidelines are based on observational
case studies or case reports (category II; grade 2C
recommendation).1 Thrombocytapheresis should also
be electively considered for cytoreduction in patients
at increased risk of hemorrhage in whom hydroxyurea
is contraindicated, such as in cases of pregnancy,208-210
or if cytoreductive therapy with hydroxyurea is likely
to be too slow (eg, urgent surgery is required).211,212
Because the beneficial effect of platelet reduction is
January 2015, Vol. 22, No. 1
generally quite brief, repeat procedures are often necessary, and it is generally recommended that platelet-lowering agents be given whenever possible to prevent rapid reaccumulation of circulating platelets.205,206
Each thrombocytapheresis procedure (treating
1.5–2 blood volumes) lowers the platelet count by
about 30% to 60%. Pre- and post-platelet counts
should be closely monitored to gauge the effectiveness of platelet removal and to guide subsequent
treatments. The goal of thrombocytapheresis in acute
thromboembolism or hemorrhage is the normalization
of the platelet count and maintenance of a normal
platelet count until pharmacological cytoreductive
therapy takes effect. The goal for prophylaxis in highrisk patients who are pregnant or undergoing surgery
or postsplenectomy should be based on the patient’s
history of bleeding or thrombosis.
Erythrocytapheresis
Polycythemia Vera/Primary Erythrocytosis
Polycythemia vera is characterized by bone marrow
hypercellularity, atypical megakaryocyte hyperplasia,
leukocytosis, thrombocytosis, splenomegaly, and a
clinical predilection for thromboembolism, bleeding,
hyperviscosity complications, and the evolution to
myelofibrosis or AML. The JAK2 V617F mutation is
found in more than 90% of cases.213,214
In polycythemia vera, whole blood viscosity increases significantly as the hematocrit level exceeds
50%. Malaise, headache, visual disturbances, pruritus,
dizziness, confusion, slow mentation, and myalgia
are the most common symptoms. Similar to essential thrombocythemia, 15% to 40% of patients with
polycythemia vera may experience major arterial
cerebrovascular or cardiovascular thromboembolic
events, deep venous thrombosis, pulmonary embolism, or intra-abdominal venous thrombotic events.
Thrombotic risk factors with polycythemia vera include uncontrolled erythrocytosis (hematocrit > 55%),
age older than 60 years, history of prior thrombosis,
cardiovascular comorbidities, immobilization, pregnancy, and surgery.215
RBC depletion by manual phlebotomy or by
automated therapeutic erythrocytapheresis can correct hyperviscosity complications with uncontrolled
polycythemia vera by lowering the hematocrit level,
thereby reducing capillary shear and increasing microcirculatory blood flow and tissue perfusion. Classical
manual phlebotomy is a simple, safe, and low-cost
method. However, it can require a significant number
of procedures to reach target values.216-218 Adverse
events related to hypovolemia with manual phlebotomy occur in a substantial number of patients, and,
thus, this treatment modality may not be tolerated in
the elderly, those with small blood volumes, and those
with cardiovascular compromise. However, with autoCancer Control 73
mated therapeutic erythrocytapheresis, up to 800 mL
of RBCs per single procedure can be separated from
other blood components and concurrently exchanged
with a crystalloid or colloid solution, thus offering a
far more efficient method in removing RBCs while
maintaining isovolemic conditions.
In the past 2 decades, 1 randomized trial and a
number of small case series have described the advantages of automated therapeutic erythrocytapheresis
for the treatment of hereditary hemochromatosis and
erythrocytosis with improvements seen in treatment
efficiency, morbidity, and patient experience.219-223 For
patients with polycythemia vera and acute thromboembolism, severe microvascular complications, or
bleeding, automated therapeutic erythrocytapheresis
may be a useful alternative to emergent large-volume
phlebotomy, particularly if the patient is hemodynamically unstable. Automated therapeutic erythrocytapheresis can also be successfully utilized with
polycythemia vera complicated by thrombocytosis;
during the same session, the hematocrit level can be
lowered to 42% ± 45% and the platelets reduced to
500,000 to 600,000/μL.220,224 Therapeutic erythrocytapheresis may also be appropriate prior to surgery
to reduce the high risk of perioperative thrombotic
complications in a patient with polycythemia vera and
a hematocrit level of more than 55%.
A number of studies have been published supporting the use of therapeutic erythrocytapheresis
as maintenance therapy. One study of 76 patients
with polycythemia vera saw improvement in platelet
function, as measured by thromboelastography, after
therapeutic erythrocytapheresis, suggesting that the
hemodilution achieved with the procedure may reduce thrombotic risk.225 A retrospective cohort analysis
of 98 patients, including 6 with polycythemia vera
and 92 with secondary erythrocytosis, observed that
chronic automated therapeutic erythrocytapheresis
allowed significantly greater treatment intervals (median, 135–150 days; range, 2–7 months) to maintain
the target hematocrit level compared with chronic
phlebotomy (median, 40 days; range, 20–60 days).226
The advantage of therapeutic erythrocytapheresis may
be due to the relatively greater loss of iron that is
associated with this modality that, in turn, limits the
growth of hematopoietic cells.227
The ASFA guidelines designate polycythemia vera
as a category I indication (grade 1B recommendation)
for therapeutic erythrocytapheresis.1 Decisions to use
an automated procedure over simple phlebotomy remain based on clinical urgency, necessity, cost, and
consideration of the risk of adverse events that may
be associated with automated procedures. Although
the costs of a single therapeutic erythrocytapheresis
procedure are substantially higher than phlebotomy,
cost analysis has shown no significant difference in
74 Cancer Control
maintenance treatment costs as a result of the fewer
treatment procedures needed to reach recommended target values.221 One group developed a simple
and practical mathematical model for predicting the
efficiency of a single cycle of therapeutic erythrocytapheresis compared with a single phlebotomy procedure, which could in daily clinical practice aid in
optimizing therapeutic erythrocytapheresis use and
selecting a proper treatment modality for the individual patient.228 For example, the researchers determined
that therapeutic erythrocytapheresis would not be
optimal for patients with a small blood volume and/
or marginal achievable change in hematocrit level.228
For patients with polycythemia vera, the goal of
therapeutic erythrocytapheresis is rapid normalization
of hematocrit (ie, < 45%). A single procedure should
be designed to achieve the desired postprocedure
hematocrit level. Automated instruments allow the
operator to choose a postprocedure hematocrit level
and calculate the volume of blood removal necessary
to attain the goal. Saline boluses may be required
during the procedure to reduce blood viscosity in the
circuit and avoid pressure alarms.1
Conclusions
Therapeutic apheresis (TA) is an important treatment
option utilized in patients to manage specific complications associated with malignancy. TA has been used
as an emergent procedure, including as a therapeutic
plasma exchange to treat symptomatic hyperviscosity
or leukocytapheresis for the treatment of leukostasis.
TA can be effective as first-line therapy — as seen in
the use of extracorporeal photopheresis for erythrodermic cutaneous T-cell lymphoma — although often
TA is attempted as salvage or adjunct therapy for conditions not responding to conventional chemotherapy
or immunotherapy. Examples of such circumstances
include therapeutic plasma exchange for the removal
of antibodies associated with underlying paraneoplastic processes or the use of extracorporeal photopheresis for non–skin-associated graft-vs-host disease.
TA modalities are relatively safe procedures; however, they are not without risk. In order for these modalities to be performed, experienced staff members
are required. In all cases, the risks, benefits, and costs
must be strongly considered before prescribing. The
expert-based practice guidelines from the American
Society for Apheresis have been developed to inform
hematology/oncology professionals and apheresis
physicians about the efficacy and limitations of TA for
malignancy-related indications as well as to support
clinical decision-making. However, well-designed, prospective intervention trials are still needed to better
define the role of TA for a variety of disorders.
January 2015, Vol. 22, No. 1
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January 2015, Vol. 22, No. 1
HLA assays have a role in
pharmacogenomics, disease
association, platelet transfusion,
solid organ transplantation,
and HSCT.
Ray Paul. Currant, 2014. Acrylic, latex, enamel on canvas, 20" × 20".
Using HLA Typing to Support Patients With Cancer
Mark K. Fung, MD, PhD, and Kaaron Benson, MD
Background: The human leukocyte antigen (HLA) system plays a crucial role in immune function, and HLA testing
is often needed in the support of patients with cancer.
Methods: We briefly review the published literature to clarify the nomenclature of the HLA system, currently
available methods for HLA testing, and commonly used HLA assays. The uses of HLA testing in pharmacogenomics,
disease association, platelet transfusion support, and in the management of both solid organ and hematopoietic stem cell
transplantation are also reviewed.
Results: HLA testing is commonly performed for select patient populations, including patients with cancer and in
those requiring solid organ and hematopoietic stem cell transplantation.
Conclusion: Newer molecular typing methods have helped improve patient outcomes following hematopoietic stem
cell transplantation.
Introduction
The human leukocyte antigen (HLA) region encompasses a crucial set of genes that regulate immune
function. It is the most polymorphic region of the
human genome. HLA testing is often required in support of patients with cancer; for example, HLA testing
is used in both solid organ and hematopoietic stem
cell transplantation (HSCT), for selected pharmacogFrom the University of Vermont College of Medicine (MKF),
the Department of Pathology (MKF), Blood Bank and HLA Laboratory, University of Vermont Medical Center, Burlington, Vermont,
the H. Lee Moffitt Cancer Center & Research Institute (KB), and
the University of South Florida Morsani College of Medicine (KB),
Tampa, Florida.
Submitted October 7, 2014; accepted October 27, 2014.
Address correspondence to Mark K. Fung, MD, PhD, Department
of Pathology, Blood Bank and HLA Laboratory, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401.
E-mail: [email protected]
No significant relationships exist between the authors and
the companies/organizations whose products or services may be
referenced in this article.
January 2015, Vol. 22, No. 1
enomics testing for a personalized medical approach,
and in support of immune-platelet refractory patients.
The HLA nomenclature has been updated to address
new information gained with molecular assays. Both
serological and molecular HLA assays are available
and the use of these tests will be addressed.
Methods of Testing for HLA Antigens,
Antibodies, and Genes
A number of methods for determining HLA types were
developed over the years as different technologies
were discovered and used. Initially, the presence or
absence of certain HLA types and the specific HLA
type were determined with the use of antibodies via
serological methods, including the microcytotoxicity
method,1 whereby T or B lymphocytes from a patient
or donor are incubated in vitro with serum containing HLA antibodies of a certain specificity (reactive
against a particular HLA type), and, if the antigen is
present, an in vitro activation of complement would
occur, leading to detectable cell death in this assay.
Cancer Control 79
Thus, an HLA type for an individual would be determined with the use of an array of sera with different
HLA specificities on a plastic tray with multiple wells
within which the lymphocytes of an individual would
be added. The ability to identify different HLA types
by this method is limited to the availability of sera
containing the various HLA specificities. Therefore,
this method is less commonly used as an initial method for HLA typing due to these limitations. However, it does have value in confirming the presence
or absence of an antigen in rare instances in which
molecular-based methods predict a certain HLA type
but fail to recognize that the antigen is not produced
due to mutations present in a gene or promoter not
routinely tested. In addition, some laboratories continue to use this serological method for determining
the presence or absence of certain disease-associated
HLA types (eg, HLA-B27 for ankylosing spondylitis).
Advancement in the use of antibodies to determine
HLA type for a specific application has been seen in
the use of flow cytometry with fluorescent conjugates
added to anti-B27 to identify patients positive for
HLA-B27. Otherwise, serological or antibody-based
typing of HLA antigens is only used in applications
in which knowledge of the HLA type at a broader
serological grouping level (low-resolution HLA type)
is sufficient (eg, HLA typing of platelet donors, for
solid organ transplantation in certain countries where
this is still permitted). It is rare to use serological
HLA typing methods for patients receiving HSCT except perhaps for identifying HLA-matched siblings.
Therefore, health care professionals should routinely
confirm that the method used for patients receiving
HSCT is via a molecular method, and that the method
employed can generate sufficient specificity to identify the patient or donor HLA types to the allelic level
where appropriate.
The development of molecular methods for determining an individual’s HLA type was a significant
advancement in avoiding the past technical challenges
of needing serum with antibodies of all HLA types, including uncommon types present in only small groups
of individuals. Although the HLA genes are highly
polymorphic at multiple locations, the majority of
these DNA sequence variations are contained within exons 2 and 3. With current molecular methods,
once the specific nucleotide sequence polymorphisms
unique to a particular HLA type are characterized, the
necessary DNA probes or primers can be artificially
synthesized and readily incorporated into commercial
assay kits.
The number of molecular methods that currently exist can be grouped into 3 categories, ie, sequence-based typing (SBT), sequence-specific primer
(SSP) typing, and sequence-specific oligonucleotide
(SSO) typing. SBT can be performed via the tradi80 Cancer Control
tional Sanger nucleotide termination method or via
next-generation sequencing methods for which several platforms have been developed for HLA typing. In
general, SSP typing is performed through the use of
a heat-stable DNA polymerase to generate detectable,
specific DNA amplification products that can be produced and detected if HLA-type specific DNA primers properly bind to the individual’s template DNA.
SSO typing is accomplished through the ability to
detect more broadly generated, exon- and locus-specific DNA amplification products, but which are not
HLA type-specific, that bind to SSO probes. By contrast, SSP typing requires multiple wells of reactions
to determine the presence or absence of particular
DNA polymorphisms, whereas SSO typing allows for
the use of a single tube of locus-specific amplified
products that must then bind to a specific location on
a solid-phase surface or a uniquely identified bead
associated with the particular polymorphism. With
all 3 molecular methods, an HLA type is determined
based on the collection of polymorphisms identified.
With few exceptions, the majority of the molecular
HLA typing assays commercially available and in use
focus on identifying polymorphisms in exons 2 and 3
of the various HLA genes tested. As mentioned above
with serological HLA testing, rare polymorphisms may
exist outside of exons 2 and 3 that lead to lack of
expression or altered expression of the HLA molecule,
which is a specific limitation of the molecular method. Exon 4 testing may be added for HLA-A, HLA-B,
and/or HLA-C typing for recipients of HSCT and their
donors for more readily achievable high-resolution
typing results. Future and ongoing developments in
next-generation sequencing will eliminate these limitations when incorporating broader sequencing of
the entire coding and noncoding regions.
Nomenclature
The nomenclature of the HLA system has significantly
changed in recent years. Serological typing had to
account for older “parent” and newer “split” antigens
(eg, B12[44], B12[45]). Molecular methods required
significant nomenclature changes; the latest major update from 2011 involved the reorganization of alleles
so that they were properly aligned to allow similar
antigens to be within the same group. Refer to Fig 1
for an example of the new molecular fields and what
they represent.2
Molecular typing methods revealed that many
serologically defined antigens were actually created
by multiple alleles that could be individually defined.
Individual alleles linked to the same antigen may
behave differently and affect outcomes in areas like
HSCT. Novel alleles are constantly being identified
and the extensive polymorphism of the HLA system continues to be recognized. Applying the terms
January 2015, Vol. 22, No. 1
HLA-A*02:101:01:02N
HLA-A*
02:
Locus* Field: 1
101: 01: 02N
2
3 4
Fig 1. — Nomenclature details for one single HLA allele at high resolution.
HLA-A locus/gene, * separator: field 1/allele group (02): field 2/specific HLA
protein (101): field 3/synonymous DNA substitution within the coding region
(01): field 4/used to show differences in a noncoding region (02N). Oftentimes,
the first 2 fields alone are reported by laboratories performing HLA typing
because this information alone is clinically relevant (eg, HLA-A*02:101).
The suffix N is added to denote a null allele, an allele that is not expressed.
HLA = human leukocyte antigen.
Data from reference 2.
High-resolution molecular typing
HLA-B*08:01, 51:01
Intermediate-resolution molecular
typing
HLA-B*08:01/02, 51:01/02/03
Low-resolution molecular typing
HLA-B*08, 51
Serological typing
HLA-B8, 51
Fig 2. — Serological and molecular low-, intermediate-, and high-resolution
HLA typing results. The same HLA-B type is shown first by high-resolution
molecular typing followed by intermediate-resolution, low-resolution, and
serological typing. HLA = human leukocyte antigen.
sponses. For example, by prospectively HLA typing
patients with HIV-positive status to identify those with
HLA-B*57:01, a significant reduction was seen in the
risk of adverse events due to the strong association
of hypersensitivity with the use of abacavir in these
patients. In European populations, this allele is relatively common with a frequency of 6% to 7%.7 The
highest frequency of HLA-B*57:01 has been reported
in southwestern Asian populations in which up to
20% of the population are carriers.7 The US Food
and Drug Administration recommends prescreening
patients for B*57:01 prior to starting treatment with
this antiretroviral medication.8,9
Refer to Table 1 for selected examples of drug-related adverse events and the identified HLA alleles
associated with those events.10-13
Not all pharmacogenomics testing that held
promise has been realized. Prescreening of patients
before treatment with vitamin K antagonists such as
warfarin for single-nucleotide polymorphisms in the
genes VKORC1, CYP2C9, or both have not improved
outcomes.14,15 With the advent of next-generation
sequencing of the whole exome or genome,
further research is likely to identify critical and
non-HLA genes associated with both the beneficial
and detrimental responses to select medications.
low, intermediate, and high resolution helps explain
the specificity of a given HLA type; low resolution
is equivalent to serological typing results, and high
resolution provides the specific allele pairs for a given
locus. Intermediate resolution is the term for small
numbers of allele pairs and indicates some additional
testing beyond low resolution.
Low-resolution typing is at the level of the digits
comprising the first field in the DNA-based nomenclature and generally corresponds to the serological
typing result (see Fig 1).2 An example is A*01; A*02,
which would be A1, A2 by serology.
Intermediate-resolution typing results include a
subset of alleles sharing the digits in the first field of
their allele name and for which some alleles sharing
those digits are excluded. Examples include A*02:01
or A*02:02 or A*02:07 or A*02:20 but not other A*02
alleles and may be written as A*02:01/02/07/20.
High-resolution typing is defined as a DNA-based
typing result that includes a set of alleles that specifies and encodes the same protein sequence for the
peptide-binding region of an HLA molecule and also
excludes alleles not expressed as cell-surface proteins
Disease Associations
(Fig 2).3,4
Given the role of the immune system in many disThe letter G is a code that signifies a group of aleases, it is not surprising that certain polymorleles in which all have identical nucleotide sequences
phisms in the HLA system, with specific HLA types,
across the exons that encode for the peptide-binding
are associated with an increased risk for disease
region of the HLA molecule and includes
exons 2 and 3 for class I and exon 2
Table 1. — Examples of Important Adverse Events and Their HLA Associations
alone for HLA class II alleles. For exDrug
HLA Allele
HLA Frequency
Adverse Event
Study
ample, HLA-B*27:05G represents alleles
Abacavir
B*57:01
6%–8% Caucasian
Drug
Shear10
B*27:05 and B*27:13 and these 2 alleles
hypersensitivity
2.5% African American
have the same clinical relevance.5,6
Allopurinol
B*58:01
9%–11% Han Chinese
1%–6% Caucasian
Drug
hypersensitivity
Hung11
Carbamazepine
B*15:02
10%–15% Han Chinese
< 0.1% Caucasian
Stevens–Johnson
syndrome/toxic
epidermal necrolysis
Chung12
Flucloxacillin
B*57:01
6%–8% Caucasian
Drug-induced
liver injury
Daly13
Pharmacogenomics
Pharmacogenomics refers to specific
genes in a given individual associated
with particular responses, both beneficial and detrimental, to medications and
other therapies. The HLA genes are well
recognized as influencing select drug reJanuary 2015, Vol. 22, No. 1
HLA = human leukocyte antigen.
Cancer Control 81
(Table 2). Despite these associations, the mechanism of the association with certain HLA types remains under investigation; the HLA type is one of
multiple risk factors. The presence of a disease-associated HLA type alone is not sufficient to trigger
disease. For example, HLA-B27 is commonly present in
patients with ankylosing spondylitis, but many individuals who have HLA-B27 are without disease
because HLA-B27 is a relatively common antigen
and ankylosing spondylitis is an uncommon disease.
Therefore, the health care professional should keep
this in mind when obtaining and reviewing HLA typing results of a patient with cancer.
Associations with HLA types for certain lymphoid
malignancies have also been studied, including certain
HLA types to chronic lymphocytic leukemia, multiple
myeloma, acute lymphoblastic leukemia, and diffuse
large B-cell lymphoma.16 In fact, the earliest association with HLA type and disease was with HLA-B types
and Hodgkin disease.17 Findings have been more limited of associations of certain HLA types with solid
Table 2. — HLA Alleles and Associated Diseases
Disease
HLA Allele
Ankylosing spondylitis
B*27:XX alleles
(except B*27:06 and B*27:09)
Antiglomerular basement
membrane disease
DRB1*15:01
DRB1*15:02
Birdshot retinochoroidopathy
A*29:01
A*29:02
Celiac disease
DQA1*05/DQB1*02
DQA1*03/DQB1*03:02
Idiopathic myopathy
DQA1*04:01
DQA1*05:01
Narcolepsy
DQB1*06:02
Pemphigus vulgaris
DRB1*04:02
DRB1*04:03
DRB1*04:06
DRB1*08:02
DRB1*08:04
DRB1*14:04
DRB1*14:05
DRB1*14:08
Psoriasis
C*06:XX
Reiter syndrome
B*40:01
Type 1 diabetes mellitus
DRB1*03:01/02/11
Multiple alleles
of DRB1*04:XX, including:
DRB1*04:01/02/03/04/05/
06/07/08/09/10/11/17/26
DQA1*03:01
DQB1*02:01
DQB1*03:02
HLA = human leukocyte antigen.
82 Cancer Control
organ malignancies and include an increased risk of
progression to hepatocellular carcinoma in patients
with chronic hepatitis B18 and long-term survival rates
among patients with gastric cancer.19 Despite the associations of HLA type with certain malignancies, HLA
typing of patients with cancer is not routinely performed because these associations are relatively weak
to date. However, HLA typing is routinely performed
for patients and their potential donors when HSCT
is considered.
Platelet Support
A poor response to platelet transfusion (ie, platelet
transfusion refractoriness) can be due to nonimmune
causes, immune causes, or both. Immune refractoriness is most often the result of HLA antibodies (either single or multiple specificities) and, much less
commonly, antibodies directed against human platelet-specific antigens (HPAs). The risk of HLA alloimmunization can be significantly reduced with the
use of leukoreduced red blood cells and platelets.20
Despite wide adoption of the leukoreduction of red
blood cell and platelet components for patients with
cancer, HLA alloimmunization remains a challenge.
