1. Healthcare

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Hematopoietic Growth Factors for Graft Failure After Bone Marrow
Transplantation: A Randomized Trial of Granulocyte-Macrophage
Colony-Stimulating Factor (GM-CSF) Versus Sequential GM-CSF
Plus Granulocyte-CSF
By Daniel J. Weisdorf, Catherine M. Verfaillie, Stella M. Davies, Alexandra H. Filipovich, John E. Wagner Jr,
Jeffrey S. Miller, Jory Burroughs, Norma K.C. Ramsay, John H. Kersey, Philip B. McGlave, and Bruce R. Blazar
Delay in hematologic recovery after bone marrow transplantation (BMT) can extend and amplify therisks of infection and hemorrhage, compromise patients' survival, and
increase the duration and cost of hospitalization. Because
current studies suggest that granulocyte-macrophage (GM)
colony-stimulating factor (CSF) may potentiate the
sensitivity ofhematopoietic progenitor cells t o G-CSF, we performed a prospective, randomized trial comparing GM-CSF
(250 pg/m2/d x 14 days) versus sequential GM-CSF x 7 days
followed by G-CSF (5 pg/kg/d x 7 days) as treatment for
primary orsecondary graft failure afterBMT. Eligibility criteria included failure t o achieve a white bloodcell (WBC) count
=lOO/pL by day +21 or r3OOlpL by day +28, no absolute
neutrophil count (ANC) =2OO/pL by day +28, or secondary
sustained neutropenia afterinitial engraftment. Forty-seven
patients were enrolled: 23 received GM-CSF ( I O unrelated,
8 related allogeneic, and 5 autologous), and 24 received GMCSF followed by G-CSF (12 unrelated, 7 related allogeneic,
and 5 autologous). For patients receiving GM-CSF alone,
neutrophil recovery (ANC =500/pL) occurred between 2 and
61 days (median, 8 days) after therapy, while thosereceiving
GM-CSF + G-CSF recovered at a similar rate of 1 t o 36 days
(median, 6 days; P = .39). Recovery t o red blood cell (RBC)
transfusion independence was slow, occurring 6 t o 250 days
(median, 35 days) after enrollmentwithno
significant
difference between thet w o treatment groups (GM-CSF: median, 30 days; GM-CSF + G-CSF; median, 42 days; P = .24).
Similarly, platelet transfusion independence was delayed
until 4 t o 249 days (median, 32 days) after enrollment, with
no difference between thetwo treatment groups (GM-CSF:
median, 28 days; GM-CSF + G-CSF: median, 42 days; P =
.38). Recovery times were not different between patients
with unrelated donors andthose withrelated donors or autologous transplant recipients. Survival at 100 days after
enrollmentwas
superior after treatment with GM-CSF
alone. Only 1of 23 patients treatedwith GM-CSF died versus
7 of 24 treated with GM-CSF + G-CSF who died 16 to 84
days (median, 38 days) after enrollment, yielding KaplanMeier 100-day survival estimates of 96% k 8% for GM-CSF
versus 71% k 18% for GM-CSF + G-CSF ( P = ,026). These
data suggest that sequential growth factor therapy with
GM-CSF followed by G-CSF offers no advantage over GMCSF alone in accelerating trilineage hematopoiesis or preventinglethal complications in patients with poorgraft
function after BMT. GM-CSF should still be considered the
standard for graftfailure against which other, newer growth
factors, sequential treatments, or combinationtherapies are
tested.
0 1995 by The American Society of Hematology.
I
tion of their effectiveness in promoting engraftment after
BMT.4"0 Onlylimited data are available assessing their value
in accelerating recovery and improving survival for patients
with delayed or poorly functioning grafts after transplantation.""'
Preclinical data suggest that early-acting growth factors
suchas GM-CSF, interleukin (IL)-3, or stem cell factor
might increase the responsiveness of committed hematopoietic progenitors to later-acting factors such as G-CSF or
erythropoietin."-**To evaluate the clinical value of this type
of sequential growth factor therapy, we performed a formal,
prospective, randomized, comparative trial of GM-CSF
alone versus GM-CSF followed by G-CSF for stimulating
hematologic recovery in patients with primary or secondary
graft failure after BMT. This report describes the hematologic and clinical outcomes of this comparative trial.