Parous women have been previously exposed to fetal
HLA epitopes that may have elicited prior alloimmunization; the risk is greater with an increasing number
of pregnancies.21 Men and nulliparous women may
also have been HLA alloimmunized due to a prior
blood transfusion that was either nonleukoreduced or
was truly leukoreduced (leukoreduction is not 100%
protective).
Patients with poor responses to platelet transfusion at 10 minutes or 1 hour following transfusion
should be investigated for possible immune causes
for refractoriness.22 By using the correct count increment, one can calculate that the average-sized person
receiving an average dose of platelets should increase
his or her platelet count about 15,000/µL above the
baseline platelet result at 1 hour following the transfusion if the precount was performed in close proximity
to the transfusion.23
Qualitative screening assays are available to detect antiplatelet antibodies with HLA specificity, HPA
specificity, or both. These specificities can also be
identified when antigen-negative platelet transfusions
are being considered (eg, HLA-A2-negative platelets
for a patient with anti-HLA-A2 antibodies). The management of thrombocytopenia with HLA alloimmunization is covered in the article by Dr Fletcher and
others in this issue. Care of these patients can often
be quite difficult and preventive strategies are crucial.
Hematopoietic Stem Cell Transplantation
The outcomes of both related and unrelated donor
HSCT are impacted by the extent of HLA matching
January 2015, Vol. 22, No. 1
between the transplantation recipient and the donor.
Several large studies have demonstrated that a greater
degree of HLA match between donor and recipient
improves overall survival rates,24 reduces both the
incidence and severity of acute and chronic graft-vshost disease (GVHD)25 and improves rates of engraftment.26,27 When a suitable, related HLA-matched donor
is unavailable, unrelated donor registries, such as the
Be the Match Registry run by the National Marrow
Donor Program, can often identify a perfect or wellmatched unrelated donor. The recipient’s racial and
ethnic group will affect the likelihood of finding a
high-resolution HLA-A, HLA-B, HLA-C, and HLA-DRB1
match, although whites of European descent have
the highest probability (75%) and blacks of South or
Central American descent have the lowest (16%).28
When these large, unrelated donor registries also fail
to identify a matched unrelated donor, alternative donors such as mismatched adult unrelated donors, haploidentical-related donors, and umbilical cord blood
(UCB) stem cell products are often used.29
The widespread use of DNA-based tissue typing
methodologies has increased the accuracy and specificity of HLA typing, thus allowing for more precise
HLA matching between recipients and donors. For
most HSCT, a minimum of 4 HLA loci (HLA-A, HLA-B,
HLA-C, HLA-DRB1) and, more often, 5 (HLA-A, HLA-B,
HLA-C, HLA-DRB1, HLA-DQB1) are generally matched
between recipient and donor pairs. Volunteer unrelated adult donors are selected to be closely matched to
recipients at HLA-A, HLA-B, HLA-C, and HLA-DRB1
at the allele level when related HLA-matched donors
are not available.30 High-level donor–recipient HLA
matching is crucial for the success of unrelated adult
donor HSCT.31,32 Additional loci considered by some
HSCT programs include DPB1 and KIR.
Although close HLA matching is crucial, it is not
always possible and some mismatches fare better than
others. Pidala et al33 identified certain amino acid
substitutions that affected the peptide-binding site
of the HLA class I antigen and increased the risk of
severe acute GVHD and mortality. Some mismatches
appear to have little to no increased risk.34 These “permissible” HLA mismatches have been perhaps most
studied in the Japanese population.35,36 In Japan, fewer
HLA haplotypes gives greater opportunity for studying
isolated mismatches between recipient–donor pairs.
The only potential curative measure for many
patients with hematological malignancies is HSCT;
however, about 70% of patients will not have an HLAmatched sibling donor considering the number of
children per family in the United States and the likelihood of HLA identity being 25% with any 1 sibling.37
Therefore, the majority of recipients must turn to the
unrelated volunteer donor pool. The National Marrow
Donor Program has more than 20 million HLA-typed
January 2015, Vol. 22, No. 1
donors in its database and affiliated registries.38 Many
patients, particularly those of diverse racial and ethnic backgrounds, will not have a suitable matched,
unrelated donor identified in the time period needed.
UCB has helped to fill that gap for these patients,
and more than 30,000 UCB transplants have been
performed to date.39
UCB units are typically selected using low-resolution HLA typing (antigen level) for HLA-A and -B and
high resolution (allele level) for HLA-DRB1. HLA-C
matching was not generally considered in the past,40
but further study has shown that HLA-C matching
with UCB may minimize mortality risks.41 While the
degree of matching for UCB transplantation is not as
extensive as it is for non-UCB sources, greater degrees
of matching (eg, high resolution for HLA-A, HLA-B,
HLA-C, and HLA-DRB1 vs low resolution for HLA-A
and HLA-B) may also improve neutrophil recovery
and reduce nonrelapse mortality rates when single
cord blood units are transplanted.42
In general, for non-UCB HSCT, any single locus
mismatch is associated with worse outcomes in overall
survival, treatment-related mortality, and acute GVHD
(ie, 9/10 worse than 10/10 match) with the exception
of a mismatch at the DQB1 locus. There is no statistical difference if a single-locus mismatch occurs at the
antigen or allele level, except perhaps for HLA-C with
antigen mismatch worse than allele-level mismatch.30,43
Because the HLA-A, HLA-B, HLA-C, HLA-DRB1,
and HLA-DQB1 loci influence the success of HSCT,
investigators have also looked at the DPB1 locus to
determine its impact. Early studies suggested that
DPB1 matching does not impact overall survival rates,
a fact that appeared fortunate because tight DPB1
linkage with other loci are lacking and would create difficulty in finding a DPB1 match.44 About 20%
of 10/10 matched unrelated donor transplantations
will be matched for DPB1.44 More recent work in
grouping DPB1 mismatches based on T-cell epitopes
has distinguished mismatches that might be tolerated
(permissive) from those with increased risks (nonpermissive). Retrospective analyses in both 9/10 and
10/10-matched transplantations have shown that nonpermissive DPB1 mismatches were associated with a
significantly increased risk of overall mortality, nonrelapse mortality, and severe acute GVHD than permissive mismatches.45
HLA alloantibodies directed against mismatched
antigens are well established as a significant risk
factor in solid organ transplantation (particularly for
the kidney, heart, and pancreas); therefore, prescreening is required and frequently repeated. Increased
risk of graft failure in HLA mismatched pairs with
positive cytotoxicity crossmatch tests (39%) compared
with those with negative compatible tests (10%) was
reported by Anasetti et al.46
Cancer Control 83
Approximately 35% of patients receiving unrelated HSCT possess HLA antibodies, and the presence of
donor-specific HLA antibodies (DSAs) against HLA-A,
HLA-B, and/or DRB1 specificities, as determined by
solid-phase immunoassay testing, is associated with
graft failure.47 Therefore, HLA antibody evaluation in
the recipient should be part of the routine workup
for mismatched HSCTs.48 Both the National Marrow
Donor Program and the Center for International Blood
and Marrow Transplant Registry recommend the evaluation of HLA-DSAs in both adult and cord blood HLA
mismatched HSCTs.24
The concept of considering noninherited maternal antigens (NIMAs) when selecting particular mismatched donors is an interesting one. Humans are
exposed to NIMA HLA antigens in utero and the immature fetus appears to develop less reactivity to these
non–self-antigens compared with non-NIMA alloantigens. Some treatment-related mortality associated
with HLA-mismatched UCB HSCT may be alleviated
with the use of NIMA-matched vs mismatched donor
units and has been associated with improved rates of
overall survival (Fig 3).44,49,50
The ability to provide NIMA-matched donors
may prove difficult as the relative frequency of these
donors may be low and searching may delay transplantation. In the Rocha et al49 and van Rood et al50
studies cited above, 7% to 10% of transplantations
were NIMA matched.
Natural killer cells have killer cell, immunoglobulin-like receptors (KIRs) on their surface that allow
them to recognize HLA class I and, primarily, HLA-C
surface molecules; they then can distinguish “self”
from “non-self” and ultimately provide a benefit with
such feats as destruction of virally infected cells or
HLA-A
HLA-B
HLA-DRB1
NIMA Match
Recipient
A*02, 24
B*18, 35
DRB1*01:01, 11:04
UCB unit/donor
A*02, 32
B*18, 35
DRB1*01:01, 11:04
UCB donor mother
A*24, 32
B*07, 35
DRB1*01:01, 13:01
NIMA Mismatch
Recipient
A*02, 11
B*18, 35
DRB1*01:01, 11:04
UCB unit/donor
A*02, 32
B*18, 35
DRB1*01:01, 11:04
UCB donor mother
A*24, 32
B*07, 35
DRB1*01:01, 13:01
Fig 3. — Examples of NIMA-matched and mismatched UCB donors. HLA-A*24
is not carried by the UCB donor but is carried by the mother of the UCB donor
and the recipient; thus, this represents a NIMA-matched UCB HSCT. HLA-A*11
is not carried by the UCB donor or the mother of the UCB donor; thus, this
represents a NIMA-mismatched UCB HSCT.
HLA = human leukocyte antigen, HSCT = hematopoietic stem cell transplantation,
NIMA = noninherited maternal antigen, UCB = umbilical cord blood.
Adapted from ​van Rood JJ, Stevens CE, Smits J, et al. Reexposure of cord blood
to noninherited maternal HLA antigens improves transplant outcome in hematological malignancies. Proc Natl Acad Sci U S A. 2009;106(47):19952-19957.
Republished with permission by Washington, DC: National Academy of Sciences.
84 Cancer Control
cancer cells.51 All HLA-C alleles can be classified as
either HLA C group 1 (C1) or group 2 (C2) and the
KIR haplotypes are either grouped as A or B depending on which genes are present. Different pairings of
the HLA and KIR molecules elicit either inhibitory or
activating signals.52 Although early studies showed
KIR mismatching could provide a survival advantage
in acute myeloid leukemia, subsequent studies have
had varied conclusions. Use of KIR data for donor
selection should be considered within the framework
of a clinical trial alone.53
The best approach to using HLA typing results
when searching for an unrelated HSCT donor includes
the following:
• Look for a 7/8 or optimal 8/8 HLA-A, HLA-B,
HLA-C, or DRB1 allele-matched donor.
• Consider DQB1 allele-matched donors when
multiple 7/8 or 8/8 matches are present for a
preferred 9/10 or 10/10 HLA-A, HLA-B, HLA-C,
DRB1, and DQB1 match.
• Consider UCB HSCT when no 7/8 or 8/8
matches are identified.
• Identify UCB units that are a minimum of
4/6 HLA-A, HLA-B, and DRB1 match with
adequate cell dose.
• A NIMA-matched donor may benefit the
recipient and could be sought if there are
multiple, similarly mismatched unrelated donor
or UCB units and the HSCT is not delayed.
• HLA antibody screening/matching should be
performed when mismatched donors are
considered.
The National Marrow Donor Program recommends
that high-resolution HLA typing be performed at the time
of diagnosis for all adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic
syndromes with an intermediate or high International
Prognostic Scoring System, some with chronic myeloid
leukemia, such as when an inadequate hematological
or cytogenetic response occurs after a trial of tyrosine
kinase inhibitors, and in certain chronic lymphocytic
leukemia cases with, for example, high-risk cytogenetic
or molecular features (eg, del[11q] or del[17p], ZAP70 or
Cor CD38 positiv­ity, unmutated immunoglobulin variable region heavy chain mutational status, short initial
remission, resistant to fludarabine).54
The use of blood relatives as blood donors
prior to stem cell infusion should be avoided because
sensitization of the patient to donor minor histocompatibility antigens can increase the risk of allograft
rejection.55
Solid Organ Transplantation
Unlike stem cell transplantation, HLA matching is
not initially required for solid organ transplantation
(heart, liver, lung, kidney, pancreas, or bowel) if the
January 2015, Vol. 22, No. 1
patient is not alloimmunized; rather, identifying and
confirming ABO compatibility to avoid hyperacute rejection is more important. The use of HLA matching is
associated with potentially improved allograft survival
and reduced alloimmunization rates that might otherwise limit the availability of HLA-compatible organs.
Furthermore, the preference for HLA matching does
not require complete matching of all loci unless the
patient is broadly alloimmunized against the majority of non-self HLA types. Typically, low-resolution
HLA typing alone is required. No benefit has been
identified with the use of allele-level or high-resolution typing in solid organ transplantations except in
instances in which a patient might have allele-specific antibodies. In patients who are waiting for an
available cadaveric allograft, those who are highly
sensitized (> 90% of panel donors are reactive) will
be eligible to receive an HLA-matched kidney from
outside of their region.
Whenever organ dysfunction is present in a patient
with a history of solid organ transplantation (heart,
liver, lung, kidney, pancreas, or bowel), an assessment
of the possibility of allograft rejection should be considered. Allograft biopsy and testing for HLA antibody
production would help assess for cellular and humoral
allograft rejections, respectively. An examination of
the biopsied tissue includes looking for evidence of
lymphocytic infiltrates and thickening or fibrosis of
vessel walls. Staining for the complement component
C4d is used in kidney biopsies to look for evidence
of humoral rejection. Testing for the presence of HLA
antibodies against donor-mismatched antigens may be
an initial noninvasive approach to identifying humoral
graft rejection in patients with cancer and solid organ
allografts. However, the absence of detectable DSAs
does not exclude the possibility of humoral rejection
because the allograft may adsorb most of the antibodies before any excess antibodies are detectable in the
serum or plasma (termed silent alloimmunization).
Furthermore, previously transplanted solid organ donor-mismatched HLA types should be avoided whenever possible in the selection of stem cell donors for
subsequent stem cell transplantation due to the risk
of prior alloimmunization and the increased risk of
stem cell engraftment failure if a donor is chosen who
expresses the same mismatched HLA type.
In the instance of known humoral rejection,
monitoring levels or titers of the DSA is commonly
performed when detecting antibodies using a single-antigen bead flow cytometry method (eg, Luminex
[Life Technologies, Carlsbad, California]) in addition to
measuring fluorescence intensity. However, variation
in the fluorescence intensity detected might be sufficiently high so that identification of an increasing or
decreasing trend in antibody reactivity might require
the use of normalization techniques or the use of
January 2015, Vol. 22, No. 1
paired testing of a prior and current sample concurrently to minimize run-to-run variation and identify
a true change in the level of reactivity.
Conclusions
Polymorphisms in the human leukocyte antigen (HLA)
system influence the immune system in ways not yet
completely understood, but associations are known
to increase risk among patients with certain diseases
and hypersensitivity to certain drugs. Knowledge of
HLA type and whether alloimmunization has occurred
may inform treatment and transfusion support plans.
Numerous methods for HLA typing exist that include
a single, multiple, or all clinically relevant HLA loci.
In addition, these different methods may generate
different degrees of detail regarding the HLA type depending on the specific treatment needed. HLA matching can be defined with different levels of stringency
for different loci, thus balancing the increasing time
needed to find the “perfect” allograft donor match
and the risk of further disease progression/relapse
prior to additional treatment with allogeneic stem
cell transplantation versus less-stringent matching and
an increased risk of allograft failure or life-threatening graft-vs-host disease. HLA antibody production
through allosensitization may lead to more difficult,
but not necessarily impossible, platelet transfusion
support. However, HLA antibodies can also increase
the risk of allograft failure for both stem cell and organ transplantations if patient antibodies are directed
against donor HLA types. Therefore, it is critical for
health care professionals to understand what HLA
information (antigen typing, allele typing, or antibody
testing) is needed for patient care and what impacts
or risks are associated with that HLA type.
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18. Jin YJ, Shim JH, Chung YH, et al. Relationship of HLA-DRB1 alleles
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21. Triulzi DJ, Kleinman S, Kakaiya RM, et al. The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications
for a transfusion-related acute lung injury risk reduction strategy. Transfusion.
2009;49(9):1825-1835.
22. O’Connell B, Lee EJ, Schiffer CA. The value of 10-minute posttransfusion platelet counts. Transfusion. 1988;28(1):66-67.
23. Davis KB, Slichter SJ, Corash L. Corrected count increment and percent
platelet recovery as measures of posttransfusion platelet response: problems
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24. Spellman SR, Eapen M, Logan BR, et al; National Marrow Donor
Program; Center for International Blood and Marrow Transplant Research.
A perspective on the selection of unrelated donors and cord blood units for
transplantation. Blood. 2012;120(2):259-265.
25. Petersdorf EW. Risk assessment in haematopoietic stem cell transplantation: histocompatibility. Best Pract Res Clin Haematol. 2007;20(2):155-170.
26. Petersdorf EW, Hansen JA, Martin PJ, et al. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation.
N Engl J Med. 2001;345(25):1794-1800.
27. Crocchiolo R, Ciceri F, Fleischhauer K, et al. HLA matching affects clinical outcome of adult patients undergoing haematopoietic SCT from unrelated
donors: a study from the Gruppo Italiano Trapianto di Midollo Osseo and Italian
Bone Marrow Donor Registry. Bone Marrow Transplant. 2009;44(9):571-577.
28. Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339-348.
29. Kekre N, Antin JH. Hematopoietic stem cell transplantation donor sources in the 21st century: choosing the ideal donor when a perfect match does
not exist. Blood. 2014;124(3):334-343.
30. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient
HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110(13):4576-4583.
31. Flomenberg N, Baxter-Lowe LA, Confer D, et al. Impact of HLA class
I and class II high-resolution matching on outcomes of unrelated donor bone
marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood. 2004;104(7):1923-1930.
32. Petersdorf EW, Anasetti C, Martin PJ, et al. Limits of HLA mismatching
in unrelated hematopoietic cell transplantation. Blood. 2004;104(9):2976-2980.
33. Pidala J, Wang T, Haagenson M, et al. Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute
GVHD and mortality. Blood. 2013;122(22):3651-3658.
34. Fernandez-Viña MA, Wang T, Lee SJ, et al. Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation. Blood.
2014;123(8):1270-1278.
35. Harkensee C, Oka A, Onizuka M, et al. Single nucleotide polymorphisms and outcome risk in unrelated mismatched hematopoietic stem cell
transplantation: an exploration study. Blood. 2012;119(26):6365-6372.
36. Morishima S, Ogawa S, Matsubara A, et al; Japan Marrow Donor Program. Impact of highly conserved HLA haplotype on acute graft-versus-host
disease. Blood. 2010;115(23):4664-4670.
37. McCullough J, Perkins HA, Hansen J. The National Marrow Donor
Program with emphasis on the early years. Transfusion. 2006;46(7):1248-1255.
38. Appelbaum FR. Pursuing the goal of a donor for everyone in need. N
Engl J Med. 2012;367(16):1555-1556.
39. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122(4):491-498.
40. Barker JN, Byam C, Scaradavou A. How I treat: the selection and
acquisition of unrelated cord blood grafts. Blood. 2011;117(8):2332-2339.
41. Eapen M, Klein JP, Sanz GF, et al; Eurocord-European Group for Blood
and Marrow Transplantation; Netcord; Center for International Blood and Mar86 Cancer Control
row Transplant Research. Effect of donor-recipient HLA matching at HLA A,
B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for
leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet
Oncol. 2011;12(13):1214-1221.
42. Eapen M, Klein JP, Ruggeri A, et al; Center for International Blood and
Marrow Transplant Research, Netcord, Eurocord, and the European Group
for Blood and Marrow Transplantation. Impact of allele-level HLA matching on
outcomes after myeloablative single unit umbilical cord blood transplantation
for hematologic malignancy. Blood. 2014;123(1):133-140.
43. Woolfrey A, Klein JP, Haagenson M, et al. HLA-C antigen mismatch is
associated with worse outcome in unrelated donor peripheral blood stem cell
transplantation. Biol Blood Marrow Transplant. 2011;17(6):885-892.
44. Zino E, Frumento G, Marktel S, et al. A T-cell epitope encoded by
a subset of HLA-DPB1 alleles determines nonpermissive mismatches for
hematologic stem cell transplantation. Blood. 2004;103(4):1417-1424.
45. Fleischhauer K, Shaw BE, Gooley T, et al; International Histocompatibility Working Group in Hematopoietic Cell Transplantation. Effect of T-cell-epitope
matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell
transplantation: a retrospective study. Lancet Oncol. 2012;13(4):366-374.
46. Anasetti C, Amos D, Beatty PG, et al. Effect of HLA compatibility on
engraftment of bone marrow transplants in patients with leukemia or lymphoma.
N Engl J Med. 1989;320(4):197-204.
47. Yoshihara S, Taniguchi K, Ogawa H, et al. The role of HLA antibodies in
allogeneic SCT: is the ‘type-and-screen’ strategy necessary not only for blood
type but also for HLA? Bone Marrow Transplant. 2012;47(12):1499-1506.
48. Spellman S, Bray R, Rosen-Bronson S, et al. The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell
transplantation is predictive of graft failure. Blood. 2010;115(13):2704-2708.
49. Rocha V, Spellman S, Zhang MJ, et al; Eurocord-European Blood and
Marrow Transplant Group and the Center for International Blood and Marrow
Transplant Research. Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood
transplantation for hematologic malignancy. Biol Blood Marrow Transplant.
2012;18(12):1890-1896.
50. van Rood JJ, Stevens CE, Smits J, et al. Reexposure of cord blood to
noninherited maternal HLA antigens improves transplant outcome in hematological malignancies. Proc Natl Acad Sci U S A. 2009;106(47):19952-19957.
51. Kärre K. Immunology. A perfect mismatch. Science. 2002;295(5562):
2029-2031.
52. Parham P. MHC class I molecules and KIRs in human history, health
and survival. Nat Rev Immunol. 2005;5(3):201-214.
53. Miller JS, Blazar BR. Control of acute myeloid leukemia relapse--dance
between KIRs and HLA. N Engl J Med. 2012;367(9):866-868.
54. National Marrow Donor Program. HLA typing and matching. https://
bethematchclinical.org/transplant-therapy-and-donor-matching/hla-typing-andmatching. Accessed October 30, 2014.
55. Gajewski JL, Johnson VV, Sandler SG, et al. A review of transfusion
practice before, during, and after hematopoietic progenitor cell transplantation.
Blood. 2008;112(8):3036-3047.
January 2015, Vol. 22, No. 1
Special Report
Mobilization and Transplantation Patterns of Autologous
Hematopoietic Stem Cells in Multiple Myeloma and
Non-Hodgkin Lymphoma
Luciano J. Costa, MD, PhD, Shaji Kumar, MD, Stephanie A. Stowell, MPhil, and Shari J. Dermer, PhD
Background: The mobilization of hematopoietic stem cells can be a limiting factor for transplantation, yet
little is known about how the availability of novel mobilizing agents has affected the practices of oncologists
and transplant specialists.
Methods: US-based oncologists (n = 48) and transplant specialists (n = 46) were separately surveyed with a
partial overlap of assessed information.
Results: More transplant specialists than oncologists believed that the time between referral and first
consultation is adequate (89.1% vs 54.2%; P < .001). The presence of comorbidities was the most common
reason for patients not being referred for transplantation. Among oncologists, 31.3% avoided cyclophosphamide
and 16.7% avoided lenalidomide to prevent mobilization impairment in patients with multiple myeloma (MM).
Chemotherapy mobilization for MM was used by 23.9% of transplant specialists due to higher CD34+ yields
and by 21.7% due to its anti-MM effect. In non-Hodgkin lymphoma (NHL), 26.1% of transplant specialists used
chemotherapy mobilization due to higher CD34+ yields, and 26.1% collected hematopoietic stem cells on the
rebound prior to chemotherapy. With regard to plerixafor use in MM, 36.9% of transplant specialists reported
that they did not use it, and 28.3% said they reserved it for second mobilization. In NHL, 4.3% of transplant
specialists reported not using plerixafor, and 39.1% reserved it for second mobilization.
Conclusions: Educational needs were identified to promote adequate referral for transplantation as well as
successful and cost-effective methods for the mobilization of hematopoietic stem cells.
Introduction
Autologous hematopoietic stem cell transplantation
From the Department of Medicine (LJC), Medical University
of South Carolina, Charleston, South Carolina, the Division
ofHematology (SK), Mayo Clinic, Rochester, Minnesota, and
Med-IQ (SAS, SJD), Baltimore, Maryland.
Dr Costa is now affiliated with the University of Alabama at
Birmingham.
Submitted July 22, 2014; accepted September 3, 2014.
Address correspondence to Luciano J. Costa, MD, PhD, Department
of Medicine and UAB-CCC, Bone Marrow Transplantation and
Cell Therapy Program, University of Alabama at Birmingham,
North Pavilion - NP 2554, 1802 6th Avenue South, Birmingham,
AL 35294. E-mail: [email protected]
Dr Costa has received consulting fees from sanofi-aventis and
Onyx Pharmaceuticals. Dr Kumar has received consulting fees
from Merck and has performed contracted research on behalf
of the Mayo Clinic for Celgene Corporation, Cephalon, Genzyme,
and Novartis. Ms Stowell’s spouse has conducted clinical research
for Allergan, F. Hoffmann-La Roche, and Novo Nordisk and has
received consulting fees from Bristol-Myers Squibb. Dr Dermer has
nothing to disclose.
This project was funded by an unrestricted educational grant
provided by sanofi-aventis to Med-IQ. Sanofi-aventis was not
involved in the elaboration of the survey, analysis of results,
or writing of the manuscript.
The authors thank Catherine Bretz Mullaney for grant oversight,
Alyson Siclaire for project management, Robert Geist and Hollie
Devine for assistance with survey development, Mary Catherine
Downes and Kenny Khoo for outcomes management, Suzanne
Jenkins for IT support, and Lisa Rinehart for editorial assistance.
January 2015, Vol. 22, No. 1
(HSCT) is an increasingly important treatment option for several hematological malignancies, including
multiple myeloma (MM) and non-Hodgkin lymphoma
(NHL).1-5 The increasing use of autologous HSCT in
individuals older than 65 years is partly due to the
accumulation of data on the safety and efficacy of
autologous HSCT for this age group.6,7 Furthermore,
the emergence of novel mobilization agents has reduced the risk of mobilization failure, potentially extending the use of autologous HSCT to even more
patients.8,9
The mobilization of hematopoietic stem cells fails
in approximately 20% of patients with MM and up to
40% of patients with NHL.9,10 Poor mobilization can
lead to poor engraftment, increased morbidity, greater
resource utilization, and increased costs.10,11 The cause
of poor mobilization can be partially explained by
clinical variables (ie, age, underlying disease, prior
therapies, underlying marrow function) and cannot
be predicted.12 To ensure optimal mobilization, factors
such as mobilization strategy, timing of hematopoietic
stem cell collection, and identification of risk factors
for poor mobilization must be considered; such factors
have been summarized in published guidelines.13,14
Early communication between the primary oncologist and the transplant specialist is key to the critical
timing of patient referral to a transplantation center.15
Cancer Control 87
Inconsistencies in practice approaches to hematopoietic stem cell mobilization and collection exist
among health care professionals.16,17 To further understand perceptions and practices from the points of
views of both oncologists and transplant specialists, a
national survey was conducted. An accredited medical
education company (Med-IQ, Baltimore, Maryland)
collaborated with academic-based faculty to identify perceptions and practices affecting hematopoietic
stem cell mobilization and transplantation as well as
to identify barriers to successful transplantation in
MM and NHL.
Methods
Two separate electronic survey tools assessed oncologist and transplant specialist perceptions and current
practices related to autologous hematopoietic stem
cell mobilization and transplantation. Eligible health
care professionals were US-based, English-speaking physicians or nurse practitioners specializing in oncology or hematology. A random sample
of 16,707 health care professionals meeting the
inclusion criteria was e-mailed or faxed an invitation to complete the online surveys. Eligible participants expressing interest were provided a link to the
Web-based surveys and asked to self-identify as either
an oncologist (defined as one who did not perform
autologous HSCT for patients with MM, lymphoma, or
both) or a transplant specialist (defined as one who
did). A total of 132 health care professionals responded to the invitation and, after self-identification, were
directed to the appropriate survey. All participants
were required to complete a consent form prior to
beginning the survey. Those who completed both the
consent form and a survey received a $50 honorarium
as compensation for their time.
The oncologist survey consisted of 17 multiple-choice
questions; 4 questions required estimates of average
number of patients and 1 question was open ended.
The transplant specialist survey was composed of 21
multiple-choice questions and 1 open-ended question.
Ten questions were common between the 2 surveys.
The study protocol, including surveys, was submitted to an independent institutional review board
(Chesapeake Review, Columbia, Maryland) and
deemed exempt from oversight. For each survey, responses were anonymously pooled and data were
downloaded from the online survey program and
saved in an unidentified format.
We described continuous numerical variables on
the basis of median and interquartile range (IQR)
and, where appropriate, categorical variables in terms
of percentage with a 95% confidence interval (CI).
Comparisons between proportions were performed
using a chi-square test. All statistical analyses were
88 Cancer Control
performed utilizing SPSS (IBM, Armonk, New York).
In all inference analyses, 2-sided P values less than
.05 were considered statistically significant.
Survey Completion
Forty-eight oncologists completed the survey
(44 physicians and 4 nurse practitioners). The majority
(n = 38) practiced in a nonacademic setting. The median number of new MM cases seen by oncologists each
month was 2 (IQR, 1.37–4), and the median number of
new NHL cases was 3.5 (IQR, 2–6). Oncologists managed a median of 20 patients with MM (IQR, 10–40)
and 40 patients with NHL (IQR, 22.25–67) in their
practices at the time they completed the survey.
Overall, 46 transplant specialists completed the
survey (44 physicians and 2 nurse practitioners). Eleven (23.9%) practiced in an academic setting and were
fully dedicated to HSCT. Twenty-eight practiced in an
academic setting dedicated to HSCT and also managed hematological malignancies. Seven transplant
specialists were in nonacademic practices. The volume
of HSCT procedures performed each year (including
autologous and allogeneic) was self-reported to be
less than 25 by 8.7% of transplant specialists, 25 to
49 by 4.3%, 50 to 99 by 41.3%, 100 to 200 by 17.4%,
and more than 200 by 6.1%.
Transplantation Referral
We examined the possibility of delays in the referral
process from the oncologist to the transplant specialist. Overall, oncologists perceived the process to
be lengthier than transplant specialists (Fig 1), with
80.5% of transplant specialists stating that it took less
than 2 weeks from referral to first encounter with a
candidate for transplantation, whereas 39.6% of oncologists stated that patients referred to transplantation were typically seen within 2 weeks of referral
(P < .001). The majority of oncologists (54.2%) believed
the time between referral and first appointment was
adequate (95% CI: 40.3–67.4), whereas 41.7% believed
it was long but thought that the wait time had no
detrimental effect on patient care (95% CI: 28.8–55.7).
A total of 4.2% of oncologists believed that the time
from referral to transplantation was too long and affected patient care (95% CI: 1.1–14.0). A higher proportion of transplant specialists (89.1% vs 54.2% of oncologists) believed that the time between referral and
first appointment was adequate (95% CI: 76.9–95.2 vs
95% CI: 40.3–67.4, respectively; P < .001).
Referral Patterns
Multiple Myeloma
When asked what percentage of their patients with
MM younger than 65 years of age consulted with
a transplant specialist in the first 6 months following diagnosis, 6.25% of oncologists indicated fewer
January 2015, Vol. 22, No. 1
surance coverage (95% CI: 1.2–14.0),
4.2% cited lack of response to salvage therapy (95% CI: 1.2–14.0), and
70
27.1% cited none of the survey-sug60
gested reasons (95% CI: 16.6–41.0).
39.6
Similarity existed between the
33.3
50
opinions of oncologists and transplant specialists on when patients
40
19.6
with diffuse large B-cell lymphoma,
14.6
30
mantle cell lymphoma, and follicu13.0
lar lymphoma should be referred to
6.5
20
6.3
6.3
autologous HSCT (Fig 3). More trans0.0
plant specialists than oncologists
10
believed that patients with diffuse
0
large B-cell lymphoma and high>8
>8
<1
1–2 3–4
5–8
<1
1–2
3–4
5–8
risk disease should be evaluated for
Week Weeks Weeks Weeks Weeks
Week Weeks Weeks Weeks Weeks
transplantation during initial therapy
Transplant Clinicians
Oncology Clinicians
(P = not significant), and a larger
proportion of transplant specialists
Fig 1. — Perceptions of transplant specialists and oncologists on the time between referral and first
believed
that all patients with mantle
appointment with a transplant physician.
cell lymphoma should be considered
than 5% (95% CI: 2.1–16.8), 25% indicated 6% to 20%
for autologous HSCT while still undergoing first-line
(95% CI: 14.9–38.8), 39.6% indicated 21% to 50% (95%
therapy (P = .02).
CI: 27.0–53.7), 16.7% indicated 51% to 80% (95%
CI: 8.7–29.6), and 12.5% indicated more than 80%
Prior Therapy and Mobilization
(95% CI: 5.8–24.7). In regard to the reasons patients
Because they were aware that some MM drugs influwith MM younger than 65 years of age would not be
ence the efficacy of mobilization, 4.2% of oncologists
referred for consultation with a transplant specialavoided the use of bortezomib in patients who might
ist, 50% of oncologists cited comorbidities (95% CI:
be eligible for transplantation (95% CI: 1.1–14.0),
36.9–63.6), 31.2% cited patient preference (95% CI:
31.3% avoided cyclophosphamide (95% CI: 19.9–45.3),
19.9–45.3%), 6.3% cited lack of insurance coverage
16.7% avoided lenalidomide (95% CI: 8.7–29.6), 8.3%
(95% CI: 2.1–16.8), and 12.5% cited none of the above
avoided liposomal doxorubicin (95% CI: 3.3–19.5),
reasons (95% CI: 5.9–2.5). Among the
oncologists, 18.7% considered the
role of autologous HSCT in MM to
80
62.5
58.7
be in front-line therapy alone (95%
70
CI: 10.2–31.9), 66.7% felt that autologous HSCT should be employed in
60
both front-line and relapsed settings
32.6
(95% CI: 52.5–78.3), and 14.6% be50
lieved it should be used in relapsed
40
20.8
MM alone (95% CI: 7.3–27.2). Yet,
little difference was seen between
30
10.4
opinions of when patients with MM
6.5
6.3
20
should be referred for transplantation consult (Fig 2).
0.0
10
60.9
Percent
Percent
80
Non-Hodgkin Lymphoma
When asked to identify reasons why
patients younger than 65 years of age
with relapsed diffuse large B-cell lymphoma would not have a transplantation consult, 41.7% of oncologists cited comorbidities (95% CI: 28.8–55.7),
16% cited patient preference (95%
CI: 8.7–29.6), 4.2% cited lack of inJanuary 2015, Vol. 22, No. 1
0
A
i
td
ag
no
si
On
s
in
iti
t
al
On
he
ly
py
ra
hi
gh
s
-ri
k
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nt
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re
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se
Transplant Clinicians
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i
td
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si
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s
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ly
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-ri
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s
Up
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l
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ap
se
Oncology Clinicians
Fig 2. — Opinions of transplant specialists and oncologists for which patients with multiple myeloma
should be referred for a transplant evaluation.
Cancer Control 89
80
A
Fig 3A–C. — Opinion of transplant specialists and oncologists for which patients with
(A) diffuse large B-cell lymphoma, (B) mantle
cell lymphoma, and (C) follicular lymphoma
should be referred for transplantation evaluation. AHSCT = autologous hematopoietic stem
cell transplantation, CR = complete response,
PR = partial response.
60.4
54.3
70
60
Percent
50
40
23.9
18.8
17.4
30
12.5
20
4.3
4.2
4.2
10
0
ne rapy rapy rapy
ne rapy rapy rapy one
t li
t li
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e
e
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e
e
firs e th e th e th
firs e th e th e th
g
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g
g
g
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g
g
n
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uri salva salva salva
uri salva salva salva
d
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re
isk
isk
On After
On After
h r Befo
h r Befo
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Hig
80
B
58.7
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60
39.6
33.3
Percent
50
23.9
40
22.9
15.2
30
20
4.2
2.2
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y
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rap
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on
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d/r
d/r
se
se
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/re
Hig lapse Relap
Hig lapse Relap
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C
30.4
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33.3
28.3
23.9
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22.9 22.9
35
18.8
Percent
30
13.0
25
20
15
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2.1
10
5
0
a
a
e
e
R
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rs
rs
se
se
R/C 2 yea ny tim relap SCT phom PR/C 2 yea ny tim relap SCT phom
t
tP
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a
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m
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s
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d
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r
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e
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Transplant Clinicians
90 Cancer Control
Oncology Clinicians
and 2.1% avoided thalidomide (95%
CI: 0.4–10.9). A total of 54.2% of
oncologists did not avoid any specific MM drug for this reason (95%
CI: 40.3–67.4). When asked how
the known impairment of lenalidomide on mobilization should be
managed, similarity was seen between opinions: 4.2% of oncologists
and 2.2% of transplant specialists
believed that lenalidomide should
not be used in induction therapy
for MM, and 35.4% of oncologists
and 28.3% of transplant specialists
believed that lenalidomide could
be used for induction, but patients
would require chemomobilization
to obtain an adequate number of
CD34+ cells. The majority of responders (56.2% of oncologists and
63.0% of transplant specialists) believed that lenalidomide could be
used, but hematopoietic stem cell
mobilization and collection should
occur after no more than 4 cycles of
therapy. A small minority — 4.2% of
oncologists and 6.5% of transplant
specialists — answered that lenalidomide could be used for induction,
but hematopoietic stem cell mobilization would be possible with the
use of plerixafor alone. When oncologists were asked how the known
effect of lenalidomide on mobilization affected their choice to use
lenalidomide in patients with MM
eligible for transplantation, 4.2% indicated that they did not use lenalidomide (95% CI: 1.1–14.0), 77.1%
indicated that they used this agent
but referred patients to transplantation before 4 completed cycles of
therapy (95%
CI: 63.5–86.7), and 18.8% used
this agent without a specific cycle
limit and were confident that the
transplantation team could collect
hematopoietic stem cells regardless
of prior lenalidomide use (95% CI:
January 2015, Vol. 22, No. 1
A
80
70
58.3
60
41.3
50
Percent
10.2–31.9).
Similarly, because treatment for
NHL can also influence the success of
hematopoietic stem cell mobilization,
18.8% of oncologists avoided using
bendamustine in patients eligible for
transplantation (95% CI: 10.2–31.9),
4.2% avoided bortezomib (95% CI:
1.1–14.0), 60.4% avoided fludarabine
(95% CI: 46.3–73.0), 16.7% avoided
the hyperfractionated regimen of
cyclophosphamide/vincristine/doxorubicin/dexamethasone (95% CI:
8.7–29.6), and 50.0% avoided radio
immunotherapy (95% CI: 36.9–63.6).
A total of 18.7% of oncologists did
not avoid the use of any specific
treatment in NHL for this reason
(95% CI: 10.2–31.9).
35.4
28.3
40
19.6
30
20
8.7
10
4.2
2.2
2.1
0.0
0
<5
%
%
%
%
0%
–10
–20
–30
>3
5% 11% 21%
<5
%
%
%
%
0%
–10
–20
–30
>3
5% 11% 21%
80
B
70
Mobilization Practices
52.1
60
Percent
We explored how decisions regarding hematopoietic stem cell
50
mobilization were made at differ31.3
32.6
ent centers. Two decision-making
40
28.3
26.1
processes were equally common:
30
(1) the transplantation center had
12.5
a uniform method of mobilization
20
accepted and followed by all prac8.7
4.3
titioners, and (2) a mobilization
10
2.1 2.1
0.0
strategy was chosen based on strat0
ification for perceived risk of mobi%
% N /A
%
%
%
%
%
%
%
%
< 5 %–10 –20 –30 > 30
< 5 %–10 –20 –30 > 30
lization failure (34.8% of respond5
5
11% 21%
11% 21%
ers for both; 95% CI: 22.7–49.2).
Other frequently reported processTransplant Clinicians
Oncology Clinicians
es were that each individual physician at his or her site chose the Fig 4A–B. — Perceived risk of mobilization failure for (A) multiple myeloma and (B) non-Hodgkin
mobilization method for his or her lymphoma.
patients or that his or her center
followed an algorithm to stratify patients to differtransplant specialists mentioned that their preferred
ent strategies of mobilization based on peripheral
method of hematopoietic stem cell mobilization for
blood CD34+ enumeration (15.2% of responders for
patients with MM was growth factor and planned or
both; 95% CI: 7.5–28.3).
“just-in-time” plerixafor, followed by high-dose cycloA notable discrepancy existed between oncolophosphamide and growth factor (26.1%) or growth
gists and transplant specialists in terms of their perfactor alone (17.4%). For patients with NHL, 47.8% of
ceived risk of inadequate mobilization in both MM and
transplant specialists utilized growth factor following
NHL (Fig 4). Although 83.4% of oncologists believed
the last cycle of disease-appropriate chemotherapy as
that the risk of mobilization failure in NHL was less
a mobilization strategy, 34.8% utilized growth factor
than 10%, 50.9% of the transplant specialists thought
with or without planned or “just-in-time” plerixafor.
the same (P = .02). Similarly, the risk of mobilization
Growth factor following high-dose cyclophosphamide
failure in MM was considered to be less than 5% by
was the preferred method of hematopoietic stem cell
58.3% of oncologists, whereas 41.3% of the transplant
mobilization in patients with NHL for 10.9% of transspecialist assessed this risk in the same way (P = .09).
plant specialists.
The preferred method of hematopoietic stem
In regard to the use of chemotherapy mobilicell mobilization among transplant specialists varied
zation in MM, 54.3% of transplant specialists indiaccording to underlying disease. Overall, 47.8% of
cated that they did not use it because it is more
January 2015, Vol. 22, No. 1
Cancer Control 91
toxic than other modalities and not necessary (95%
CI: 40.2–67.8). By contrast, 23.9% indicated that they
utilized chemomobilization primarily because of the
higher CD34+ yields, and 21.7% indicated that they
used chemomobilization because they believed the
additional dose of chemotherapy would help the patient with better disease control. When asked when
they utilized plerixafor for hematopoietic stem cell
mobilization, 36.9% of transplant specialists indicated
that they never used it because the drug is expensive
or unnecessary (95% CI: 24.5–51.4), 28.3% indicated
that they used it following mobilization failure (95%
CI: 17.3–42.6), 39.1% indicated that they used it in
patients with MM at risk of mobilization failure (95%
CI: 26.4–53.5), and 17.4% indicated that they used it
“just in time” for patients with a low number of CD34+
cells in peripheral blood following the use of a growth
factor (95% CI: 9.1–30.7).
For the use of chemomobilization in NHL, 39.1%
of transplant specialists indicated that they did not
use this modality (95% CI: 26.4–53.6), 26.1% used
chemomobilization due to higher CD34+ yield (95%
CI: 15.6–40.3), and 26.1% indicated that they used
chemomobilization because the patient was already
receiving chemotherapy for the management of NHL
(95% CI: 26.4–53.6). A total of 8.7% indicated a preference for chemomobilization (95% CI: 3.4–20.3), citing
the belief that the extra chemotherapy could help
consolidate remission and prevent post-transplantation relapse. In regard to hematopoietic stem cell
mobilization in NHL, 4.3% of the transplant specialists
reported that they did not use plerixafor because it
was expensive and unnecessary (95% CI: 1.2–14.5),
17.4% used plerixafor in all mobilizations (95%
CI: 9.1–30.7), 26.1% used this agent in patients at
risk of mobilization failure (95% CI: 15.6–40.3), 36.9%
used a “just-in-time” approach with administration for
patients with low CD34+ in the peripheral blood (95%
CI: 24.5–51.4), and 39.1% used plerixafor following
first mobilization failures (95% CI: 26.4–53.6).
Discussion
Surveys provide a fast and relatively inexpensive approach to gather information. However, a caveat of
selection bias can be present such that the small proportion of responding health care professionals has
dissimilar characteristics and opinions from all other
practicing oncologists and transplant specialists. It is
difficult to assess the representativeness of this sample
because no detailed characterizations of these groups
are available, particularly with regard to transplant
specialists as discussed in a recent assessment of the
transplant specialist workforce.18 Nevertheless, it appears that the survey captured the opinions of oncologists with intense activity in MM and NHL, as reflected
in the high number of patients reported; in addition,
92 Cancer Control
the transplant specialist group represented different
practice types and volumes of patients treated.
We identified that a high proportion of patients
with MM younger than 65 years of age was not referred for transplantation consultation early in the
course of disease, despite the fact that most oncologists supported a role for early HSCT in MM. This is
in synchrony with data showing the increasing but
low utilization of autologous HSCT among younger
patients with MM.6
In terms of NHL, an overlap was seen in the opinion of oncologists and transplant specialists on the
appropriate time for referral, although more transplant
specialists believed that patients with mantle cell lymphoma should be referred for autologous HSCT while
undergoing primary therapy. Even though oncologists
and transplant specialists agreed on when patients
should be referred for transplantation, a large number
of oncologists perceived the referral process to be
lengthy. This perception was not shared by a large
majority of transplant specialists, who indicated that
time from oncologist referral until first encounter with
a transplant specialist may be a barrier and transplant
centers may want to re-examine their processes to
ensure that access is prompt and effective.