N THE EARLY pancytopenic period after bone marrow
transplantation (BMT), infection, and hemorrhage are
the major morbidand life-threatening complications observed.' Any delay in hematopoietic recoverycan extend
and exaggerate this period of risk.*,' Poor graft function or
secondary graft failure leading to secondary neutropenia may
also increase these hazards and compromise patient survival.
Delayed hematologic recoveryis a primary factor in extending hospitalization and markedly increasing the cost of
BMT therapy. The availability of granulocyte macrophage
colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) as licensed products for use
in stimulating hematopoietic function has allowed investigaFrom the Departments of Medicine, Pediatrics, Laboratory Medicine, and Pathology and the Bone Marrow Transplantation Program, University of Minnesota, Minneapolis, MN.
Submitted November 14, 1994; accepted January 31, 1995.
Supported in part by a grant from the National Cancer Institute
( N U : CA21737). B.R.B. is a recipient of the Edward Mallinckrodt
Jr Scholar Award, and J.H.K. is arecipient of an Outstanding Investigator Award (CA49721) fromthe NCI.
Addresscorrespondenceto Daniel J. WeisdoffMD, Box 480,
University of Minnesota Hospital, 420 DelawareSt SE, Minneapolis,
MN 55455.
The publication costsof this article were defrayedin part by page
chargepayment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 I995 by The American Society of Hematology.
0006-4971/95/85I2-0013$3.00/0
3452
PATIENTS AND METHODS
All patients with graft failure after BMT at the University of
Minnesota (Minneapolis, MN) were eligible for this trial. Patients
had received either autologous bone marrow or peripheral blood stem
cells or were allogeneic transplant recipients (from either related or
unrelated donors). Patients were eligible for enrollment if they met
the following definitions of graft failure: (1) failure to achieve a
leukocyte count of >100/pL by day +21 after transplantation, (2)
failure to achieve a leukocyte count 2300/pL or an absolute neutrophil count (ANC) 2200/pL by day + 28; or (3) failure to maintain
a mean ANC 2500/pL for 7 days after having previously achieved
an ANC =-5OO/pL at any time beyond day +28 (secondary neutropenia). Patients receiving recombinant cytokines under different
study protocols at the University of Minnesota (including a trial of
Blood, Vol 85, No 12 (June 15), 1995: pp 3452-3456
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3453
GROWTH FACTORS FOR GRAFT FAILURE AFTER BMT
Table 1. Patient Characteristics
recombinant IL-laZ3and a trial of recombinant ~ 2 were
’ excluded
~
until day +28, after which time they could be enrolled still
if eligible
GM-CSF x 7 days
GM-CSF
becauseofgraft failure. Patients undergoing allogeneic BMT for
+ G-CSF x 7 days
X 14 days
severe combined immunodeficiency (SCID) or familial erythropha23
24
N
gocyticlymphohistiocytosis (FEL), thosereceivinggranulocyte
32; 3-51
37; 4-51
Median age; range (yr)
transfusions, and those undergoing autologousBMT for acute non14:9
17:l
lymphocytic leukemia (ANLL) and treated under Children’s Cancer Sex (M:F)
Type of transplant
Group studies that specifically excluded cytokine use were ineligible.
7
8
Allogeneic related
During the study period, seven eligible patients were not enrolled
10
12
Unrelated donor
due to patient refusal (n = 3), attending physician preference (n =
5
5
Autologous
3). and prior adverse reaction to GM-CSF (n = 1).
Diagnosis
Eligible, consenting patients were assigned to receive either GM4
Acute leukemia
9
CSF (250 pg/m2/d over 2 hours intravenously X 14 days) or GM14
Chronic
myelogenous leukemia
5
CSF (250 pg/m’/d over 2 hours intravenously X 7 days) followed
4
Other malignancy+
6
immediately by G-CSF (5 pg/kg/d intravenously over 15 minutes
2
Nonmalianantt
3
x 7 days). This prospective, randomized enrollment was stratified
Includes non-Hodgkin‘s lymphoma (n = 6). myelodysplastic synintogroupsof either unrelated donor marrow recipients or other
dromes (n = 3). and neuroblastoma (n = 1).
recipients that included recipientsof either related donor allogeneic
or autologous transplantation. All patients except one were enrolled t Includes aplastic anemia (n = 4) and hypereosinophilic syndrome
(n = 1).
for treatment for primary graft failure.
The primary endpoint for response to cytokine therapy was the
development of a sustained ANC 2500/pL for 3 consecutive days.
Secondary endpoints included recoveryof red cells and platelets to
treated with GM-CSF alone and those
treated with GM-CSF
transfusion-independence, adverse reactions to cytokine infusions,
+
G-CSF (P = .39; Table 2). The neutrophil recovery times
and 100-day survival. Patients not responding to the first
14 days
were similar in the two patient strata: those receiving unreof therapy were eligible for retreatment, as previously assigned, for
lated
donor BMT (median, 8 days; range, 1 to 61 days) and
a secondfullcourse. Ifgraft failure wasrefractorytotreatment,
some patients subsequently received reinfusion of donor or back-up those receiving related donor or autologous BMT (median,
8 days; range, 2 to 36 days; P = .78). After 14 days, 75%
autologous ma~row.’~
Inadditiontotheseretransplantedpatients,
t 18% (95% confidence interval) of those treated with GMfive others (three in the GM-CSF a r m ; two in the GM-CSF + GCSF alone achieved
neutrophil recovery compared with 79%
CSF m )
continued their assigned growth factors beyond 14 days.
The trial was performed using the commercially available products+. 16% of thosereceivingGM-CSF
G-CSF ( P > S ) .
(GM-CSF Immunex Corp, Seattle,WA; and G-CSF: Amgen, Thou- Recovery to red cell transfusion-independence was delayed
sand Oaks, CA) withno external funding from the manufacturers.
but occurred between 6 and 250 days after enrollment (meThe study protocol was reviewed and approved
by the University
dian, 35 days). There was no difference between
the two
of Minnesota Institutional Review Board: Human Subjects Committreatment arms (P = .24). Recovery to platelet transfusiontee, and all patients(or their parents) gave written informed consent.
independence was also delayed and occurredbetween 4 and
Statistical analysis. Times to hematologic recovery and survival
35 days), but the two
249 days after enrollment (median,
were evaluated by Kaplan-Meier calculations, and differences betreatment arms were similarly effective ( P = .38; Fig 1).
tween groups werecomparedusingtheMantel-Coxtest
statistic.
Survival. We next evaluated survival over the first 100
Short-term survival was evaluated censoringall patients at 100 days
days after enrollment. We observed
a statistically significant
after enrollment. Comparisonsof patient characteristics betweenthe
two study groups were performed using a x’ statistic. All analyses
advantage ( P = .026) favoring GM alone versus GM-CSF
were performed by intention-to-treat according to the randomized
+ G-CSF. Only 1 of 23 GM-CSF patients died(at day +34)
assignment.
after enrollment versus 7 of 24 GM-CSF G-CSF patients
who died between days 16 and 84 (median,
38 days) after
RESULTS
enrollment (Fig2). The primary and secondary causes
of
Of 472 BMT procedures performed at the University of
death in all eight patients who died were directly related to
Minnesota between January 1992 and March 1994, 47 pagraft failure, including hemorrhage and infection in six of
tients metthe criteria for entry, consented, and were enrolled eight patients (Table 3). Of the patients who died, the one
in this randomized trial. Theirclinical characteristics are
receiving GM-CSF alone had undergone an allogeneic
reshowninTable
1. The groupsincluded 15 related-donor
lated-donor transplant, while the seven GM-CSF + G-CSF
allogeneic transplant recipients (of 167 transplanted within
deaths occurred in one of five autologous and two of seven
the same time interval); 22 unrelated-donorrecipients (of
related-donor allogeneic transplants and 4 of 12 unrelated
recipients (of 174 trans131 transplanted), and 10 autologous
donor transplants. Deaths attributable to infection occurred
planted). Of the 47 patients, 23 received GM-CSF for 14
20 to 84 days after study entry and cannot be
ascribed to
days, and 24 received GM-CSF for 7 days followed by Gdifferences in active infections at study entry.