Among oncologists, comorbidities were cited
as the most frequent reason patients younger than
65 years of age with a clinical indication for autologous HSCT would not be referred. Even though some
of these patients may have obvious contraindications
(eg, end-stage heart failure, liver failure, dementia),
we found it concerning that autologous HSCT may
be ruled out as a therapeutic option without the recommended assessment of a transplant specialist.15
Transplant eligibility based on age, comorbidities, and
underlying disease are best evaluated by a transplant
specialist. Even though the age of 65 years is frequently cited as a limit for autologous HSCT, the safety and
efficacy of this treatment in older individuals has been
demonstrated.19,20 Similarly, common comorbidities
may be compatible with autologous HSCT, including
chronic kidney disease, stable coronary artery disease, controlled cardiac arrhythmias, hypertension,
diabetes, and prior treated malignancies. Therefore,
oncologists should be encouraged to refer patients
for evaluation by a transplant specialist in accordance
with accepted guidelines.15
Nearly one-third of oncologists avoided cyclophosphamide-containing regimens in patients with
MM because they believed the drug would impair
mobilization despite evidence suggesting otherwise.21,22 This proportion was even higher than the
proportion of oncologists who avoided lenalidomide,
a drug shown to impair mobilization.23,24 More than
one-half of health care professionals from both specialties acknowledged that lenalidomide can be used
January 2015, Vol. 22, No. 1
in induction as long as patients proceed with early hematopoietic stem cell mobilization. However,
1 in 3 oncologists and 1 in 4 transplant specialists
believed that patients who received lenalidomide
induction should be mobilized with chemotherapy
despite data that demonstrate these patients can be
effectively mobilized with growth factor or growth
factor plus plerixafor, particularly when referred early for mobilization.25,26 In regard to NHL, oncologists
seemed concerned about the use of fludarabine and
radioimmunotherapy in patients who are candidates
for transplantation.
Several important observations were made in regard to mobilization practices. Oncologists perceived
mobilization failure to be a less frequent problem than
transplant specialists. This lack of awareness may be
a contributing factor for late referral for autologous
hematopoietic stem cell collection. In approximately
one-third of the cases, we found that transplantation
programs have a standard mobilization strategy; in
another one-third of cases, mobilization strategy is
chosen based on perceived risk of inadequate mobilization. A minority of transplant specialists adapted
mobilization strategies based on the CD34+ enumeration, a practice that can lead to resource rationalization and a high rate of mobilization.27-29
Transplant specialists indicated more frequent use
of chemomobilization in NHL, partly because such
patients are already receiving disease-specific chemotherapy and mobilization can often be performed
during recovery from the previous cycle of chemotherapy. In MM, most transplant specialists who indicated a preference for chemomobilization believed that
its use would offer better long-term disease control,
which is an unconfirmed hypothesis.30,31
A large proportion of transplant specialists indicated that they do not use plerixafor mobilization due
to its high cost or reserve its use for a second attempt
in patients who have failed initial mobilization. However, some studies suggest that, although plerixafor is
costly, its judicious use based on individualized risk
of poor mobilization avoids the expense of remobilization and medical care for the complications of
chemotherapy mobilization, thereby neutralizing the
cost difference and potentially allowing more patients
to proceed to transplantation.27,32,33
Conclusions
This survey suggests that several areas are in need of
improvement. Oncologists may benefit from additional education on the importance of referring potential
candidates for autologous hematopoietic stem cell
transplantation early on as well as the implication
of their therapy choices on the collection of hematopoietic stem cells. Because hematopoietic stem cell
mobilization methods remain diverse, more education
January 2015, Vol. 22, No. 1
and broader discussions involving transplant specialists may improve patient outcomes. In addition, more
prospective trials and clinical data are needed to further delineate mobilization practices. Oncologists and
transplant specialists should be encouraged to work
together to streamline processes that promote easy
and fast access for referred patients.
References
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standards and emerging strategies in mantle cell lymphoma [Erratum appears
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2. Oliansky DM, Gordon LI, King J, et al. The role of cytotoxic therapy with
hematopoietic stem cell transplantation in the treatment of follicular lymphoma:
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3. Child JA, Morgan GJ, Davies FE, et al; Medical Resesarch Council
Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic
stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875-1883.
4. Attal M, Harousseau JL, Stoppa AM, et al; Intergroupe Francais du Myelome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335(2):91-97.
5. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow
transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333(23):15401545.
6. Costa LJ, Zhang MJ, Zhong X, et al. Trends in utilization and outcomes
of autologous transplantation as early therapy for multiple myeloma. Biol Blood
Marrow Transplant. 2013;19(11):1615-1624.
7. McCarthy PL Jr, Hahn T, Hassebroek A, et al. Trends in use of and
survival after autologous hematopoietic cell transplantation in North America,
1995-2005: significant improvement in survival for lymphoma and myeloma
during a period of increasing recipient age. Biol Blood Marrow Transplant.
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8. Gertz MA. Current status of stem cell mobilization. Br J Haematol.
2010;150(6):647-662.
9. DiPersio JF, Micallef IN, Stiff PJ, et al. Phase III prospective randomized
double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor
for autologous stem-cell mobilization and transplantation for patients with
non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27(28):4767-4773.
10. Pusic I, Jiang SY, Landua S, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous
transplantation. Biol Blood Marrow Transplant. 2008;14(9):1045-1056.
11. Gertz MA, Wolf RC, Micallef IN, Gastineau DA. Clinical impact and
resource utilization after stem cell mobilization failure in patients with multiple
myeloma and lymphoma. Bone Marrow Transplant. 2010;45(9):1396-1403.
12. Costa LJ, Nista EJ, Buadi FK, et al. Prediction of poor mobilization of
autologous CD34+ cells with growth factor in multiple myeloma patients: implications for risk-stratification. Biol Blood Marrow Transplant. 2014;20(2):222228.
13. Duong HK, Savani BN, Copelan E, et al. Peripheral blood progenitor cell
mobilization for autologous and allogeneic hematopoietic cell transplantation:
guidelines from the American Society for Blood and Marrow Transplantation.
Biol Blood Marrow Transplant. 2014;20(9):1262-1273.
14. Giralt S, Costa L, Schriber J, et al. Optimizing autologous stem cell
mobilization strategies to improve patient outcomes: consensus guidelines
and recommendations. Biol Blood Marrow Transplant. 2014;20(3):295-308.
15. National Morrow Donor Program. Recommended timing for transplant
consultation. https://bethematchclinical.org/WorkArea/DownloadAsset.aspx?id=3545. Accessed October 8, 2014.
16. Lee SJ, Joffe S, Artz AS, et al. Individual physician practice variation
in hematopoietic cell transplantation. J Clin Oncol. 2008;26(13):2162-2170.
17. Bevans M, Tierney DK, Bruch C, et al. Hematopoietic stem cell
transplantation nursing: a practice variation study. Oncol Nurs Forum.
2009;36(6):E317-E325.
18. Gajewski JL, LeMaistre CF, Silver SM, et al. Impending challenges in
the hematopoietic stem cell transplantation physician workforce. Biol Blood
Marrow Transplant. 2009;15(12):1493-1501.
19. Sharma M, Zhang MJ, Zhong X, et al. Older patients with myeloma
derive similar benefit from autologous transplantation. Biol Blood Marrow
Transplant. 2014. Epub ahead of print.
20. Buadi FK, Micallef IN, Ansell SM, et al. Autologous hematopoietic stem
cell transplantation for older patients with relapsed non-Hodgkin’s lymphoma.
Bone Marrow Transplant. 2006;37(11):1017-1022.
21. Mikhael JR, Reeder CB, Libby EN III, et al. Results from the phase
II dose expansion of cyclophosphamide, carfilzomib, thalidomide and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma.
Blood. 2012:120(21):445.
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22. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib
and dexamethasone induction for newly diagnosed multiple myeloma: high
response rates in a phase II clinical trial. Leukemia. 2009;23(7):1337-1341.
23. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem
cell transplantation in patients with newly diagnosed myeloma. Leukemia.
2007;21(9):2035-2042.
24. Paripati H, Stewart AK, Cabou S, et al. Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma. Leukemia.
2008;22(6):1282-1284.
25. Costa LJ, Abbas J, Hogan KR, et al. Growth factor plus preemptive
(‘just-in-time’) plerixafor successfully mobilizes hematopoietic stem cells in
multiple myeloma patients despite prior lenalidomide exposure. Bone Marrow
Transplant. 2012;47(11):1403-1408.
26. Sinha S, Gertz MA, Lacy MQ, et al. Majority of patients receiving initial
therapy with lenalidomide-based regimens can be successfully mobilized with
appropriate mobilization strategies. Leukemia. 2012;26(5):1119-1122.
27. Micallef IN, Sinha S, Gastineau DA, et al. Cost-effectiveness analysis
of a risk-adapted algorithm of plerixafor use for autologous peripheral blood
stem cell mobilization. Biol Blood Marrow Transplant. 2013;19(1):87-93.
28. Costa LJ, Alexander ET, Hogan KR, et al. Development and validation
of a decision-making algorithm to guide the use of plerixafor for autologous
hematopoietic stem cell mobilization. Bone Marrow Transplant. 2011;46(1):6469.
29. Li J, Hamilton E, Vaughn L, et al. Effectiveness and cost analysis of
“just-in-time” salvage plerixafor administration in autologous transplant patients
with poor stem cell mobilization kinetics. Transfusion. 2011;51(10):2175-2182.
30. Gertz MA, Kumar SK, Lacy MQ, et al. Comparison of high-dose CY
and growth factor with growth factor alone for mobilization of stem cells for
transplantation in patients with multiple myeloma. Bone Marrow Transplant.
2009;43(8):619-625.
31. Dingli D, Nowakowski GS, Dispenzieri A, et al. Cyclophosphamide
mobilization does not improve outcome in patients receiving stem cell transplantation for multiple myeloma. Clin Lymphoma Myeloma. 2006;6(5):384-388.
32. Costa LJ, Miller AN, Alexander ET, et al. Growth factor and patient-adapted use of plerixafor is superior to CY and growth factor for autologous hematopoietic stem cells mobilization. Bone Marrow Transplant.
2011;46(4):523-528.
33. Shaughnessy P, Islas-Ohlmayer M, Murphy J, et al. Cost and clinical
analysis of autologous hematopoietic stem cell mobilization with G-CSF and
plerixafor compared to G-CSF and cyclophosphamide. Biol Blood Marrow
Transplant. 2011;17(5):729-736.
94 Cancer Control
January 2015, Vol. 22, No. 1
Special Report
Functional Health Literacy, Chemotherapy Decisions,
and Outcomes Among a Colorectal Cancer Cohort
Evan L. Busch, MPH, Christopher Martin, MSPH, Darren A. DeWalt, MD, and Robert S. Sandler, MD
Background: Functional health literacy is essential for the self-management of chronic diseases and preventive
health behaviors. Patients with cancer who have a low level of health literacy may be at greater risk for poor
care and poor outcomes.
Methods: We assessed health literacy using the Short Test of Functional Health Literacy in Adults in 347 participants
with colorectal cancer who were nested within a prospective observational study of system, health care provider,
and participant characteristics influencing cancer outcomes.
Results: Having adequate health literacy increased the likelihood that participants with stage 3/4 disease
received chemotherapy (odds ratio, 3.29; 95% confidence interval, 1.23–8.80) but had no effect on cancer
stage at diagnosis or vital status at last observation during postenrollment follow-up. No difference was seen
in health literacy status regarding participant beliefs and preferences about chemotherapy among those with
stage 3/4 disease, nor in participant roles in deciding whether to receive chemotherapy.
Conclusions: Patients with lower levels of health literacy were less likely to receive chemotherapy compared
with participants with higher levels of health literacy. Therefore, clear communication related to key health
care decisions may lead to fewer disparities due to a patient’s level of health literacy.
Introduction
Functional health literacy, including the ability to read
and understand medication labels, educational materials, hospital directional signs, and appointment slips,
is essential for the self-management of chronic diseases and preventive health behaviors.1 However, individuals with the greatest health care needs may have
the least ability to read and comprehend information
needed to successfully function as patients.1,2 Inadequate
health literacy could decrease the likelihood that
these individuals at high risk will have beneficial
health outcomes.
Having inadequate or marginal functional health
literacy places patients at increased risk for medication nonadherence, hospital admission, poor
health status, and worse clinical outcomes than their
counterparts with higher levels of health literacy.1,3-5
From the Departments of Epidemiology (ELB) and Medicine
(CM, DAD, RSS), University of North Carolina, Chapel Hill, North
Carolina.
Submitted July 2, 2014; accepted August 18, 2014.
Address correspondence to Robert S. Sandler, MD, Department of
Medicine, University of North Carolina at Chapel Hill, 4157 Bioinformatics Building, Campus Box 7555, Chapel Hill, NC 27599-7555.
E-mail: [email protected]
No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced
in this article.
This work was supported in part by grants from the National
Institutes of Health (P30 DK034987, U01 CA93326).
January 2015, Vol. 22, No. 1
A lower level of health literacy has also been associated with lower patient information seeking.6 Patients
with poor reading ability may have issues accessing
the health care system, understanding recommended
treatments, and following the instructions of health
care professionals. The American Medical Association
has recognized that limited patient literacy impedes
diagnosis and treatment, so it has adopted policies
to increase the recognition of — and effect change
in — functional health literacy.1
In particular, health literacy levels may influence
cancer outcomes. New patients may receive large
amounts of unfamiliar technical information about
their diagnosis. Oftentimes, health care professionals
invite patients to participate in choosing among complicated treatment options. Adhering to chosen treatments can be a Byzantine process of understanding
and complying with surgery, radiation therapy, multiple and varying chemotherapy regimes, and follow-up
visits involving several health care professionals.
To evaluate the role of health literacy in decisions
related to cancer treatment and to estimate the impact
of health literacy on patient outcomes, we assessed
health literacy in a set of patients with colorectal
cancer (CRC) enrolled in a cohort study of health
care processes. CRC has one of the largest disease
burdens of any form of cancer, with approximately
140,000 new cases and 50,000 deaths in 2014 in the
United States,7 making it a good test case of the effects
of health literacy on cancer outcomes. We hypotheCancer Control 95
sized that greater levels of health literacy would be
associated with early-stage disease, increased patient
participation in treatment decisions, receipt of more
appropriate treatment, and improved rates of survival.
Methods
Study Population
Participants were enrolled in the Cancer Care Outcomes Research and Surveillance Consortium
(CanCORS), a prospective, population-based, multisite
observational study of participants with lung and colon cancers that has been previously described.8 The
population was diverse with respect to race, socioeconomic status, and geography. The purpose of the
study was to assess the impact of system, care provider, and patient factors on cancer outcomes. Participants were at least 21 years of age at the time of
CRC diagnosis and were enrolled within 3 months of
diagnosis during 2003 to 2006. The study collected
participant surveys, surrogate surveys for participants
who were deceased or too ill to participate, and medical records data.
Abstractors at each site collected information on
tumor characteristics and cancer treatments received.
Participant and, when necessary, surrogate surveys
were completed using computer-assisted telephone
interviews. Surveys included items about demographic and socioeconomic factors (age, insurance
coverage, income), communication with health care
professionals, and beliefs and preferences regarding
cancer treatments. The surveys have been previously
described.9
CanCORS included patients with colorectal and
lung cancers who were enrolled by 7 groups of investigators.8 North Carolina recruited 990 patients with
CRC, and it was the only site to administer health
literacy assessments.
The study population was a random sample of
347 participants from the North Carolina–based CanCORS study. The sample was stratified by self-reported
years of education with oversampling of lower strata
to achieve similar-sized strata of adequate vs inadequate or marginal health literacy, ultimately with the
goal of enhancing power for planned analyses. We
used the following sampling fractions for the respective ranges of years of education: 0 to 8 years (100%),
9 to 11 years (100%), 12 years (70%), and more than
12 years (40%).
The sample included all cancer stages. The Institutional Review Board at the University of North
Carolina at Chapel Hill approved the protocol. All
participants provided informed consent.
Measure of Health Literacy
Functional health literacy was assessed using the
Short Test of Functional Health Literacy in Adults
96 Cancer Control
(S-TOFHLA).10,11 A trained interviewer visited participant homes to administer the assessment in person.
The assessment tested reading comprehension using
36 questions in response to 2 prose passages.
Across the entire sample, 4 different interviewers
were used, but 1 interviewer alone administered the
assessment for any given participant. All interviewers
were trained in how to administer the S-TOFHLA.
The interviewer read a scripted introduction and instructions to the participant, and then remained silent
while the participant completed the questionnaire.
Participants were given up to 7 minutes to complete
the questionnaire, but they were not told beforehand
that the assessment would be timed.
S c o r e s we r e c a t e g o r i z e d a s i n a d e q u a t e
(0–16 correct), marginal (17–22 correct), or adequate
(23–36 correct). For analysis, we combined marginal
and inadequate scores into 1 category.
Chemotherapy Decisions
As part of the surveys, participants in CanCORS answered questions about whether they received adjuvant chemotherapy, how the chemotherapy decision
was made, and their beliefs and preferences regarding chemotherapy. Chemotherapy is generally recommended for patients with colon cancer diagnosed with
stage 3 or 4 disease.12 We examined responses about
chemotherapy decisions among participants with CRC
in whom health literacy was assessed and who were
diagnosed with either stage 3 or 4 disease. Survey responses of “Do not know,” “Declined to answer,” “Not
applicable,” or were missing were considered noninformative. Noninformative responses were excluded
when conducting Fisher exact tests to compare survey
responses by level of health literacy.
Outcomes
CanCORS tumors were staged according to the TNM
classification system. We considered stage 1/2 to be
early-stage disease and stage 3/4 to be late-stage
disease.
Participants were followed for survival after baseline data collection. Vital status for all participants
was verified using the Social Security Death Index
on May 4, 2010, providing at least 42 months of follow-up observation time for each person. We defined
participant survival as dichotomous vital status (alive
or dead) at last observation.
Statistical Analysis
Among participants in the literacy sample with any
stage of cancer (N = 347), we calculated overall and
health literacy–stratified descriptive statistics for
demographic and socioeconomic characteristics.
Chi-square tests of association were conducted to
examine differences in participant characteristics
January 2015, Vol. 22, No. 1
by level of health literacy. We
performed logistic regression
analyses to estimate associations between health literacy
and (1) whether participants received chemotherapy (for stage
3/4 disease), (2) cancer stage at
diagnosis (for all participants),
and (3) all-cause mortality at last
observation after baseline (for all
participants). Across all stages,
we estimated the marginal effect
of health literacy on survival as
well as its conditional effect on
demongraphic and socioeconomic covariates.
Among 130 participants with
stage 3/4 disease in the health
literacy sample, we calculated
overall and health literacy–stratified descriptive statistics for responses to survey questions
about their beliefs and preferences regarding chemotherapy,
communication with health care
professionals about chemotherapy, and their role in making the
decision whether to receive chemotherapy. We used Fisher exact
tests to evaluate whether survey
responses differed by participant
health literacy level.
For all tests of association,
P values less than .05 were considered statistically significant.
Analyses were performed at
the University of North Carolina at Chapel Hill, which was
the CanCORS site for all participants included in this study.
We used CanCORS core data
(version 1.16), medical record
data (version 1.12), and participant survey data (version 1.12).
All analyses were performed using SAS version 9.3 for Windows
(SAS Institute, Cary, North Carolina).
Results
Table 1 presents descriptive statistics among the 347 participants for whom health literacy
was assessed. Despite our goal
of a sample with approximately
equal numbers with adequate
January 2015, Vol. 22, No. 1
Table 1. — Participant Characteristics
Characteristic
Overall
(N = 347)a
n
%
Adequate
Literacy
(n = 242)a
n
Marginal/Inadequate
Literacy (n = 105)a
%
n
%
43
58
57
57
44
43
P valueb
Sex
Male
159
47
101
Female
178
53
134
.02
Race
White
264
78
201
86
63
62
Nonwhite
73
22
34
14
39
38
< .0001
Age, years
< 65
160
47
130
55
30
29
≥ 65
177
53
105
45
72
71
< .0001
Education
Less than high
school
72
23
36
16
36
43
High school/GED 112
36
80
35
32
39
Above high
school
82
26
76
33
6
7
Other
44
14
35
15
9
11
< .0001
Marital Status
Currently
married/living
with partner
211
63
158
67
53
52
Widowed,
divorced,
separated, or
never married
126
37
77
33
49
48
.008
Household Income ($), past year
< 20,000
75
24
42
19
33
40
20,000–39,999
82
27
56
25
26
31
40,000–59,999
52
17
42
19
10
12
≥ 60,000
78
25
73
32
5
6
Refused/
do not know
22
7
13
6
9
11
< .0001
Cancer Stage
1/2
187
59
3/4
130
41
132
60
55
57
89
40
41
43
.7
Received Chemotherapy
Yes
164
No
146
53
129
57
35
42
47
98
43
48
58
.02
Vital Status at Last Observation
Alive
260
77
187
80
73
72
Dead
77
23
48
20
29
28
.1
Differences between numbers of patients for each column and number of patients for each characteristic are representative of missing data. Percentages are representative for nonmissing data for the characteristic.
b
P values were based on chi-square tests of each characteristic by levels of health literacy.”
GED = general educational development.
a
Cancer Control 97
and marginal/inadequate levTable 2. — Participant Preferences and Role in Receipt of Chemotherapy by Literacy Levela
els of health literacy, 105 (30%)
Total
Number of Patients (%)
P
were categorized as marginal/ Survey Question
b
(N
=
130)
value
inadequate. Compared with
Adequate
Marginal/
Literacy
Inadequate
those with an adequate level
(n
=
89),
%
Literacy
(n = 41), %
of health literacy, participants
Did
any
of
your
doctors
tell
you
not
to
have
chemotherapy?
with marginal/inadequate
health literacy were more Yes
2
1 (1)
1 (4)
.4
frequently men, nonwhite, at No
108
84 (99)
24 (96)
least 65 years of age, not curAfter talking with your doctors about chemotherapy, how likely did you think it was that
rently married or living with chemotherapy would help you live longer?
a partner, had not completed
9
9 (11)
0 (0)
.1
high school, and had annu- Not likely/a little likely
95
71 (89)
24 (100)
al household incomes below Somewhat likely/very likely
$40,000.