CSF for 7 days. Forty (85%) recovered (ANC 250O/pL)
Adverse reactions and compliance with therapy. For all
between 1 and 61 days after initiation of cytokine therapy
47 patients enrolled on the trial, we assessed completeness
(median, 8 days). Seven patients were censored from analyof therapy and adverse reactions to
treatment. Because treatsis at the time of reinfusion of supplemental marrow (three
ment on both study arms was the same for the first 7 days
recipients of allogeneic related donor and fourunrelated dooftherapy and the therapeuticinterventionsdiffered
only
nor marrow).
between days 8 and 14 of treatment, we evaluated the 2
There were similar rates of neutrophil recovery in those
weeks separately. Overall, 43 of 47 patients received at least
+
+
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3454
WEISDORF ET AL
Table 2. Hematology Recovery After Cytokine Therapy
for Graft Failure
~~~
~~~~
-
Median Time
to Recovery; Range (d)
GM-CSF
+ G-CSF
GM-CSF
x 14 days
(N = 23)
(N = 24)
P
ANC 2 500/pL
.391-36 6;
8; 2-61
RBC transfusion-independence
(first of 30+ d)
30; 6-12442;11-250.24
Platelet transfusion-independence
(first of 15+ d)
28;6-127 42;
4-249
.38
~~
~~~
P values represent Mantel-Cox tests
~
of significance between the
two groups.
five of the seven planned doses of GM-CSF during the first
treatment week, 19 of 23 received at least five of the seven
randomly assigned GM-CSF doses, and 20
of the 24 received
at least five of the planned seven G-CSF doses.Of those 10
patients who received less than the scheduled therapy, eight
were stopped according to protocol because
neutrophil recovery made cytokine therapy no longer necessary. No significant adverse reactions (eg, fevers, rash,serositis, bone
pain) led to discontinuationof either GM-CSF or G-CSFon
either treatment a r m . Graft-versus-host disease (GVHD)was
similarly frequent in both treatment arms. Fourteen of the
18 allogeneic transplant recipientsreceiving GM-CSF and16
of 19 receiving GM-CSF G-CSF developed acute GVHD.
+
DISCUSSION
Bone marrow graft failure or poor hematologic function
after BMT is frequent, can contribute to greater post-BMT
mortality, and often complicates and prolongs hospitaliza-
tion,thusincreasingtreatment
costs.'.' in a retrospective
evaluation of delayed engraftment at ourinstitution that preceded initiation of this trial, of S91 patientstransplanted,
196 (33%) had not achieved an ANC ?SOO/yL by 28 days
after BMT. Thisone-third rate of delayed hematologic recovery(defined by alessstringentendpoint
than that of the
current study) was similar in all three cohorts (autologous,
related-donor, and unrelated-donor BMT) before hematopoietic growth factors were available as therapeutic tools. However, we also observed that 6-month survival was equivalent
for those with or without neutrophil recovery to zS00/pL
by day 28 (70% v 62%, respectively; P = . l 8). although
hospitalstay was oftenprolongedsecondary
to persisting
neutropenia. With that institutional background data available,we initiatedthe current trial in which we evaluated
sequentialtherapy of GM-CSF followed by G-CSF cornpared with GM-CSF alone to reduce the early
morbidity and
improve survival for patients with graft failure.
Numerous reportssuggestthatseveralhematopoietic
growth factors, including GM-CSF,G-CSF, 1L-la, 1L-3, and
some growth factor combinations can
accelerate engraftment
whenusedimmediatelyafter
BMT""".'X.''.27.'h.'7 although
data demonstrating improvements insurvivalafter growth
factor administration are limited. In contrast,onlya
few
reports describe the use of growth factors for treatment of
delayed hematologic recovery or secondary graft failure. For
example, Nemunaitis et all' first reported that 21 of 37 patients responded to GM-CSF administered for graft failure
and suggested superior 100-day and l-year survival rates in
the GM-CSF-treated patients compared withinstitutional
historical controls. Similar results with growth factortherapy
for delayed engraftment have been reported by others using
either GM-CSF or G-CSF,'2"4 butno conclusive data are
available comparing GM-CSF to G-CSF for acceleration of
1o
.-
RBC Recovery
p=o2,
0.0
0
20
40
0.8
80
1W
120
140
160
GYCSftGCBF
1.o,
0.2
60
i
0.6
0.0
0
1
0
2
0
3
0
4
0
s
o
e
o
r
n
Days post treatment
Platelet Recovery
.~ p ;03
0.0
0
20
BO 80 100 120
~ a y post
s
treatment
40
140
I
160
Fig 1. Shown are the hematologic recovery rates [time to
ANC =500/1.~L;to red blood cell
[RBC) independence, and
to
platelet independence) for graft
failure patients treated with GMCSF x 14 days In = 23) or GMCSF x 7 davs followed bv G-CSF
x 7 days In = 24).