After talking with your doctors about chemotherapy, how likely did you think it was that
Among participants with chemotherapy would help you with problems you were having because of your (cancer)?
stage 3/4 disease having an Not likely/a little likely
9
9 (18)
0 (0)
.1
adequate level of health lit- Somewhat likely/very likely
61
42 (82)
19 (100)
eracy increased the odds
Which statement best describes the role you played when the decision was made about
of receiving chemotherapy chemotherapy?
compared with those with You made the decision with little
5
4 (5)
1 (4)
.2c
a marginal/inadequate level or no input from your doctors.
of health literacy (odds ratio
You made the decision after
27 (33)
5 (20)
[OR], 3.29; 95% confidence in- considering your doctors’ opinions. 32
terval [CI], 1.23–8.80). HowYou and your doctors made the
58
44 (53)
14 (56)
ever, across all stages, having decision together.
an adequate level of health
Your doctors made the decision
5
5 (6)
0 (0)
literacy did not increase after considering your opinion.
the odds of presenting with
Your doctors made the decision
8
3 (4)
5 (20)
early-stage compared with with little or no input from you.
late-stage disease (OR, 1.11;
If you had to make a choice now, would you prefer treatment that extends life as much as possi95% CI, 0.68–1.80).
ble, even if it means having more pain and discomfort, or would you want treatment that focuses
For participants with on relieving pain and discomfort as much as possible, even if it means not living as long?
stage 3/4 disease, Table 2 Extend life as much as possible
58
45 (58)
13 (52)
.6
presents responses to survey
Relieve pain or discomfort as much
questions about participant
44
32 (42)
12 (48)
as possible
beliefs and preferences regarding chemotherapy, their If you had to make a choice now, would you prefer treatment that extends life as much as
possible, even if it means using up all of your financial resources, or would you want treatroles in deciding whether to ment that costs you less, even if means not living as long?
receive chemotherapy, and
Extend life as much as possible
65
46 (61)
19 (73)
.3
their communication with
Treatment
that
costs
less
37
30
(39)
7
(27)
health care professionals
about chemotherapy. Of the aThis analysis is limited to patients with stages 3 and 4 (ie, those for whom chemotherapy is recommended). For each
item, differences between presented frequencies and total number of participants represent missing or noninformative
130 participants with stage
responses (eg, “Do not know”).
b
3/4 disease, 89 (68%) had
P values were based on 2-sided Fisher exact tests and excluded missing and noninformative responses.
an adequate level of health cFor the Fisher exact test, responses dichotomized as “Patient principally made the decision/patient and doctors made
decision together” vs “Doctors principally made the decision.”
literacy and 41 (32%) had inadequate/marginal levels of
health literacy — percentages comparable with those
with marginal/inadequate level of health literacy) and
for the sample across all stages. We found no statistito help them with issues related to their cancers (82%
cally significant differences in participant responses
of those with an adequate level of health literacy and
by level of health literacy. Participants of all levels of
100% of those with a marginal/inadequate level of
health literacy thought that, after discussing chemohealth literacy).
therapy with a health care professional, the treatment
Although the differences were not statistically
was likely to help them live longer (89% of those with
significant, participants with stage 3/4 disease
an adequate level of health literacy and 100% of those
and an adequate level of health literacy played
98 Cancer Control
January 2015, Vol. 22, No. 1
63% of patients with 9 to 11 years of
education and 34% of patients who
Variablea
Univariate
Multivariateb
graduated from high school had a
marginal/inadequate level of functionOR
95% CI
OR
95% CI
al health literacy.13 Furthermore, low
Health literacy (inadequate/marginal
1.55
0.91–2.64
0.90
0.42–1.94
rates of adequate levels of functional
vs adequate)
health literacy are common, particularSex (male vs female)
1.93
1.15–3.24
2.16
1.09–4.28
ly among the elderly and those with
Race (nonwhite vs white)
1.50
0.84–2.70
1.45
0.66–3.19
less formal education.4,10,14-17 Among
Age (≥ 65 vs < 65 years)
1.46
0.87–2.45
1.59
0.82–3.08
elderly patients (> 60 years of age)
Education (less than high school
1.63
0.90–2.97
1.46
0.70–3.03
at urban public hospitals, one study
vs completed high school/GED)
found that 81% of English speakers and
Marital status (not living with anyone
1.55
0.92–2.59
1.40
0.68–2.88
83% of Spanish speakers had marginal/
vs married/living with a partner)
inadequate levels of functional health
Household income (< $40,000
1.46
0.82–2.59
1.23
0.57–2.67
literacy.17 Functional health literacy is
vs ≥ $40,000)
lower among older age groups even
Cancer stage (3/4 vs 1/2)
2.62
1.52–4.52
2.25
1.21–4.20
after adjusting for differences in mental
a
For each variable (a vs b), a = index group and b = reference.
status, frequency of reading the news,
b
Results from a model with all variables in the table simultaneously included as independent variables.
health status, and visual acuity.18 The
CI = confidence interval, OR = odds ratio.
GED = general educational development.
physical health of participants with
lower reading levels has been found
a more prominent role in deciding whether to
to be poor compared with that of participants with
receive chemotherapy than those with inadehigher reading levels even after adjusting for conquate/marginal levels of health literacy (see Table
founding sociodemographic variables.2,19 Individuals
2). Among those with informative responses, 75 of
with an inadequate level of health literacy are also
83 (90%) participants with an adequate level of health
more likely to report depressive symptoms, explained
literacy reported either making the decision to receive
in part by their worse health status.2,20
chemotherapy themselves or together with their
Health care professionals must be sensitive to
health care professional (in constrast with the
the level of functional health literacy of their patients
health care professional alone making the deciwhen they provide information regarding treatment
sion) compared with 20 of 25 (80%) among those
options and prognoses. Analyses of the readability of
with an inadequate/marginal level of health litpatient education materials, discharge instructions,
eracy. Three of the 83 participants (4%) with an
and consent forms have found that these materials
adequate level of health literacy and informative
are typically written at too complex a level for many
responses reported that their health care profesor most patients.21,22 Some evidence suggests that taisional made the decision about chemotherapy
loring communications for adults with low literacy
with little or no patient input compared with 5 of
can be effective.23 However, patients with a variety
25 (20%) among those with a marginal/inadequate
of health literacy levels may have difficulty underlevel of health literacy and informative responses.
standing health information; therefore, improving
In the unadjusted regression of survival on health
communication may help patients across all levels
literacy, those with a marginal/inadequate level of
of health literacy.
health literacy had increased odds of being deceased
To mitigate barriers to health literacy, health care
at last observation compared with those with an adprofessionals should take steps when meeting with
equate level of health literacy, but the effect was not
patients to ensure that communication is clear and
statistically significant and disappeared when conthat patients understand what is being taught to them.
ditioned on cancer stage as well as demongraphic
One recommended strategy involves the health care
and socioeconomic covariates (Table 3). Male sex and
professional asking the patient questions toward the
stage 3/4 disease were associated with greater odds
end of a clinical encounter to assess whether the
of being deceased at last observation, but no other
patient recalls and understands the information or
notable effects were detected.
instructions provided.24 For example, the health care
professional might ask the patient about the name,
Discussion
dose, and frequency of a medication that was just
Functional health literacy in patients with cancer may
prescribed. This approach, which is often called the
play a crucial role in successful treatment and out“teach-back” method, provides health care profescomes. Importantly, health literacy is distinct from
sionals with an opportunity to confirm patient underformal education. For example, one study found that
standing and gives patients the opportunity to solidify
Table 3. — Factors Associated With Death at Last Observation (n = 347)
January 2015, Vol. 22, No. 1
Cancer Control 99
their understanding.
Previous studies of health literacy found that lower levels of literacy were correlated with being male,16
elderly,4,15-17 and having less formal education15,16 and
income.16 The demongraphic and socioeconomic
characteristics of our sample followed these patterns
(see Table 1).
In evaluating our hypotheses, we found that an
adequate level of health literacy increased the likelihood of receiving chemotherapy among patients
with stage 3/4 disease, a finding that suggests greater
levels of health literacy might help patients receive
better care. However, we detected no other clear differences by level of health literacy in patient beliefs,
preferences, or decision-making about chemotherapy.
We did not find an association between level of health
literacy and either cancer stage at diagnosis or vital
status at last observation.
Limitations
Our study had several limitations. First, our small
sample limited our power to detect differences by
health literacy status. Second, the S-TOFHLA might
not precisely capture the desired construct of health
literacy. Instead, it could be better regarded as a test
of reading comprehension in a health care context
rather than as a test of the broader concept of health
literacy.25 Specifically, the S-TOFHLA might not evaluate aspects of health literacy other than reading,
such as oral health literacy, navigation, and culture.
The limitations of the instrument as a measure of
health literacy could attenuate its association with
some health outcomes. A third potential limitation that
might be more general to health literacy research is
the challenge of including sufficiently large numbers
of participants with marginal/inadequate levels of literacy to detect the effects of health literacy levels. As
noted, our goal was a sample of approximately 50%
marginal/inadequate health literacy, but our actual
sample had 30% marginal/inadequate health literacy.
We targeted patients for inclusion in the health literacy
substudy using formal education as a proxy, and our
results reinforced the conclusion of prior research that
formal education and health literacy, while related,
are distinct.13 Several previous studies of health literacy using the S-TOFHLA (not all on cancer) obtained
samples with even lower percentages of marginal/
inadequate levels of health literacy.15,16,26
The lower-than-expected numbers of participants
with marginal/inadequate levels of proficiency in
studies of health literacy suggest that selection bias
might influence which patients enter these studies.
To be eligible for inclusion in our sample, participants had to enroll in CanCORS, complete a baseline
survey, and be administered the S-TOFHLA. Patients
who died before completing any of these steps could
100 Cancer Control
not have participated in the sample. For included
patients, the mean number of days from cancer diagnosis to CanCORS enrollment and baseline survey was
150 days and from diagnosis to S-TOFHLA administration was 640 days.
It is possible that, if the level of health literacy
was associated with rates of survival, then patients
with CRC who died before enrolling in CanCORS, or
before they could complete the baseline survey or
the S-TOFHLA, might have had disproportionately
low levels of health literacy. Poor health and difficulty completing surveys among those with low levels of health literacy might systematically limit these
patients’ participation in studies of health literacy.
Future studies of health literacy should be designed
to account for this possibility.
Conclusions
In the context of previous research, patients with CRC
could benefit from health care professionals’ sensitivity toward, and adjustment to, different levels of patient
health literacy. In addition, health care professionals
could consider that any of their patients might have
difficulty understanding and making decisions about
health care. Therefore, clear communication is likely
to help both lower and higher health literacy patients.
Among patients with stage 3/4 disease, those
with lower levels of health literacy were less likely
to receive chemotherapy compared with patients with
higher levels of health literacy. To provide high-quality, patient-centered care, health care professionals
should consider strategies of clear communication
and patient engagement, recognizing that health literacy might affect physician–patient interactions and
choices in medical care.
References
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16. von Wagner C, Knight K, Steptoe A, et al. Functional health literacy and
health-promoting behaviour in a national sample of British adults. J Epidemiol
Community Health. 2007;61(12):1086-1090.
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January 2015, Vol. 22, No. 1
Cancer Control 101
Pathology Report
Familial Gastrointestinal Stromal Tumor Syndrome:
Report of 2 Cases With KIT Exon 11 Mutation
Derek H. Jones, MD, Jamie T. Caracciolo, MD, Pamela J. Hodul, MD, Jonathan R. Strosberg, MD,
Domenico Coppola, MD, and Marilyn M. Bui, MD, PhD
Background: As with cases of sporadic gastrointestinal stromal tumor (GIST), familial GIST syndrome
arises from mutations in KIT or PDGFRA. Only a few dozen such families have been described in the literature.
Methods: Cases of 2 individuals from 2 different newly described kindreds with familial GIST syndrome were
retrospectively reviewed. Pertinent immunohistochemical stains, including CD117, CD34, DOG1, desmin, and
S100, were performed. Samples from each case were sent to outside facilities for molecular analysis. A review of
the relevant literature was performed and the number of familial GIST syndrome cases reported was updated
through July 2014.
Results: In case 1, a woman 40 years of age with a family history of GIST presented with abdominal pain and
gastrointestinal bleeding. Biopsy of a gastric mass revealed spindle-cell type GIST. Molecular analysis revealed
a heterozygous mutation of p.Asp579del in exon 11 of KIT. The patient was placed on imatinib therapy and an
initial positive response was demonstrated by imaging. Disease regression was seen on computed tomography,
and several GIST tumors were surgically resected. The patient has had stable disease since surgery. In case 2,
an asymptomatic woman 29 years of age presented for screening due to a family history of GIST. One small
nodule was noted in her stomach and another was noted in the duodenum; both were surgically resected.
The patient recovered well following surgery. The GIST in this patient was noted to have similar histological,
immunohistochemical, and molecular findings as case 1.
Conclusions: Imatinib has often been shown to be an effective therapy in both the familial and sporadic forms
of GIST. There is no standard protocol for addressing the surveillance of patients with spindle-cell type GIST
seen in the setting of familial GIST syndrome and with a p.Asp579del mutation of exon 11 on KIT.
Introduction
Although gastrointestinal stromal tumor (GIST) is the
most common mesenchymal tumor of the gastrointestinal tract, the incidence of familial GIST syndrome
is rare, representing fewer than 5% of cases.1 Familial
GIST syndrome is an autosomal dominant disease
caused by germline mutations in KIT or PDGFRA,
both of which are also involved in the initiation of
most sporadic GIST cases. Other hereditable forms
of GIST include deficiencies in the succinate dehydrogenase complex, Carney–Stratakis syndrome, and
type 1 neurofibromatosis.1-3
From the University of South Florida Morsani College of Medicine (DHJ) and the Departments of Diagnostic Imaging and
Interventional Radiology ( JTC), Gastrointestinal Oncology
(PJH, JRS, DC), Anatomic Pathology (DC, MMB), and Sarcoma
(MMB), H. Lee Moffitt Cancer Center & Research Institute, Tampa,
Florida.
Submitted August 17, 2014; accepted August 29, 2014.
Address correspondence to Marilyn M. Bui, MD, PhD, Moffitt
Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail:
[email protected]
No significant relationships exist between the authors and
the companies/organizations whose products or services may
be referenced in this article.
102 Cancer Control
In 2013, Neuhann et al4 summarized 24 cases of
familial GIST syndrome arising from KIT. In addition
to this publication, 5 other cases of familial GIST syndrome have been described that involve KIT5-9 and
3 reported cases of familial GIST syndrome arising from PDGFRA.10-12 The 2 additional kindreds
described in this report raise the total number of
reported familial GIST syndrome cases to 34.
Here we present clinical, gross, histological, immunological, and molecular findings of 2 cases of
familial GIST involving the same mutation in exon 11
of KIT. We also provide an update of the literature on
familial GIST syndrome since the work of Neuhann
et al4 and review its molecular findings and clinical
characteristics. Knowledge of this entity is important
for the appropriate management of this condition
among these patients.
Materials and Methods
Clinical, radiological, and pathological data from the
2 patients were retrospectively reviewed following
the research guidelines of the University of South
Florida and the Moffitt Cancer Center in Tampa,
Florida. The tissues were processed, sectioned,
January 2015, Vol. 22, No. 1
and stained according to the guidelines from the
College of American Pathologists. The hematoxylin
and eosin stain and immunohistochemical studies
were performed at the histology laboratory of the
Moffitt Cancer Center. The immunohistochemical
staining was carried out using the Discovery XT
System (Ventana Medical Systems, Tucson, Arizona) per the manufacturer’s protocol. Samples from
each case were subjected to genetic analysis. Case
1 was performed with Sanger sequencing by ARUP
Laboratories (Salt Lake City, Utah), and case 2 was
performed with Sanger sequencing by Knight Diagnostic Laboratories (Portland, Oregon).
Clinical and Radiological Information
Case 1
A 40-year-old woman presented with epigastric pain
and recurrent gastrointestinal bleeding. Her family history was significant for GIST in her aunt and
grandmother. The patient history included anemia
and a small, spontaneously healing gastrointestinal
perforation. Laboratory values, including liver aminotransferases and bilirubin, were within normal limits.
Contrast-enhanced abdominal computed tomography
(CT) with intravenous contrast demonstrated numerous hypervascular, exophytic, mural-based, soft-tissue
masses arising from the stomach, duodenum, and jejunum (Fig 1A). No evidence of hepatic or intraperitoneal metastatic disease was seen.
Biopsies of an exophytic gastric mass and a peripancreatic duodenal mass were performed with the
guidance of endoscopic ultrasonography. Both tumors
were diagnosed as GIST. Molecular analysis revealed
a mutation of exon 11 on KIT, and imatinib therapy
was initiated. The patient underwent follow-up CT
with oral and intravenous contrast 6 months following
the initiation of imatinib therapy that demonstrated
the decreased size of disease sites consistent with a
partial response to therapy (Fig 1B). However, within
9 months of initiating imatinib, the patient presented
with increased abdominal pain. Abdominal CT was
repeated and demonstrated an increase in size of
several lesions, including the duodenal mass (Fig 1C).
Given the relatively limited extent of her multifocal
disease and the absence of metastatic disease, surgical debulking was recommended. She underwent
partial gastrectomy, pancreas-sparing duodenectomy,
proximal jejunal resection, and cholecystectomy. The
patient recovered well from surgery and reports that
she is feeling better. CT was obtained 4 months following surgery, and the imaging demonstrated no
evidence of recurrence or distant metastatic disease.
Case 2
A woman 29 years of age who was asymptomatic presented for screening secondary to a family history of
January 2015, Vol. 22, No. 1
familial GIST in her mother and grandmother. After an
initial evaluation, the patient exhibited mild epigastric
discomfort and subsequently presented with a mildly
elevated level of alanine transaminase, possibly due
to hepatic steatosis. The patient did not exhibit anemia and other laboratory values were not abnormal.
Endoscopic ultrasonography performed with esophagogastroduodenoscopy had demonstrated subcentimeter, mural-based, hypoechoic, gastric, and duodenal
soft-tissue nodules (Fig 2). These small, submucosal,
intramural nodules were isodense and isoenhancing
to the gastric and duodenal walls; therefore, they were
not readily evident with CT imaging. Abdominopelvic
CT did not demonstrate evidence of hepatic metastatic disease or peritoneal carcinomatosis. Both lesions
A
B
C
Fig 1A–C. — Serial CT scans at a similar level over time from case 1. (A) Axial
contrast-enhanced abdominal CT demonstrates a 3.9-cm exophytic, mural-based, hypervascular duodenal mass (white arrow) and a similarly appearing jejunal mass (yellow arrow). The red asterisk denotes the duodenum. (B)
Six months after CT shown in Fig 1A, both masses demonstrated decreased
size on imatinib therapy consistent with tumor response. The duodenal mass
measured 2.9 cm. No new lesions or interval development of metastatic
disease was seen. (C) Six months after CT shown in Fig 1B, the duodenal
mass increased in size and measured 3.3 cm, which was consistent with
resistance to imatinib therapy.
CT = computed tomography.
Cancer Control 103
Fig 2. — Endoscopic ultrasonography from case 2 demonstrates a submucosal, intramural, hypoechoic, soft-tissue nodule of 6 × 5 mm in size within
the posterior wall of the second portion of the duodenum. CBD = common
bile duct, GIST, gastrointestinal stromal tumor, HOP = head of pancreas,
POSTR = posterior.
Fig 3. — Gross findings for case 1. Duodenal and proximal jejunal resection with an expanded cross-section of tumor demonstrates 6 nodules with
diameters up to 4.0 cm on the serosal aspect of the resection. Nodules are
pink-tan to tan-white in appearance.
were subsequently surgically resected. The patient
is not on imatinib therapy and was recovering well
1 month following surgery.
observed; some extended to the serosa.
Histologically, the resected tumor specimens
were of similar morphology as the gastric and duodenal biopsies (Fig 4A–C). The mitotic rate was
3 per 5 mm2. Minimal tumor necrosis was observed
(approximately 5% of total tumor volume), corresponding to a minimal treatment effect. The viability
rate of the tumor cells observed was 90% to 95%.
Tumors were diagnosed as spindle-cell type GIST and
staged as T2M0N0.
Gross, Histological, and
Immunohistochemical Findings
Case 1
Histologically, cells from both the gastric and duodenal mass biopsies were of spindle-cell morphology and largely uniform in appearance. The cells had
cigar-shaped nuclei and pale eosinophilic cytoplasm.
Skeinoid fibers were present in the interstitium.
Necrosis was not identified. Mitotic rate could not be
accurately determined due to the small sample size.
The tumor was immunohistochemically positive for
CD117 and DOG1, while negative for CD34, desmin,
actin, S-100, and pan-keratin (AE1/AE3/CAM 5.2).
Findings were consistent with the diagnosis of spindle-cell type GIST.
The surgical resection specimens consisted of a
3.0 × 1.3 × 0.8-cm section of the lesser gastric curvature, a
2.8 × 1.0 × 0.5-cm section of the posterior stomach
wall, a 5.4 × 2.4 × 1.8-cm wedge of an anterior gastric wall body mass, a 3.8 × 1.0 × 0.8-cm wedge of a
posterior gastric wall mass, and a section of duodenum and proximal jejunum approximately 44.0 cm
in length with attached adipose tissue yellow-tan in
color on the serosal aspect (Fig 3). In the gastric sections, various nodules up to 1.0 cm extending to the
serosa that ranged from tan-pink, tan-white, to white
in color were observed. In the duodenal and proximal
jejunal resections, approximately 6 tan-white to pinktan nodules ranging from 0.6 to 4.0 cm in size were
104 Cancer Control
Case 2
Macroscopically, a 1.5 × 0.6 × 0.4-cm section of the
anterior gastric mucosa was resected. It contained a
circumscribed nodule that was tan-white in color and
measured 1.1 × 0.9 × 0.6 cm in size. In addition, a
0.9 × 0.6 × 0.5-cm section of duodenum containing a
small nodule was resected. It consisted of cauterized
fibrotic tissue brown-tan in color.
Histologically, findings were also consistent
with spindle-cell type GIST. The mitotic rate was
0 per 5 mm2. The tumor was immunohistochemically positive for CD117 (Fig 5A), strongly positive for
DOG1 (Fig 5B), and negative for S100, actin, and
desmin. The Ki-67 labeling index was between 1%
and 2%. Cell necrosis was not identified.
Molecular Analysis
Case 1
The core biopsy of the gastric mass guided by endoscopic ultrasonography was found to have a mutation
on exon 11 of KIT. A deletion of GAT was present in
positions 1735 to 1737 (c.1735_1737delGAT), which
January 2015, Vol. 22, No. 1
A
A
B
B
C
Fig 4A–C. — Nodules from jejunal and duodenal resection of case 1.
(A) Histology from a 4.0-cm nodule. Longitudinal positioning of the cells is
observed. H & E, × 60. (B) Histology from a 0.6-cm nodule. Cigar-shaped
nuclei with a uniform appearance and distinct, spindle-cell morphology.
H & E, × 20. (C) High power image of the nodule from Fig 4B. Skeinoid fibers
are visible in the interstitium. H & E, × 60.