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GROWTHFACTORSFORGRAFT
3455
FAILURE AFTER B M 1
hematologic recovery after t r a n s p l a n t a t i ~ n . ~Therefore,
~~'~~~
we initiated the comparative trial reported herein.
Current understanding of the physiologic maturation of
hematopoietic cells suggests that GM-CSF-primed progenitors may be more susceptible to secondary stimulation with
G-CSF. In addition to the early reports and Food and Drug
Administration-licensed indications for the use of GM-CSF
for graft failure, we reasoned that the known endogenous
high circulating levels of G-CSF (but not GM-CSF) in the
plasma accompanying post-BMT n e u t r ~ p e n i a *and
~ - ~the
~ sequential and potentially synergistic role these two factors
have in stimulating hematopoietic differentiation and proliferation suggested that GM-CSF as primary therapy followed
by G-CSF might effect superior recovery and reduce the
morbidity and mortality associated with delayed engraftment.
Somewhat disappointingly, within this trialboth treatments produced similar rates of trilineage hematologic recovery after initial graft failure. Compared with GM-CSF
alone, sequential therapy with GM-CSF followed by G-CSF
was of no advantage in stimulating more rapid or more frequent neutrophil recovery, while red cell and platelet transfusion-dependence persisted for a median of 5 weeks after
enrollment. The observation that this delayed erythrocyte
and platelet transfusion-dependence persisted for many
weeks in many patients indicates that additional measures
are needed beyond either single or sequential growth factor
therapy to satisfactorily promote trilineage hematologic recovery in those with initially poor graft function.
Importantly, a significant difference in 100-day survival
was observed favoring GM-CSF alone as compared with
sequential therapy with GM-CSF + G-CSF. The primary
and secondary causes of death were related to graft failure
in all patients and can in no way be attributed to treatment
with G-CSF during the second therapeutic week, and we
can offer no sound explanation for this observed difference.
However, there were no findings observed in this trial that
favored changing growth factor treatment to G-CSF after the
first week of GM-CSF. Because neither hematologic recov-
Table 3. Causes of Death Within 100 Days After
Cvtokine Theraov for Graft Failure
Day of Death PostEnrollment (days
post-BMT)
Primary; Secondary Causes of Death
GM-CSF x 14 days
34 (54)
GM-CSF + G-CSF
16 (37)
20 (46)
26 (47)
3% (59)
39 (61)
70 (90)
84 (140)
Multisystem organ failure
Pulmonan/ hemorrhage; hepato-renal failure,
GVHD
Cytomegalovirus pneumonitis
Sepsis
(Pseudomonas
aeruginosa)
Sepsis (Staphylococcus; Candida glabrata)
Liver failure; DIC, GI bleeding, GVHD
Multisystem organ failure
Aspergillosis; GVHD
All patients also had delayed engraftment as a contributing cause
of death.
Abbreviations: DIC, disseminated intravascular coagulation; GI,
gastrointestinal.
ery of red cells, neutrophils, or platelets nor survival favored
GM-CSF + G-CSF, this sequential cytokine therapy cannot
be accepted as advantageous, at least in this dose and schedule. GM-CSF treatment for delayed engraftment should remain the standard against which other, newer growth factors,
sequential treatments, or combination therapies are tested.
Finally, it must be remembered that in addition to hematopoieticgrowthfactorsthatshould
be initiatedpromptlyif
engraftment delay is suspected or observed, strong consideration
must be given to second marrow infusion if engraftment delay
persists. In the current report,80%+ of all patients who eventually respondedwithsatisfactoryneutrophilrecoverydid
so
within 21 days of growth factor therapy (usually by day +42
post-BMT). We have previously reported that second infusions
of bone marrow after graft failure have led to successful engraftment in over half of patients, and24%of reinfused patients
survive at 1 year.25Althoughstilldisappointing,these
data
show the demonstrable value of second marrow infusion as a
legitimate therapeutic intervention when recombinant cytokine
therapy is unsuccessful.
REFERENCES
g
0.41
0
10
20
30
40
50
60
70
80
90 100
Days post treatment
Fig 2. Shown are 100-day survivalrates after cytokine therapy for
graft failure with GM-CSF alone or GM-CSF followed by G-CSF (P=
,026).