H & E = hematoxylin and eosin.
resulted in the loss of aspartic acid at position 579
(p.Asp579del). The mutation was heterozygous. Exon
9 from KIT was intact.
Case 2
Molecular studies were performed from a peripheral blood sample. Similar to the results from case 1,
a heterozygous p.Asp579del mutation was detected
in exon 11 of KIT.
Discussion
Mutations in familial GIST syndrome involve KIT and
PDGFRA, which are the same genes mutated in 80%
January 2015, Vol. 22, No. 1
Fig 5A–B. Histological and immunohistochemical images from stomach
tumor in case 2. (A) CD117 was diffusely positive in the cell cytoplasm.
CD117, × 40. (B) DOG1 was strongly positive in the cell membranes and
cytoplasm. DOG1, × 40.
to 88% of cases of sporadic GIST.13 Wild-type GIST
arising from other molecular pathways may comprise
up 15% of GIST cases,13 and they are typically negative for KIT and PDGFRA mutations but positive
for mutations of BRAF V600E, the RAS family, and
the succinate dehydrogenase complex.1 However, it
is possible that cases of wild-type GIST might be
less common than previously thought. For example,
one study suggests that 1% to 2% of GIST previously
regarded as the wild-type form may actually harbor
mutations in exon 8 of KIT.14
The Table demonstrates similarities and differences between the molecular basis of familial and
sporadic GIST caused by KIT mutations.15,16 In familial
GIST syndrome, KIT mutations in exon 9 have not
been reported as they have with sporadic GIST. The
reasons for a lack of exon 9 mutations in familial GIST
syndrome remain unclear, but reasons may become
elucidated as more information is gained on familial
GIST. Six cases have been reported of familial GIST
syndrome due to mutations in KIT exon 13 and 4 cases
have been reported due to mutations in exon 17.4,6,8,9
By comparison, exon 9 mutations account for 15% of
KIT mutations in the setting of sporadic GIST, whereas
exons 13 and 17 account for 2% and 1%, respectively.15
Although pure insertions involving KIT are documented in sporadic GIST, none have been documented in
Cancer Control 105
Table. — KIT Findings for GIST
Genetic Finding
Sporadic GIST
Familial GIST
Syndrome
Involved KIT exons
8, 9, 11, 13, 17
8, 11, 13, 17
Type of mutation
Substitution
Duplication
Deletion
Insertion
Deletion–insertion
Substitution
Duplication
Deletion
Deletion–insertion
KIT mutations
involving exon 11, %
70–9015,26
65
GIST = gastrointestinal stromal tumor.
familial GIST syndrome (see Table).15,16 Our literature
review demonstrates that, as a whole, mutations of
exon 11 of KIT are more common among sporadic
GIST than familial GIST syndrome. However, given
the small number of familial GIST syndrome cases
to compare with the much larger number of sporadic GIST cases, these differences must be thoroughly
examined. In the future, reports of additional cases
of familial GIST will help achieve a better analysis of
these underlying similarities and differences.
Twenty families with familial GIST have arisen from
exon 11 of KIT as described by Neuhann et al,4 Nakai
et al,5 Adela et al,7 and the cases presented here. KIT and
PDGFRA are members of the family of class 3 tyrosine kinase receptors. The juxtamembrane domain of this family
is highly conserved and has been demonstrated to have
an inhibitory effect on the kinase domain of the tyrosine
kinase receptor.17 The juxtamembrane domain of KIT is
encoded by exon 11.13 A mutation in this region has been
molecularly modeled to disrupt the usual autoinhibitory
state of KIT, leading an activated gain-of-function state.18
Because of this gain-of-function type mutation, individuals are typically heterozygous for these mutations. The current report describes 2 additional cases
of a mutation of p.Asp579del in exon 11 of KIT, adding 2 kindreds to the 3 previously reported families
with familial GIST syndrome demonstrating this mutation.18-20 Mutations causing familial GIST syndrome
have no clear differentiating factors from mutations
causing sporadic GIST, and the mutation of p.Asp579del has also been documented in sporadic GIST.21
The p.Asp579del mutation is not within the region of
high-frequency mutations noted at positions 556 to 560
in exon 11 of KIT in patients with GIST.18 However, 11 of
the 20 cases of familial GIST syndrome with a mutation
in exon 11 of KIT are located in this high-frequency
region. Of these 11 cases, 7 are from the most common
mutation in familial GIST syndrome, p.Val559Ala. The
KIT exon 11 mutation p.Val559Ala is also a common
missense mutation in GIST.22 A large study found that
patients with deletions in exon 11 of KIT from positions 562 to 579 have significantly higher risk for meta106 Cancer Control
static disease than patients with mutations at positions
550 and 561, suggesting that patients with the mutation
of p.Asp579del, such as the patients in this report, may
be at high risk for metastatic disease.23
These 2 cases also contribute to the body of evidence suggesting that phenotypic features cannot reliably indicate the presence of familial GIST syndrome.
As with sporadic GIST, nonspecific signs and symptoms in familial GIST syndrome include gastrointestinal
bleeding, abdominal pain, ulcer-type symptoms, and a
variety of other gastrointestinal complaints. No specific
serum markers are currently used to routinely screen or
diagnose GIST. Familial GIST syndrome has classically
been associated with hyperpigmentation, urticaria pigmentosa, and dysphagia. However, a growing number
of cases do not demonstrate these symptoms, including
our 2 patients. Notably, patient age can be a guiding
feature as patients with familial GIST syndrome typically
present at least 10 years prior to patients with sporadic
GIST, presenting at a median age of 60 to 65 years.1,2
Patients with familial GIST syndrome or other
GIST-related syndromes, such as type 1 neurofibromatosis, typically present with multifocal disease,
whereas most patients with sporadic GIST usually
present with solitary primary tumors.24 Sporadic GIST
may present with multiple gastrointestinal masses in
the setting of metastatic disease or from independent mutations. Metastatic disease may be diagnosed
in the setting of peritoneal sarcomatosis, the second
most common pattern of metastatic disease following
hepatic metastatic disease. Approximately 11% of patients presenting with GIST have metastatic disease
identified at the time of initial diagnosis.25
Several studies indicate that a substantial portion
of patients with multifocal disease may arise from independent mutational events. Two large studies, one
by Agaimy et al26 and the other by Gasparotto et al,27
indicate the presence of multiple molecular origins
in multifocal GIST in 7 of 11 and 6 of 10 cases, respectively. The presence of multiple mutations could
be explained by premutational epigenetic changes.26
Current guidelines from the National Comprehensive
Cancer Network recommend mutational testing for
KIT and PDGFRA in the primary evaluation of GIST,
but they make no recommendations for further analysis in the case of multifocal disease.28 Due to the
variety of possible etiologies in patients presenting
with multifocal disease, genetic screening for familial
GIST syndrome may be a prudent step in the initial
evaluation of multifocal disease. In addition, genetic
counseling for individuals with familial GIST syndrome should be considered to identify other family
members at risk.
In general, histological and immunohistochemical
features do not differentiate cases of familial GIST
syndrome from cases of sporadic GIST. Both feature
January 2015, Vol. 22, No. 1
spindle cell or, less frequently, epithelioid histologies. Both are usually positive for CD117 and DOG1
and negative for desmin, keratin, and S100. Similar to
sporadic GIST, CD34 variability has also been noted
in familial GIST syndrome.
A high rate of response to imatinib has been well
documented in cases of sporadic GIST, and familial
GIST may also be sensitive to imatinib treatment. Typically, patients with mutations of exon 11 of KIT have
an especially strong response to imatinib.28 Tarn et al18
reported that the mutations of exon 11 on KIT may not
affect the nucleotide-binding site, thereby lowering
the probability of imatinib resistance. However, recent
data demonstrate that changes to the juxtamembrane
domain can affect the structure of the kinase domain,
thus resulting in imatinib resistance, such as the case
with p.Val559Ile.29 Kleinbaum et al20 noted a strong
response to imatinib in patients with familial GIST
syndrome who had a KIT exon 11 p.Asp579del mutation. Nine of the 11 family members who did not
receive imatinib eventually died from metastatic GIST,
whereas all 4 patients receiving imatinib achieved stable disease for more than 4 years.20 Typically, sunitinib
is a second-line therapy following treatment failure
with imatinib.
Currently, several reports have focused on the
general topic of familial GIST syndrome. Burgoyne
et al1 provided a review of nonsporadic GIST, and
Corless et al13 provided a comprehensive review of
the molecular basis of GIST. No guidelines currently
exist for screening patients with familial GIST, nor
do any clear indications exist for the role or extent
of surgery in the setting of multifocal disease. The
patient in case 1 had symptomatic multifocal tumors
and achieved palliation with neoadjuvant imatinib
followed by surgical resection, whereas the patient in
case 2 was asymptomatic and chose to undergo surgery for her identifiable sites of disease. It is unclear
whether the removal of small, low-grade tumors will
ultimately improve her long-term prognosis, particularly because additional tumors are likely to develop
over her lifetime.
The role of imatinib as a chemopreventive agent
in familial GIST is also unclear. Although it is possible
that imatinib can prevent or delay growth of multifocal GIST in this population, it is uncertain to what
extent imatinib therapy improves long-term prognoses
among patients with nonmetastatic, low-grade tumors.
Conclusions
Familial gastrointestinal stromal tumor syndrome is a
rare disease, but the number of associated families identified continues to expand. The 2 cases identified in this
report add to the growing body of evidence that will
better help researchers and clinicians understand the
epidemiology, characteristics, and optimal treatment of
January 2015, Vol. 22, No. 1
familial gastrointestinal stromal tumor syndrome.
References
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gastrointestinal stromal tumors, skin hyperpigmentations, and esophageal
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5. Nakai M, Hashikura Y, Ohkouchi M, et al. Characterization of novel
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6. Peña-Irún A, Villa-Puente M, García-Espinosa R, et al. Familial gastrointestinal stroma tumor due to mutation in exon 13 (K642E) of the KIT gene
[In Spanish]. Med Clin (Barc). 2012;139(11):512-513.
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8. Yamanoi K, Higuchi K, Kishimoto H, et al. Multiple gastrointestinal
stromal tumors with novel germline c-kit gene mutation, K642T, at exon 13.
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9. Wadt K, Andersen MK, Hansen TV, et al. A new genetic diagnosis of familiar gastrointestinal stromal tumour [In Danish]. Ugeskr Laeger.
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10. Chompret A, Kannengiesser C, Barrois M, et al. PDGFRA germline
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12. Pasini B, Matyakhina L, Bei T, et al. Multiple gastrointestinal stromal
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Metab. 2007;92(9):3728-3732.
13. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours:
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14. Huss S, Künstlinger H, Wardelmann E, et al. A subset of gastrointestinal
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15. Gounder MM, Maki RG. Molecular basis for primary and secondary
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Chemother Pharmacol. 2011;67(suppl 1):S25-S43.
16. Miettinen M, Lasota J. Gastrointestinal stromal tumors. Gastroenterol
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17. Hubbard SR. Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5(6):464-471.
18. Tarn C, Merkel E, Canutescu AA, et al. Analysis of KIT mutations in
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through protein modeling. Clin Cancer Res. 2005;11(10):3668-3677.
19. Lasota J, Miettinen M. A new familial GIST identified. Am J Surg Pathol.
2006;30(10):1342.
20. Kleinbaum EP, Lazar AJ, Tamborini E, et al. Clinical, histopathologic,
molecular and therapeutic findings in a large kindred with gastrointestinal
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24. Haller F, Schulten HJ, Armbrust T, et al. Multicentric sporadic gastrointestinal stromal tumors (GISTs) of the stomach with distinct clonal origin:
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25. Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in
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27. Gasparotto D, Rossi S, Bearzi I, et al. Multiple primary sporadic gastrointestinal stromal tumors in the adult: an underestimated entity. Clin Cancer
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108 Cancer Control
January 2015, Vol. 22, No. 1
Tumor Biology
Current and Emerging Therapies for Bone Metastatic
Castration-Resistant Prostate Cancer
Jeremy S. Frieling, David Basanta, PhD, and Conor C. Lynch, PhD
Background: A paucity of therapeutic options is available to treat men with metastatic castration-resistant
prostate cancer (mCRPC). However, recent developments in our understanding of the disease have resulted in
several new therapies that show promise in improving overall survival rates in this patient population.
Methods: Agents approved for use in the United States and those undergoing clinical trials for the treatment of
mCRPC are reviewed. Recent contributions to the understanding of prostate biology and bone metastasis are
discussed as well as how the underlying mechanisms may represent opportunities for therapeutic intervention.
New challenges to delivering effective mCRPC treatment will also be examined.
Results: New and emerging treatments that target androgen synthesis and utilization or the microenvironment
may improve overall survival rates for men diagnosed with mCRPC. Determining how factors derived from the
primary tumor can promote the development of premetastatic niches and how prostate cancer cells parasitize
niches in the bone microenvironment, thus remaining dormant and protected from systemic therapy, could
yield new therapies to treat mCRPC. Challenges such as intratumoral heterogeneity and patient selection can
potentially be circumvented via computational biology approaches.
Conclusions: The emergence of novel treatments for mCRPC, combined with improved patient stratification
and optimized therapy sequencing, suggests that significant gains may be made in terms of overall survival
rates for men diagnosed with this form of cancer.
Introduction
Prostate cancer is the second most common cancer
in American men with approximately 233,000 newly
diagnosed cases in 2014.1 With an aging population,
the incidence of prostate cancer is likely to continue
to increase. Patients whose disease is detected at an
early stage benefit from a range of treatment strategies, including radiotherapy and prostatectomy, with
survival rates near 100%.2 However, the clinical reality is that many men present with advanced stages
of the disease. Currently, the main treatment option
for men with advanced cancer is hormone therapy.
Historic contributions from Huggins and Hodges3
in 1941 revealed that removing androgens could
inhibit the progression of prostate cancer. These earFrom the Departments of Tumor Biology (JSF, CCL) and Integrated
Mathematical Oncology (DB), H. Lee Moffitt Cancer Center and
Research Institute, Tampa, Florida.
Submitted August 6, 2014; accepted September 11, 2014.
Address correspondence to Conor C. Lynch, PhD, Department
of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive,
SRB-3, Tampa, FL 33612. E-mail: [email protected]
No significant relationships exist between the authors and the
companies/organizations whose products or services may be
referenced in this article.
This work was supported in part by funding support that Dr Lynch
received from the National Cancer Institute (RO1CA143094).
January 2015, Vol. 22, No. 1
ly observations paved the way for the development
of androgen-deprivation therapy — either surgically
or chemically — which has remained the standard
treatment for men with advanced disease for the last
70 years. Despite the initial response to androgen
deprivation for most men, the disease typically progresses to a castration-resistant state within 18 to 24
months.4
Castration-resistant prostate cancer (CRPC) is
defined by disease progression that, despite chemical castration, is often indicated by rising levels of
prostate-specific antigen (PSA).5 The development
of resistance to hormonal intervention and why the
disease progresses is not fully understood, although
some mechanisms have been demonstrated, with the
majority focusing on the continued androgen receptor (AR) activity in addition to TMPRSS2/ERG fusion,
PTEN, Nkx3.1, and EGR1. As the disease progresses,
the CRPC ultimately metastasizes (mCRPC). Patients
with mCRPC have a poor prognosis and a predicted
survival rate of fewer than 2 years from the initial
time of progression, comprising a large portion of
the 30,000 prostate cancer-related deaths per year.6,7
Currently, mCRPC is an incurable disease and
represents a major clinical hurdle.
Prostate cancer preferentially metastasizes to
bone.8 As the disease transitions from castration senCancer Control 109
Fig 1. — Approved and developing mCRPC therapies and their targets. mCRPC has experienced a rapid expansion of treatment options over the last decade.
Better understanding of mechanisms of progression has allowed for the improvement of broad-acting options such as chemotherapy and hormonal therapy
as well as the development of novel targeted therapies to modulate the immune system and microenvironment.
mCRPC = metastatic castration-resistant prostate cancer.
sitive to castration resistant, the incidence of bone
metastasis increases, with more than 90% of patients
with mCRPC developing bone metastases.9,10 Patients
with mCRPC who are symptomatic are at a high risk
for skeletal-related events (SREs), including spontaneous fracture and spinal cord compression, that are
a source of significant pain and decreased quality
of life.11 Pain from the metastases is a major component of the disease and is an important aspect to
be considered regarding a patient’s treatment regimen. Depending on the level of pain, medications
ranging from ibuprofen to morphine are prescribed.12
Because prostate to bone metastases are primarily
bone-forming sclerotic lesions, bone scanning using technetium-99m is often preferred for diagnosis
due to the incorporation of the radionuclide tracer
into regions of new bone formation by osteoblasts.13
Magnetic resonance imaging (MRI) and positron
emission tomography (PET)/computed tomography
110 Cancer Control
(CT) are also used for detection. A trial comparing
18F–sodium fluoride PET/CT, 18F-fluorodeoxyglucose
PET/CT, MRI, and technetium-99m identified strengths
for each modality.14 However, the ability to detect
occult or micrometastases less than 5 mm remains a
current limitation for each imaging technique.
Approved Therapeutic Options
Currently, mCRPC remains incurable, and many treatment options are palliative in nature. However, the
treatment landscape of mCRPC is expanding both in
broad-spectrum and targeted therapies that are likely
to positively impact overall survival rates within the
next decade. This expansion began with docetaxel,
which, in 2004, was the first therapy to provide improved survival rates to patients with mCRPC. However, many patients develop resistance.15 To combat
this issue, 5 new agents have received approval by
the US Food and Drug Administration (FDA) to treat
January 2015, Vol. 22, No. 1
mCRPC since 2010 (abiraterone acetate, enzalutamide,
cabazitaxel, radium-223, and sipuleucel-T).16 Some of
these agents may be administered in combination with
steroids, such as prednisone, which has been shown to
decrease testosterone levels and reduce tumor growth
as well as counteract adverse events (eg, nausea, allergic reactions, inflammation, pain).17,18 Recently
FDA-approved agents that target the cancer and host compartments are discussed below and are also illustrated
in Fig 1.
Targeting Metastatic Castration-Resistant
Prostate Cancer Cells
One of the defining measures of mCRPC is resistance
to androgen deprivation. The mechanism of castration
resistance is not fully understood but inroads have
been made. For example, prostate cancer cells circumvent castration by overexpressing and increasing the
sensitivity of the AR to residual androgens, acquiring
AR gene mutations that lead to functional gain or promiscuous ligand interactions, splice variants resulting
in constitutive AR activation, and post-translational
modifications affecting the stability, localization, and
activity of the receptor.19 Alternative methods utilized
by prostate cancer cells to synthesize dihydrotestosterone (DHT) have also been shown to circumvent
androgen deprivation methods.20-22 Efforts to target
DHT synthesis have resulted in FDA-approved androgen deprivation therapy (ADT) options. Abiraterone
acetate is one such option that works by inhibiting the
activity of the CYP17A1 enzyme, thereby preventing
androgen synthesis. Abiraterone has improved the
overall survival and radiographic progression-free
survival rates of men with mCRPC.23,24 Another therapeutic strategy for preventing androgen utilization by
mCRPC cells is to directly target the AR with reagents
such as flutamide, nilutamide, and bicalutamide.
Enzalutamide was recently approved for the treatment of mCRPC in a postdocetaxel setting without the
administration of corticosteroids.25,26 Enzalutamide has
a superior affinity to the AR compared with other AR
antagonists and works by preventing nuclear translocation of the receptor, DNA binding, and recruitment
of coactivators of the AR to increase overall survival
rates and delay the onset of SREs.27-29 Results of a
phase 3 trial demonstrated enzalutamide activity in
patients naive to chemotherapy, and FDA approval
of enzalutamide as a first-line therapeutic option for
mCRPC may be on the horizon.30
A list of approved therapies for the treatment of
mCRPC appears in Table 1.15,23,24,27,28,31-36
In addition to ADT strategies, taxane-derived
chemotherapies are commonly used to treat mCRPC.
Docetaxel was the first therapy to demonstrate a beneficial effect on overall survival rates accompanied
by improved quality of life for men with mCRPC,
January 2015, Vol. 22, No. 1
Table 1. — Approved Therapies for the Treatment of
Metastatic Castration-Resistant Prostate Cancer
Drug
Target
Effect
CYP17A1
Reduces circulating
testosterone levels23,24
Microtubules
Microtubule stabilization,
interrupts cell cycle31
RANKL
Decreases bone resorption34
Microtubules
Microtubule stabilization,
interrupts cell cycle15,36
AR
AR antagonism,
prevents signaling27,28
Radium-223
Bone
Localized radiation35
Sipuleucel-T
Ex vivo activation
of PBMCs via
GM-CSF and PAP
T-cell activation32
Zoledronic acid
Osteoclasts
Decreases bone resorption33
Abiraterone
acetate
Cabazitaxel
Denosumab
Docetaxel
Enzalutamide
AR = androgen receptor, GM-CSF = granulocyte-macrophage colony-stimulating
factor, PAP = prostatic acid phosphatase, PBMC = peripheral blood mononucleated cell, RANKL = receptor activator of nuclear κB ligand.
and it has since become the standard therapy for
mCRPC.15,36 Cabazitaxel is a more recent derivative
of the taxoids that has shown increases in overall
survival rates, improvements in progression-free survival rates, and improved PSA response rates in men
with mCRPC.31,37 Cabazitaxel-associated toxicities were
minor, leading to the FDA approval of the therapy for
the treatment of patients with mCRPC after treatment
with docetaxel.38
Targeting the Microenvironment
Given the heterogeneity of mCRPCs and the likelihood
of ADT/chemotherapy resistance, targeting the genetically stable host microenvironment supporting the
mCRPC represents an attractive treatment approach.
Immune evasion is a hallmark of cancer progression,
and the goal of sipuleucel-T is to make mCRPC more
visible to cytotoxic T cells.32,39 Sipuleucel-T is an autologous immunotherapy approved for the treatment
of asymptomatic or minimally symptomatic mCRPC.40
Sipuleucel-T harnesses the properties of the patient’s
immune system by collecting peripheral blood mononuclear cells and activating them ex vivo by exposing them to a fusion protein consisting of prostatic acid phosphatase (PAP; commonly expressed by
prostate cancer cells) and granulocyte-macrophage
colony-stimulating factor. Patients receive 3 separate
infusions of the activated cells at 2-week intervals to
generate PAP-expressing dendritic cells that activate
T cells to recognize and eliminate PAP-expressing
prostate cancer cells.32
Most mCRPCs arise in the bone matrix where
they induce extensive bone remodeling by stimulating
osteoblasts and osteoclasts. The process promotes
the growth of the mCRPCs via the solubilization of
bone matrix–sequestered growth factors, causing
Cancer Control 111
Fig 2A–C. — Dormancy and the “vicious cycle” in bone marrow niches. (A) Disseminated tumor cells can home to the vascular niche and cluster on stable
endothelium. Decreased expression of thrombospondin 1 combined with activation of transforming growth factor β and periostin in areas of “sprouting”
vasculature can result in the outgrowth of tumor cells. (B) Cancer cells may also home to the endosteal niche via mechanisms such as chemokine motif 12/
chemokine receptor 4 where they compete with quiescent hematopoietic stem cells for osteoblast interaction. Subsequently, the cancer cells can be maintained
in a dormant state via interactions with GAS6- and ANXA2-expressing niche osteoblasts or proliferate into metastases. (C) A “vicious cycle” occurs between
tumor cells and other cells of the bone microenvironment. Factors secreted by the tumor cells act on osteoblasts, leading to the increased production of
RANKL. RANKL subsequently promotes the differentiation of osteoclast precursors into mature, bone-resorbing osteoclasts that degrade the bone and release
additional factors into the microenvironment, providing positive feedback to the cancer cells. Matrix metalloproteinases 2, 7, and 9 contribute to the vicious
cycle by regulating factors such as vascular endothelial growth factor A, RANKL, and transforming growth factor β, whereas myeloid-derived suppressor
cells contribute by releasing protumorigenic factors, suppressing T cells, and differentiating into osteoclasts. RANKL = receptor activator of nuclear κB ligand.
pain and SREs (eg, pathological fractures). Therefore, preventing the interaction of cancer and bone
has been a major focus of treatment for several decades. Bisphosphonates, such as zoledronic acid,
are reagents that can “stick” to bones undergoing
remodeling; upon resorption by osteoclasts, they
can induce apoptosis and limit the amount of cancer-induced bone disease.41 In the clinical setting,
zoledronic acid has demonstrated a benefit for patients with mCRPC by delaying the time to SRE incidence.33 However, no increase in overall survival
rates has been demonstrated. Receptor activator of
nuclear κB ligand (RANKL) is a molecule critical for
the maturation and activation of bone-resorbing osteoclasts. Denosumab is a fully humanized monoclonal antibody that prevents RANKL interaction with
the RANK receptor.42 For patients with bone mCRPC,
112 Cancer Control
a significant delay has been demonstrated in the time
to first SRE compared with zoledronic acid.34 Evidence
suggests that denosumab may have direct effects on
tumor burden, particularly tumor cells expressing
RANK.43,44 Furthermore, preclinical in vivo animal
studies have highlighted the efficacy of docetaxel/
denosumab treatment in increasing median survival
rates, suggesting that combination approaches with
denosumab could enhance the overall survival rates
of men with mCRPC.45
At the time of publication, the most recent agent
to receive FDA approval for mCRPC is radium-223.46
The bone-seeking properties of radium-223 (and
other similar radiopharmaceuticals) make it useful
for the treatment of bone metastases. Although most
radiopharmaceuticals emit ß particles, radium-223
emits α particles to deliver more localized radiation
January 2015, Vol. 22, No. 1
(< 100 µm distance) to induce cell death via DNA
damage.47 In a study of men with mCRPC previously
treated with radiotherapy, radium-223 showed improved
rates of overall survival, time to PSA progression, and
reduced alkaline phosphatase levels (a measure of bone
remodeling).35 In addition, radium-223 delays the time
to first SRE.35 Previous radiopharmaceuticals used to
treat mCRPC were effective at reducing pain alone.
Therefore, radium-223 represents an important step
forward for the field.46
stable disease in 51 patients.59 Decreases in circulating tumor cells were also observed, thus serving as a
further indication of efficacy. Based on these positive
data, phase 3 trials were initiated; however, the results
of one of those phase 3 trials indicated that orteronel
administered in combination with prednisone failed
to significantly impact overall survival rates compared
with placebo but did provide a benefit in radiographic
progression free survival rates in both chemotherapy
naive and postchemotherapy mCRPC.48,49
Emerging Therapeutic Options
Targeting the Microenvironment
Tasquinimod: In addition to the approval of some
small molecule inhibitors, several novel inhibitors are,
at the time of publication, in various phases of clinical
trials for mCRPC. Tasquinimod, a quinoline-3-carboxamide derivative, is being investigated in men with
mCRPC (NCT01234311, NCT00560482). Tasquinimod
provides an antiangiogenic effect by upregulating
thrombospondin-1 (TSP-1) and downregulating the
gene expression of vascular endothelial growth factor
(VEGF), the C-X-C chemokine receptor (CXCR) 4, and
lysyl oxidase.60 It has also been shown to reduce the
expression levels of C-X-C chemokine motif (CXCL)
12 and inhibit S100A9, both of which are important
molecules implicated in tumorigenesis and angiogeneOrteronel
sis.50,60-63 The results of a phase 2 trial in patients naive
Similar to abiraterone acetate, orteronel inhibits
to chemotherapy showed improved rates of median
CYP17A1 to reduce circulating levels of testosterprogression-free survival (7.6 months vs 3.3 months).57
one. However, orteronel possesses specificity toward
In addition, the study showed bone alkaline phoslyase activity, leaving the synthesis of adrenal cortiphatase levels, a correlate of bone turnover, were
sol unaltered.17,20 Therefore, orteronel is less likely
stabilized in patients receiving tasquinimod. Following
than abiraterone acetate to require the concomitant
the favorable outcome of the phase 2 trial, a phase 3
administration of corticosteroids.25,58 Phase 2 trials
trial comparing tasquinimod to placebo was initiated
demonstrated a significant reduction in serum levels
in patients with mCRPC naive to chemotherapy.50
of PSA that led to 10 partial responses and 22 cases of
Cabozantinib: Cabozantinib is a tyrosine kinase inhibitor that blocks
c-MET and VEGF recepTable 2. — Experimental Therapies for the Treatment of Metastatic Castration-Resistant
tor 2 and is already apProstate Cancer
proved for the treatment
of medullary thyroid
Drug
Target
Effect
Study Results
cancer. This fact, comCabozantinib
c-MET
Inhibits tyrosine kinase
Partial resolution of bone lesions,
bined with its oral adactivity
decreases
number
of
CTCs,
VEGF-R2
decreases pain51
ministration, makes it a
favorable candidate for
Custirsen
Clusterin
Improves response
Extended median survival, extends
to docetaxel
PFS, improves PSA declines52
further investigation and
Ipilimumab
CTLA-4
T-cell activation
Ongoing54,55
development in mCRPC.
Phase 2 clinical trials have
Nivolumab
PD-1
T-cell activation
Ongoing53
shown that cabozantinib
Orteronel
CYP17A1
Reduces circulating
Decreases number of CTCs,
results in partial resolu(17,20 lyase activity)
testosterone levels
improves radiographic PFS48,49
tion of bone lesions in
Prostvac-VF
Delivery of PSA transgene T-cell activation
Improves median survival32,56
56% of patients and proTasquinimod
Thrombospondin
Antiangiogenic, reduces
Improves median PFS, stable bone
vided complete resolution
S100A9
MDSC recruitment
alkaline phosphatase levels50,57
in 19%.51 A total of 64%
CTC = circulating tumor cell, CTLA = cytotoxic T-lymphocyte antigen 4, MDSC = myeloid-derived suppressor cell,
PD-1 = programmed cell death 1, PFS = progression-free survival, PSA = prostate-specific antigen, VEGF-R2 = vascular
had an improvement in
endothelial growth factor receptor 2.
pain and 46% were able
Despite the growing number of FDA-approved agents
to treat mCRPC, room remains to improve upon the
therapeutic options available to patients and clinicians. For example, although approximately 50% of
patients with mCRPC will respond to docetaxel, most
patients develop resistance and disease progression
within 1 year of beginning treatment.36 However,
some treatments that target cancer and support the
microenvironment are currently in clinical trials that
have the potential to provide health care professionals
with new therapeutic options to treat men diagnosed
with mCRPC (see Fig 1). A list of these experimental
therapies appears in Table 2.32,48-57
January 2015, Vol. 22, No. 1
Cancer Control 113
to decrease or discontinue narcotics.51 An additional exploratory analysis updated the results of this
phase 2 trial and indicated a reduction of more than
30% in the bone scan lesion area and also indicated a reduction in circulating tumor cells.64 Multiple
phase 3 trials focused on the treatment of mCRPC with
cabozantinib are either ongoing or in the recruiting
stages (NCT01428219, NCT01703065, NCT01995058,
NCT01605227, NCT01834651, NCT01599793,
NCT01522443, NCT01683994). At the time of publication, NCT01605227 failed to reach efficacy in men
with mCRPC.
Custirsen: Custirsen is an antisense oligonucleotide that targets clusterin, a chaperone induced by
stress and detected at elevated levels in several tumor
types, including prostate cancer.65 Studies of clusterin
have demonstrated its antiapoptotic and prosurvival activities in prostate cancer that are believed to
be associated with docetaxel resistance.66 As such,
inhibiting clusterin concomitantly with docetaxel
may increase the time until docetaxel resistance in
mCRPC. Phase 2 trials of weekly intravenous custirsen
plus docetaxel extended median survival rates from
16.9 months to 23.8 months compared with single-agent docetaxel.67,68 Subsequent to treatment, significant decreases in clusterin levels were noted in patients treated with custirsen.67,68 A second phase 2 trial
evaluating custirsen plus prednisone compared with
mitoxantrone plus prednisone in patients with mCRPC
who previously failed first-line docetaxel showed an
increase of 4.3 months in median overall survival and
a 3.8-month increase in progression-free survival as
well as improved declines in PSA.52 Phase 3 trials of
custirsen are ongoing (NCT01578655), although its
benefits may be limited to patients expressing high
levels of clusterin.69
Prostvac-VF: The use of cancer vaccines aims
to generate an immune response to specific tumor
antigens. The Prostvac vaccine uses a fowlpox and
vaccinia platform to deliver the PSA transgene to antigen-presenting cells, which, in turn, express and
present the antigen to T cells and T-cell activation.70
In addition to PSA, the vaccine has been engineered
to include B7-1, ICAM-1, and LFA-3 antigen-presenting cell costimulatory molecules.71 Phase 2 trials in
patients with mCRPC have shown improvements of
8 to 9 months in median survival rates.56,72 The results
of these trials suggest that Prostvac offers an improvement compared with sipuleucel-T and have resulted
in the initiation of a phase 3 trial (NCT01322490).
Nivolumab: Blocking the programmed cell death
1 (PD-1)/programmed death ligand 1 (PD-L1) immunosuppressive axis has received much attention in
recent years. Nivolumab is a monoclonal antibody
that inhibits the interaction between PD-L1 and T-cell
expressed PD-1, preventing tumor-induced loss of
114 Cancer Control
T-cell effector function.73 In trials of melanoma, 80% of
patients responded to nivolumab therapy.74 However,
limited studies in CRPC have not been as promising;
phase 1 studies have failed to reach objective responses and others have shown limited or lack of PD-L1
expression by CRPCs or the immune infiltrates.53,73
However, it is possible that prospective, individual
patients with mCRPC with high levels of PD-L1 could
benefit from nivolumab.
Ipilimumab: As cancer progresses, it can express inhibitory ligands such as B7-1, B7-2, and
PD-L1 to suppress the immune system. Ipilimumab is
a monoclonal antibody that inhibits T-cell–expressed
cytotoxic T-lymphocyte antigen 4 from interacting
with antigen-presenting cell B7-1 and B7-2 ligands
but not those on tumor cells, allowing for the continued immune-mediated destruction of tumor cells.
Ipilimumab has been studied in melanoma and is
the only FDA-approved immune checkpoint inhibitor
on the market.40 Despite encouraging results in early
clinical trials, the results of a phase 3 trial of patients
with mCRPC receiving bone-directed radiotherapy
prior to 10 mg/kg ipilimumab or placebo revealed no
significant improvement in overall survival rates.54,55
However, individual analysis of patient subsets
indicated that ipilimumab may benefit men with low
disease burden, thus emphasizing the importance of
appropriate patient selection.16,55
Therapeutic Opportunities on the Horizon
Treatment options to extend the overall survival of patients diagnosed with mCRPC remains a major clinical
challenge. Therefore, understanding the factors that
drive the process of metastasis, the homing of the metastasis to organs (eg, bone), and how prostate cancer
cells form life-threatening active metastases once in
the bone warrants extensive research to generate new
therapies to cure the disease. Although metastasis is
classically thought of as a linear sequence of events
beginning with the dissemination and invasion of
tumor cells from the primary site and ending with
proliferation at the metastatic site, recent evidence
suggests that the first steps of metastasis can occur
before a patient’s tumor is diagnosed (Fig 2).75 This
“step 0” of the metastatic cascade results in the nonrandom priming of future sites of metastasis, a concept known as the “premetastatic niche.”
Premetastatic Niche
Primary tumor-derived factors have been implicated
in the development of premetastatic niches in distant
organs.76 Through a series of in vivo experiments, it
was illustrated that conditioned media derived from
highly metastatic cancer cells lines, such as the B-16
melanoma cell line, could stimulate the mobilization
of bone marrow–derived VEGF receptor 1+ VLA4+ Id3+
January 2015, Vol. 22, No. 1
hematopoietic precursor cells to develop premetastatic niche sites, including the lungs, liver, spleen,
kidney, and testes.76 Cancer-derived exosomes have
been implicated as the mechanism for facilitating
long distance, tumor–stroma interactions and initiating the premetastatic niche.77 Exosomes are microvesicles measuring 30 nm to 100 nm that contain a
variety of functional proteins and messenger/micro
RNAs.78 In the context of premetastatic niche formation, B16-F10–derived exosomes have been labeled
and shown to “home” to common sites of melanoma
metastasis.75 Furthermore, in the premetastatic niche,
exosomes can educate bone marrow–derived cells to
support metastatic tumor growth via the horizontal transfer of the c-MET protein.75 c-MET inhibitors, such as
cabozantinib, could be used to prevent the development
of premetastatic niches and, thus, mitigate the ability of
cancers to metastasize to new sites.
Exosome shedding has also been demonstrated
in prostate cancer, and studies have shown the presence of microvesicles termed oncosomes (0.5–5 µm)
in prostate cancer–conditioned media. Oncosomes
contain a variety of signal transduction proteins, including Akt and Src, and can interact with tumor and
stromal cells to elicit disease-promoting responses.79
In addition, a correlation exists between a Gleason
score higher than 7 and the number of oncosomes
present in patient plasma.80 Based on these findings,
it is plausible that prostate cancer–derived exosomes
can play a role in the formation of premetastatic niches in the bone microenvironment. Emerging evidence
also suggests that prostate cancer cells homing to the
bone microenvironment can occupy the endosteal
niche, the vascular niche, or both.81
Defining Factors Controlling the Homing of
Bone Metastatic Castration-Resistant Prostate Cancer
An unsolved question regarding metastasis is why
prostate cancer has such a predilection for the bone
microenvironment. More than a century ago, Paget82
formulated the “seed and soil” hypothesis to address
this question. His hypothesis suggested that metastasis
is a challenging process that requires “fertile soil” for
outgrowth but begins long before the “seed” meets
the “soil.”82 Ewing83 challenged Paget’s hypothesis in
the 1920s, proposing that metastasis was instead dependent on anatomy, vasculature, and lymphatics.
Metastasis by anatomy would become the accepted
model until the 1970s when modern experiments rekindled interest in the “seed and soil” hypothesis,
notably observing that circulating tumor cells reach
the vasculature of all organs, but only certain organs
are receptive for metastasis.84,85 In reality, prostate to
bone metastasis occurs by a blend of both hypotheses: It metastasizes first to the pelvic lymph node
and then to sites in the bone, including iliac crests,
January 2015, Vol. 22, No. 1
sacrum wings, L1 to L5 vertebrae, T8 to T12 vertebrae,
ribs, manubrium, humeral heads, and femoral necks.86
Although 15% to 30% of prostate to bone metastases
are due to cells traveling through the Batson plexus
to the lumbar spine, it is clear that molecular factors,
such as chemokines and integrins, underpin the propensity for prostate cancer cells to metastasize to the
skeleton.11 Elucidating those factors could help identify new therapies to prevent bone metastatic CRPC.
Bone is the home of regulatory sites for hematopoietic stem cells (HSCs), which are cells localized to
the vascular and endosteal niches where they either
await hematopoietic demand or reside in a quiescent
state.81 One well-defined signaling axis implicated in
metastasis is that between stromal cell–derived factor
1/CXCL12 and its receptor CXCR4, a system normally
utilized by HSCs homing to the niche.87 CXCL12 expression is increased in the premetastatic niche, and
studies in prostate cancer have demonstrated that
tumor cells with high bone-homing capacity express
CXCR4 and CXCR7 to parasitize the HSC niche.76,88,89
Furthermore, CXCR4 expression correlates with poor
prognosis.90 Additional axes, including MCP-1/CCR2
and CXCL16/CXCR6, have also been found to contribute to the progression of prostate cancer through
increases in proliferation, migration, and invasion.91,92
Disseminated Tumor Cells and Dormancy
Evidence suggests that tumor cells disseminated from
the prostate localize to the bone marrow niche, displace HSCs, and either proliferate to form a metastatic
mass or enter a state of dormancy.93 Dissemination
from the primary site to reside in distant environments
is an early event seen in prostate cancer, as patients
who undergo prostatectomy may present with metastases many years later.94,95 Disseminated tumor cells
(DTCs) reside in the bone marrow niche where they
can remain dormant and resistant to chemotherapy for
long periods of time (> 10 years) before emerging to
form metastatic outgrowths.94 Although most patients
with prostate cancer harbor DTCs, not all will develop
metastases, suggesting that mechanisms exist to maintain DTC dormancy as well as to promote awakening.95
Several bone marrow–dependent mechanisms
have been identified as modulators of prostate cancer
DTC dormancy. In the endosteal niche, the osteoblast
expression of Anxa2 combined with the expression
of the Anxa2 receptor (Anxa2R) by HSCs is important
in regulating HSC homing to the niche. Anxa2R expression is elevated in metastatic prostate tumor cells
and, as such, the Anxa2/Anxa2R axis can be hijacked
to promote the homing of prostate tumor cells to the
niche. Interrupting the interaction between Anxa2
and Anxa2R is sufficient to reduce tumor burden in
the niche.96 Evidence has revealed that the ligation
of Anxa2 with Anxa2R stimulates the expression of
Cancer Control 115
the Axl receptor tyrosine kinase.97 Axl, along with
Tyro3 and Mer, are receptors for osteoblast-expressed
growth arrest-specific 6 (GAS6).98 As was the case
with Anxa2/Anxa2R, the GAS6/Axl interaction typically occurs between HSCs and osteoblasts and is one
mechanism of controlling HSC dormancy.98 Engaging
osteoblast-expressed GAS6 and tumor cell–expressed
Axl yields a similar result that includes growth arrest and enhanced drug resistance in prostate cancer
cells.97 Following-up on these observations, data show
that these activities may be specific to the Axl receptor
compared with other GAS6 receptors.98 A high ratio of
Axl to Tyro3 expression encourages maintenance of
a dormant state, whereas reducing the expression of
Axl and increasing the expression of Tyro3 has been
shown to promote outgrowth.98
Interactions between osteoblasts and tumor cells
may be important to DTC dormancy. Prostate cancer
cells that bind with osteoblasts also upregulate the expression of TANK-binding kinase 1 (TBK1). In vitro and
in vivo knockdown of TBK1 resulted in decreased drug
resistance, suggesting that TBK1 may also play a role in
dormancy and drug resistance.100 A high p38:ERK ratio
has been shown to maintain dormancy of squamous
carcinoma cells, whereas interactions with the microenvironment can stimulate a switch to high ERK:p38
and reverse dormancy.101 Bone marrow–derived transforming growth factor (TGF) β2 has been implicated in
maintaining the dormancy of DTCs by p38 activation,
and inhibiting either the TGF-β receptor 1 or p38 leads
to the proliferation and metastasis of DTCs.102 Similarly,
bone morphogenetic protein 7 triggers prostate cancer
DTC dormancy in part by activating p38.103
Although much focus has been on the endosteal
niche, the vascular niche also has implications for
DTC dormancy. Through the use of advanced imaging
techniques, dormant DTCs have been shown to home
to perivascular niches in the bone marrow and the
lungs.104 These niches promote dormancy through
the expression of TSP-1; however, dormancy is lost
in regions of sprouting vasculature due to a loss of
TSP-1 and the activation of TGF-β and periostin.104
In vivo experiments in mice receiving bone marrow transplantation revealed that fewer HSCs successfully engraft in tumor-bearing mice, suggesting that
the tumor cells occupying the niche outcompete HSCs
for residence.105 In addition, expanding the endosteal
osteoblast niche with parathyroid hormone (PTH)
promoted metastasis, whereas decreasing the size of
the niche using conditional osteoblast knockout models reduced dissemination.105 Tumor cells can also be
forced out of the niche using methods to mobilize
HSCs, perhaps offering an opportunity for therapeutic
intervention.105 Filgrastim is an agent that mobilizes
HSCs out of the niche, and plerixafor blocks the interaction with stromal cell–derived factor 1 by acting as
116 Cancer Control
a CXCR4 antagonist to mobilize HSCs.106 Both agents
have been approved by the FDA and may serve as a
method of awakening and forcing the DTCs into circulation where they would become vulnerable to chemotherapy. A small molecule inhibitor specific to CXCR6
but not other chemokine receptors was developed for
investigating the CXCL16/CXCR6 axis.107 Although the
clinical utility of such an inhibitor must be investigated,
the selectivity of small molecule antagonists could aid
in the targeting of dormant tumor cells.
Therapeutic Opportunities for “Active” mCRPC
Although therapies to prevent the homing and establishment of mCRPC in the bone microenvironment
are important clinical tactics, many patients in the
clinical setting present with “active” bone metastases
that cause extensive bone remodeling. Defining the
mechanisms that control cell–cell communication between the metastases and the microenvironment are
also likely to reveal important therapeutic targets.