1. Wingard JR: Advances in the management of infectious complications after bone marrow transplantation. Bone Marrow Transplant 6:371, 1990
2. Davies SM, Ramsay NKC, H a k e RJ, Kersey JH, Weisdorf
DJ, McGlave PW, Blazar BR: Comparison of engraftment in recipients of matched sibling or unrelated donor marrow allografts. Bone
Marrow Transplant 13:51, 1994
3. Chaplin RE, Horowitz MM, van Bekkum DW, Camitta BM,
Elfenbein GE, Gale RP, Gluckman E, Good RA, Rimm AA,Rozman
C, Speck B, Bortin MM: Graft failure following bone marrow transplantation for severe aplastic anemia: Risk factors and treatment
results. Blood 73:606, 1989
4. Sheridan WP, Morstyn G, Wolf M, Lusk J, Layton JE, Souza
L, Morstyn G, Dodd A, Maher D, Green MD, Fox RM: Granulocyte
colony-stimulating factor and neutrophil recovery after high-dose
chemotherapy and autologous bone marrow transplantation. Lancet
1:891, 1989
5. Lazarus HM, Andersen J, Chen MG, Variakojis D, Mansour
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
3456
EG, Oette D, Arce CA, Oken MM, Gerson SL: Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone
marrow transplantation for relapsed non-Hodgkin’s lymphoma:
Blood and bone marrow progenitor growth studies. A phase I1 Eastem Cooperative Oncology Group trial. Blood 78:830, 1991
6. Gorin NC, Coiffier B, Hayat M, Fouillard L, Kuentz M, Flesch
M, Colombat P, Boivin P, Slavin S, Philip T: Recombinant human
granulocyte-macrophage colony-stimulating factor after high-dose
chemotherapy and autologous bone marrow transplantation with unpurged and purged marrow in non-Hodgkin’s lymphoma: A doubleblind placebo-controlled trial. Blood 80:1149, 1992
7. Peters WP, Rosner G, Ross M, Vredenburgh J, Meisenberg B,
Gilbert C, Kurtzberg J: Comparative effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colonystimulating factor (G-CSF) on priming peripheral blood progenitor
cells for use with autologous bone marrow after high-dose chemotherapy. Blood 81: 1709, 1993
8. Schriber JR, Negrin RS, Chao NJ,Long GD, Homing SJ,
BlumeKG: The efficacy of granulocyte colony-stimulating factor
following autologous bonemarrow transplantation for non-Hodgkin’s lymphoma with monoclonal antibody purgedbone marrow.
Leukemia 7: l49 I , 1993
9. Nemunaitis J, Rabinowe SN, Singer JW, Bierman P, Vose JM,
Freedman AS, Onetto N, Gillis S, Oette D, Gold M, Buckner CD,
Hansen JA, Ritz J, Appelhaum FR, Armitage JO, Nadler LM: Recombinant granulocyte-macrophage colony-stimulating factor after
autologous bone marrow transplantation for lymphoid cancer. N
Engl J Med 324:1773, 1991
IO. Khwaja A, Mills W, Leveridge K, Goldstone AH, Linch DC:
Efficacy of delayed granulocyte colony-stimulating factor after autologous BMT. Bone Marrow Transplant 11:479, 1993
11. Nemunaitis J, Singer JW, Buckner CD, Dumam D, Epstein
C, Hill R, Storb R, Thomas ED, Appelbaum FR:Use of recombinant
human granulocyte-macrophage colony-stimulating factor in graft
failure after bone marrow transplantation. Blood 76:245, 1990
12. Ippoliti C, Przepiorka D, Giralt S, Anderson BS, Wallerstein
RO, Gutterman J, Deisseroth AB, Champlin RE: Low-dose nonglycosylated rhGM-CSF is effective for the treatment of delayed
hematopoietic recovery after autologous marrow or peripheral blood
stem cell transplantation. Bone Marrow Transplant 11:55, 1993
13. Vose JM, Bierman PJ, Kessinger A, Coccia PF, Anderson J,
Oldham FB, Epstein C, Armitage JO: The use of recombinant human
granulocyte-macrophage colony stimulating factor for the treatment
of delayed engraftment following high dose therapy and autologous
hematopoietic stem cell transplantation for lymphoid malignancies.
Bone Marrow Transplant 7: 139, 1991
14. Sierra J, Terol MJ, Urbano-Ispizua A, Rovira M, Marin P,
Carreras E, Batle M, Rozman C: Different response to recombinant
human granulocyte-macrophage colony-stimulating factor in primary and secondary graft failure after bone marrow transplantation.