Osteomimicry: A recurring theme in bone metastasis is the hijacking of normal bone mechanisms
by tumor cells. The concept of osteomimicry is that
bone metastatic prostate cells acquire the ability to
produce proteins typically restricted to bone cells,
such as osteoblasts, to survive and proliferate in the
otherwise restrictive bone microenvironment.108 Select
genes normally expressed in bone have been detected
in prostate cells, including osteocalcin, osteopontin,
bone sialoprotein, osteonectin, RANK, RANKL, and
PTH-related protein.108-111 The expression of these
genes appears to be associated with the metastatic
capacity of the cells. Studies in both the PC3 and
LNCaP cell lines have shown that the expression
of osteonectin is highest in the more invasive and
metastatic sublines, including the LNCaP metastatic
variant C4-2B.109 Analysis of patient samples support
these findings, showing that osteonectin staining in
prostate to bone metastases was more intense than
from soft-tissue metastases.109 In addition to changes
in gene expression, prostate tumor cells may adopt
biological activities usually specific to bone cells. In
vitro studies indicate that human C4-2B prostate tumor cells are capable of depositing hydroxyapatite
and contributing to mineralization, a common feature
of the sclerotic lesions observed in vivo.110
Due to the shared expression of specific bone
genes between tumor and stroma cells, these common proteins could be used to simultaneously target both compartments. Understanding that soluble
factors like bone morphogenetic protein 2, RANKL,
TGF-β, granulocyte colony-stimulating factor, and
granulocyte-macrophage colony-stimulating factor
are partially responsible for inducing osteomimetic
genes may also provide options to specifically target
osteomimicry and establish bone outgrowths.111 It has
January 2015, Vol. 22, No. 1
been suggested that promoters for the common genes
between the tumor and stroma cells could be utilized
to drive the expression of therapeutic genes, thus
targeting both the stroma and tumor cells.108
Halting the Vicious Cycle of Bone Metastases:
Once the DTCs awaken and establish micrometastases,
continued outgrowth arises through the interaction
with multiple stromal cell types, growth factors, and
enzymes in a process known as the vicious cycle model.112 Prostate to bone metastases are characterized by
areas of mixed osteogenesis and osteolysis that give
rise to painful lesions.113 A number of tumor-derived
factors, including PTH-related protein, interleukin (IL)
1, IL-6, and IL-11, have been shown to interact with
osteoblasts and stimulate the production of RANKL.114
RANKL is a crucial molecule for osteoclast differentiation; therefore, it contributes to the extensive bone
remodeling seen in bone metastasis. In addition to
bone destruction, osteoclast-mediated bone resorption also releases a multitude of bone-derived factors
such as TGF-β, insulin growth factor, platelet-derived
growth factor, and fibroblast growth factor. These factors provide positive feedback via interaction with
their respective receptors on the surface of tumor
cells, thus promoting the proliferation and continued
production of tumor-derived factors.114 The vicious cycle is continually evolving to include other cell types,
cytokines, proteases, and therapeutics.115-118 Several
studies have shown contributory roles for highly expressed host matrix metalloproteinases (MMPs) in the
vicious cycle, including the regulation of latent TGF-β
and VEGF-A bioavailability by MMP-2 and MMP-9, and
the generation of a soluble form of RANKL by MMP-7,
which promotes osteoclastogenesis and mammary
tumor–induced osteolysis in vivo.119-121 In recent years,
the interactions with immune cells have become an
integral part of the vicious cycle. For example, T cells
stimulate and inhibit the formation of osteoclasts, and
the recruitment of regulatory T cells to bone marrow
may inhibit osteoclastogenesis. Myeloid-derived suppressor cells suppress T cells and release angiogenic,
tumor-promoting factors. Recruited myeloid-derived
suppressor cells have also been shown to differentiate
into osteoclasts.118
Although the need for therapies aimed at the early
stages of metastasis has been emphasized, patients
will still present in the later stages of the disease;
therefore, improving therapies for these patients must
still remain a priority. The interactions between tumor
and stromal cells in the vicious cycle model offer
many opportunities to intervene. Therapies such as
zoledronic acid and denosumab interfere with the
osteolytic component of the vicious cycle; however,
therapies to inhibit the unique osteosclerotic component of prostate to bone metastases are lacking.
Many roles for specific MMPs have been elucidated
January 2015, Vol. 22, No. 1
in the vicious cycle,115,120,121 and the development of
MMP inhibitors with improved specificity is perhaps
a promising method to modulate the vicious cycle.122
From these discoveries, it is becoming evident that
the metastasis of prostate cancer is not a linear, stepwise procedure. Defining the mechanisms that control
CRPC metastasis may help elucidate new therapeutic
targets that directly impact the cancer cells and the
processes that facilitate the formation of a premetastatic niche, niche seeding, dormancy, and the vicious
cycle.123 Such new discoveries are highly likely to impact the clinical treatment of patients with mCRPC.
Upcoming Challenges
Our knowledge of the mechanisms driving the progression of prostate cancer is growing. Although several new therapies that target both the cancer cells
and the supporting microenvironment and are likely
to increase overall survival rates for men with mCRPC,
new challenges are also emerging, particularly within
the context of tumor heterogeneity. Heterogeneity is
a key aspect of cancer evolution and is a clinical reality in many cancers, including prostate cancer.124-126
Greater heterogeneity facilitates the evolution of the
treatment resistance of cancer but also gives the cancer a number of phenotypic strategies that allow for
growth in select microenvironments (eg, bone).
Emerging studies suggest that most patients would
be best served by therapies tailored toward cancer
cells harboring common aberrations as well as by
therapies geared toward smaller subpopulations who
could potentially become the dominant-resistant population.127 The therapies described herein constitute
new ways in which to expand the number of potential
options for the treatment of heterogeneous bone metastatic CRPCs. However, a challenge emerging with
the advent of these therapies is how to rationally
design a treatment strategy for individual patients.
Current guidelines from the National Comprehensive
Cancer Network provide recommendations for applying the sequence of existing therapies to patients
with mCRPC based on individual patient parameters.
However, some studies suggest that altering the sequence or the combination of existing therapies can
have a profound impact on overall survival rates.128
To circumvent costly and time-consuming clinical
trials assessing the combination and sequence alterations of a new line of targeted therapies currently
in clinical trials, alternative approaches are required.
In this regard, integrating computational models and
genetic algorithms with individual patient-derived
biological data might lead to the rapid optimization
of therapy choice and sequence. In the preclinical
setting, the power of this integrated approach has
been demonstrated. Recent studies have discovered
how appropriate drug combinations guided by comCancer Control 117
putational models could minimize prostate cancer
progression in vivo.129 Therefore, the refinement and
validation of these approaches may assist in overcoming the challenges posed by cancer heterogeneity.
Conclusions
Metastatic castration-resistant prostate cancer is an
incurable disease, but the advent of new therapies,
combined with an enhanced understanding of the
underlying biology, suggests that significant improvement in overall survival is within reach. An increase
in the number of available treatment options will be
challenging from a clinical perspective with regard
to patient stratification and in selecting the optimal
therapy sequence, combination, or both. However,
integrating computational models and genetic algorithms based on individual patient data may help
overcome this challenge and allow for the delivery of
individualized treatment for patients with this disease.
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120 Cancer Control
January 2015, Vol. 22, No. 1
Ten Best Readings Relating
To Transfusion Medicine
Glynn SA, Busch MP, Dodd RY, et al. Emerging
infectious agents and the nation’s blood supply:
responding to potential threats in the 21st century.
Transfusion. 2013;53(2):438-454.
This review includes a history and current status
of transfusion-transmissible risks of HIV, hepatitis C
virus, West Nile virus, Trypanosoma cruzi, Babesia,
dengue viruses, and variant Creutzfeldt–Jakob disease
prion. It addresses the challenges noted and measures
taken by the field of transfusion medicine to minimize
the risk of emerging infectious disease agents. Mitigation strategies such as specific donor deferral criteria,
screening assays, discontinuation of blood collection
in specific geographic areas, and pathogen reduction
technologies are discussed.
Price TH, McCullough J, Ness P, et al. A randomized controlled trial on the efficacy of high-dose
granulocyte transfusion therapy in neutropenic
patients with infection. Paper presented at: 56th
ASH Annual Meeting and Exposition; San Francisco, CA; December 6–9, 2014. https://ash.confex.
com/ash/2014/webprogram/Paper68775.html.
Accessed November 20, 2014.
The authors report on the results of the Resolving
Infection in Neutropenia With Granulocytes study.
The recently completed randomized controlled trial
studied the efficacy of high-dose granulocyte transfusion therapy.
provide clinical recommendations on the appropriate
use of platelet transfusion in adults. The strongest
recommendation was for the use of prophylactic transfusion to reduce the risk of spontaneous bleeding in
hospitalized adult patients with therapy-induced hypoproliferative thrombocytopenia. For such patients,
a threshold of 10,000/µL or less should be used, and
doses up to a single apheresis unit or equivalent are
sufficient; greater doses are not more effective, and
lower doses are equally effective.
Villanueva C, Colomo A, Bosch A, et al. Transfusion
strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11-21.
As compared with a liberal transfusion strategy,
a restrictive strategy significantly improved outcomes
in patients with acute upper gastrointestinal bleeding.
Stanworth SJ, Estcourt LJ, Powter G, et al; TOPPS
Investigators. A no-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J
Med. 2013;368(19):1771-1780.
The results of this study support the need for the
continued use of prophylaxis with platelet transfusion
and show the benefit of such prophylaxis for reducing
bleeding compared with no prophylaxis.
Carson JL, Grossman BJ, Kleinman S, et al; Clinical
Transfusion Medicine Committee of the AABB. Red
blood cell transfusion: a clinical practice guideline
from the AABB. Ann Intern Med. 2012;157(1):49-58.
The AABB (formerly American Association of
Blood Banks) developed this practice guideline to
provide clinical recommendations for hemoglobin
concentration thresholds and other clinical variables
that trigger red blood cell (RBC) transfusions in hemodynamically stable adults and children. The strongest recommendation was for adhering to a restrictive
transfusion strategy (7–8 g/dL) in stable patients in
the hospital.
Wandt H, Schaefer-Eckart K, Wendelin K, et al;
Study Alliance Leukemia. Therapeutic platelet
transfusion versus routine prophylactic transfusion in patients with haematological malignancies:
an open-label, multicentre, randomised study. Lancet. 2012;380(9850):1309-1316.
According to results from this study, therapeutic
platelet transfusion could become the new standard of
care after autologous stem cell transplantation; however, prophylactic platelet transfusion should remain
the standard for patients with acute myeloid leukemia.
This new strategy should be used by select hematology centers if their health care team is well educated
and experienced in the new approach and can react
in a timely way to the first signs of central nervous
system bleeding.
Kaufman RM, Djulbegovic B, Gernsheimer T, et al.
Platelet transfusion: a clinical practice guideline
from the AABB. Ann Intern Med. 2014. http://annals.org/article.aspx?articleid=1930861. Accessed
November 20, 2014.
The AABB developed this practice guideline to
Steiner ME, Triulzi DJ, Assmann SF, et al. Randomized trial results: red cell storage age is not associated with a significant difference in multiple
organ dysfunction score or mortality in transfused
cardiac surgery patients. Paper presented at: AABB
Annual Meeting; Philadelphia, PA; October 25–28,
January 2015, Vol. 22, No. 1
Cancer Control 121
2014. http://onlinelibrary.wiley.com/doi/10.1111/
trf.12845/full. Accessed November 20, 2014.
Cardiac patients often require multiple RBC units,
so they may be exposed to units that have been stored
the longest. This study aimed to determine whether
a difference in patient outcomes occurred after the
transfusion of units stored for 10 days or less versus
units stored 21 days or longer.
Holst LB, Haase N, Wetterslev J, et al; TRISS Trial
Group; Scandinavian Critical Care Trials Group.
Lower versus higher hemoglobin threshold
for transfusion in septic shock. N Engl J Med.
2014;371(15):1381-1391.
Among patients with septic shock, the rates of
90-day mortality and ischemic events as well as use
of life support were similar among those assigned to
blood transfusion at a higher hemoglobin threshold
and those assigned to blood transfusion at a lower
threshold; the latter group received fewer transfusions.
Schwartz J, Winters JL, Padmanabhan A, et al.
Guidelines on the use of therapeutic apheresis
in clinical practice-evidence-based approach from
the Writing Committee of the American Society for
Apheresis: the sixth special issue. J Clin Apher.
2013;28(3):145-284.
This Sixth Edition of the American Society for
Apheresis (ASFA) Special Issue has further improved
the process of using evidence-based medicine in the
recommendations by consistently applying the category and GRADE system definitions and eliminate level
of evidence criteria. This article consists of 78 fact
sheets for therapeutic indications in ASFA categories I
to IV and includes multiple clinical presentations and
scenarios that are individually graded and categorized.
122 Cancer Control
January 2015, Vol. 22, No. 1
Contact and General Information
Cancer Control: Journal of the Moffitt Cancer Center
is published by H. Lee Moffitt Cancer Center & Research Institute and is included in Index Medicus®/
MEDLINE® and EMBASE®/Excerpta Medica, Thomson
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and Journal Citation Reports/Science Edition. Cancer
Control currently has an impact factor of approximately 2.655.
This peer-reviewed journal contains articles on the
spectrum of actions and approaches needed to reduce
the impact of human malignancy.
Cancer Control is sent at no charge to approximately 15,000* medical professionals, including oncologists
in all subspecialties, selected primary care physicians,
medical researchers who specialize in oncology, and
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To Change Your Mailing Address:
Please provide your old address and your
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Fax: 813-449-8680
Phone:813-745-1348
To Inquire About Reprints:
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January 2015, Vol. 22, No. 1
Cancer Control 123
FACULTY POSITION: CUTANEOUS MEDICAL ONCOLOGIST
Moffitt Cancer Center, an NCI-designated Comprehensive Cancer Center, is seeking a Medical Oncologist for
its Cutaneous Oncology Program. A competitive salary package with excellent benefits, a high level of clinical
resources, and outstanding infrastructural research support are available, including protected time for research
endeavors. The prospective candidate will be appointed at the Assistant Member level or higher if warranted.
Extensive Cancer Center Core facilities for translational research are available, and their use by the candidate
for innovative clinical trials will be encouraged. The patient population at Moffitt Cancer Center is a diverse and
outstanding resource for the conduct of clinical trials. At Moffitt, significant growth in clinical and translational
research, laboratory space resources, and faculty recruitment will be a high priority in the next decade.
In 2007, Moffitt established the Comprehensive Melanoma Research Center made possible by a generous
philanthropic gift of $20.4 million from Donald A. Adam. This Center conducts research in melanoma and
translates it into cutting-edge patient treatment. Moffitt was also recently awarded an NIH Specialized Program
in Research Excellence (SPORE) grant for melanoma, and the prospective candidate will be expected to have
a substantive role in the clinical and translational research activities of the SPORE and will have access to the
career development and other developmental resources provided by the SPORE.
Applicants must have a Florida medical license or be eligible for one, an MD, or MD/PhD and be board certified or eligible in internal medicine and board eligible/certified or equivalent in medical oncology. The applicant
should be familiar with a multidisciplinary academic clinical practice setting. The successful candidate must
have clinical expertise in melanoma and a desire to participate in and design clinical trials, including those
involving drug development. Familiarity with other cutaneous malignancies besides melanoma is a plus.
Background in clinical and/or translational research is essential, as is an interest in education and teaching.
Knowledge of scientific research methods, knowledge of federal guidelines related to conducting clinical trials,
knowledge of quality assurance, and excellent spoken and written communication skills are required.
An opportunity exists to participate in the clinical activities of other Moffitt clinical programs as well.
For inquiries about the position, contact Vernon K. Sondak, MD, Chair, Cutaneous Oncology Department,
at [email protected] or 813-745-8788.
To apply, visit our Web page at MOFFITT.org/careers.
The H. Lee Moffitt Cancer Center & Research Institute, a rapidly growing NCI-designated Comprehensive Cancer
Center, is committed to education through a wide range of residency and fellowship programs. The Cancer Center
is composed of a large ambulatory care facility, a 206-bed hospital, with a 36-bed blood and marrow transplant
program, 15 state-of-the-art operating suites, a 30-bed intensive care unit, a high-volume screening program,
and a basic science research facility. The Moffitt Research Institute is composed of approximately 150 principal
investigators, 58 laboratories, and 306,000 square feet of research space. The Moffitt Cancer Center is affiliated
with the University of South Florida. Primary and secondary university appointments are available as applicable.
Academic rank is commensurate with qualifications and experience.
124 Cancer Control
January 2015, Vol. 22, No. 1
FACULTY POSITION: NEUROLOGIST
Moffitt Cancer Center’s Neuro-Oncology Department is seeking a neurologist. The Neuro-Oncology Program
employs an interdisciplinary approach, offering comprehensive therapy for patients with primary and metastatic
tumors of the brain and spinal cord, as well as neurological complications of cancer and its treatments. In addition to focusing on the neurological complications of cancer and its treatment, the neurologist would provide
in-house consultation for general neurological problems to the Cancer Center. The successful candidate will
develop a strong, clinical, or translational program in general neurology in cancer.
The ideal candidate will have significant expertise in general neurology in a cancer setting with an emphasis
in neurology. Clinical research and the ability to work closely with an interdisciplinary team of experts, including neurosurgical oncology, neuropathology, neuroradiology, neuropsychology, and laboratory scientists, are
required. Moffitt Cancer Center has strong preclinical programs in immunotherapy, drug discovery, genomics,
cell-based therapies, and bioinformatics. There is also an extraordinary effort in personalized medicine partnering with the biotechnology/pharmaceutical industry.
The Neuro-Oncology Program at Moffitt is a high-volume program, with approximately 500 new patients
with brain tumors every year, and is active in the initiation and completion of numerous clinical trials with a
well-developed clinical and translational research infrastructure. The Neuro-Oncology Program is an active
participant in the National Comprehensive Cancer Network.
Successful candidates must have a Florida medical license or be eligible for one, an MD, be board certified/
eligible in neurology, and fellowship trained in neurology. Experience in a clinical, multidisciplinary academic
setting is preferred. A commitment to develop clinical research studies is required. The candidate should be
experienced in performing and interpreting electroencephalography and electromyography. With a very active
Cancer Spine Program and Neurosurgical Division, experience in physical and rehabilitation medicine would
be desirable.
For inquiries about the position, contact Peter Forsyth, MD, Chair, Department of Neuro-Oncology,
at [email protected] or 813-745-3063.
To apply, visit our Web page at MOFFITT.org/careers.
Moffitt Cancer Center provides a tobacco-free work environment.
It is an equal opportunity, affirmative action employer and a
drug-free workplace.
January 2015, Vol. 22, No. 1
Cancer Control 125
LEADING TREATMENT
FOR WOMEN WITH CANCER
At Moffitt, we offer a
patient-centric approach
coupled with the latest
advances in breast and
gynecologic oncology, taking
into account fertility-sparing
therapies and sexual health
counseling. Our team utilizes
comprehensive treatment plans
and recovery programs to
provide women with the best
quality of life before, during
and after cancer treatment.
TO REFER A PATIENT,
CALL 1-888-MOFFITT
OR VISIT REFER2MOFFITT.com
MOFFITT CANCER CENTER
12902 MAGNOLIA DRIVE, TAMPA, FL
MOFFITT CANCER CENTER AT INTERNATIONAL PLAZA
4101 JIM WALTER BOULEVARD, TAMPA, FL
126 Cancer Control
January 2015, Vol. 22, No. 1
REFER2MOFFITT.COM
ACCESS REAL-TIME RECORDS AND PATIENT UPDATES
AN ALL-IN-ONE RESOURCE SITE NOW
AVAILABLE FOR PHYSICIAN PRACTICES
As Florida’s largest multispecialty cancer center, Moffitt Medical Group welcomes
you and your staff to our physician portal resource site. The site
is a valuable tool for following your patients’
progress as well as accessing
Moffitt’s clinical services.
• Real-time shared patient
record information
• Search the physician directory
• Process easy online referrals
• View treatment &
procedure information
• Access open clinical trials
• Find lectures & CME schedules
TO REFER A PATIENT, CALL 1-888-MOFFITT
OR VISIT REFER2MOFFITT.com
MOFFITT CANCER CENTER
12902 MAGNOLIA DRIVE, TAMPA, FL
MOFFITT CANCER CENTER AT INTERNATIONAL PLAZA
4101 JIM WALTER BOULEVARD, TAMPA, FL
MOFFITT CANCER CENTER, TAMPA, FL
1-888-MOFFITT | MOFFITT.org
January 2015, Vol. 22, No. 1
Cancer Control 127
advances in the
management of
multiple
Save the Date!
presents
Advances in the Management
of Multiple Myeloma
March 6—7, 2015
Loews Don Cesar Hotel
St. Petersburg Beach, FL
Course Directors:
Melissa Alsina, MD, Rachid Baz, MD,
and Kenneth H. Shain, MD, PhD
Moffitt Cancer Center, Tampa, FL
Conference Overview:
The Advances in the Management of Multiple
Myeloma conference is designed to foster
the exchange of the most recent advances
in the biology and treatment of multiple
myeloma. National and international leading
experts in the field will present in a format
that promotes discussion and interaction
with participants.
Target Audience:
This educational program is directed
toward hematologists, medical and surgical
oncologists, and BMT physicians who
diagnose, treat, and manage multiple
myeloma. Other health care professionals
interested in the diagnosis, treatment, and
care of patients with multiple myeloma are
also invited to attend.
To be added to the conference mailing list, contact:
Moffitt Cancer Center | Marsha Moyer, MBA | 813-745-2286 | [email protected]
128 Cancer Control
January 2015, Vol. 22, No. 1
3 RD A N N U A L
S TAT E - O F -T H E - A R T
Neuro-Oncology
CONFERENCE
SAVE THE DATE
March 19—20,2015
Sheraton Sand Key
Clearwater Beach, FL
CONFERENCE
HIGHLIGHTS
• Renownedfaculty
representingthecountry’s
leadinginstitutions
•Updatesonbrainand
spinetumors
•Preconferencedinner
presentationonMarch19
•Interactivecasepresentations
withdiscussion
• Nursetracksession
• Callforabstracts
COURSE DIRECTORS Peter Forsyth, MD • Frank Vrionis, MD, MPH, PhD
CONFERENCE CONTACT [email protected] • MOFFITT.org/NeuroOncology2015
PROVIDED BY
January 2015, Vol. 22, No. 1
Cancer Control 129
Save the Date
9TH ANNUAL
Business of Biotech
Conference
Collaborate to Innovate
Friday, April 17, 2015
7:45 AM — 4:00 PM
Vincent A. Stabile Research Building
Moffitt Cancer Center | Tampa, FL
MAKING THE VISION OF
CURING CANCER A REALITY
As the only NCI-designated Comprehensive Cancer Center
based in Florida, Moffitt is a national innovator in research
and is at the forefront of transforming cancer care for
better patient outcomes, prevention and cures.
KEYNOTE SPEAKER: Henri A. Termeer
Former CEO, Chairman and President of
Genzyme Corporation. He retired following
the acquisition of Genzyme by Sanofi in a
transaction valued at more than $20 billion.
Register today for the Business of Biotech 2015 conference
by using the QR code.
TO LEARN MORE ABOUT OTMC ALLIANCES,
EMAIL [email protected]
130 Cancer Control
January 2015, Vol. 22, No. 1