Exp Hematol 22566, 1994
15. Broxmeyer HE, Benninger L, Shreyaskumar RP, Benjamin
myeloid
RS, Vadhan-Raj S: Kinetic response ofhumanmarrow
progenitor cells toin vivo treatment of patients with granulocyte
colony-stimulating factor is different from the response to treatment
with granulocyte-macrophage colony-stimulating factor. Exp Hemato1 22: 100, 1994
16. Boulad F, Gillio A, Small TN, Bonilla MA, Philips P, Ruggiero M, Emanuel D, Ghavimi F, Kernan NA: Correction of neutropenia with rHuG-CSF after loss of response to rHuGM-CSF following autologous bone marrow transplant. Bone Marrow Transplant
13:661, 1994
WEISDORF ET AL
17. Crump M, Couture F, KovacsM, Saragosa R, McCrae J ,
Brandwein J, Huebsch L, Beauregard-Zollinger L, Keating A: Interleukin-3 followed by GM-CSF for delayed engraftment after autologous bone marrow transplantation. Exp Hematol 2 1 :405, 1993
18. Fay JW, Lazarus H, Herzig R, Saez R, Stevens DA, Collins
RH Jr, Piiieiro LA,Cooper BW, DiCesare J, Campion M. Felser JM,
Herzig G, Bernstein SH: Sequential administration of recombinant
human interleukin-3 and granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for malignant lymphoma: A phase H I multicenter study. Blood 84:2 15 I , 1994
19. Rapoport AP, Abboud CN, DiPersio JF: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colonystimulating factor (G-CSF): Receptor biology, signal transduction,
and neutrophil activation. Blood Rev 6:43, 1992
20. Welte K, Zeidler C, Reiter A, Muller W, Odenwald E, Souza
L, Riehm H: Differential effects of granulocyte-macrophage colonystimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood 7S:1056, 1990
21. Weinthal J, Sender L, Briones G, Gillan E, van de Ven C.
Cairo MS: The sequential combination of GM-CSF followed by GCSF significantly enhances myeloid engraftment compared to GMCSF alone following bone marrow transplantation. Blood 82:286a,
1993 (suppl)
22. Sonoda Y, Yang YC, Wong GG, Clark SC, Ogawa M: Analysis in serum-free culture of the targets of recombinant human hemopoietic growth factor: Interleukin 3 and granulocytelmacrophage colony-stimulating factor are specific for early development stages. Proc
Natl Acad Sci USA 85:4360, 1988
23. Weisdorf D, Katsanis E, Verfaillie C, Ramsay NKC, Haake
R, Garrison L, Blazar BR: IL- la administered after autologous transplantation. A phase I clinical trial. Blood 84:2044, 1994
24. WeisdorfDJ,Anderson
P, Blazar B, Kersey JH, Ramsay
NKC: Interleukin-2 immediately after autologous bonemarrow
transplantation for acute lymphoblastic leukemia: A phase I study.
Transplantation SS:61, 1993
25. Davies SM, Weisdorf DJ, Haake RJ, Kersey JH, McGlave
PB, Ramsay NKC, Blazar BR: Second infusion of bone marrow for
treatment of graft failure after allogeneic bone marrow transplantation. Bone Marrow Transplant 14:73, 1994
26. Gherlinzoni F, Miggiano MC, Visani G, Ricci P, Mazza P,
Zinzani PL, Motta MR, Rosti G, Bandini G, Lemoli RM, Tura S:
Granulocyte colony-stimulating factor (G-CSF) accelerates granulocytic recovery faster than granulocyte-macrophage colony-stimulating factor (GM-CSF) in non-Hodgkin’s lymphoma (NHL) patients
submitted to autologous bone marrow transplantation (ABMT).
Blood 80:522a, 1992 (suppl)
27. Spitzer G , Adkins DR, Spencer V, Dunphy FR, Petruska PJ,
Velasquez WS, Bowers CE. Kronmueller N, Niemeyer R, McIntyre
W: Randomized study of growth factors post-peripheral-blood stemcell transplant: Neutrophil recovery is improved with modest clinical
benefit. J Clin Oncol 12:66l, 1994
28. Miksits K, Beyer J, Siegert W: Serum concentrations of GCSF during high-dose chemotherapy with autologous stem cell rescue. Bone Marrow Transplant 11:375, 1993
29. Cairo MS, Gillan ER, Weinthal J, Yancik S, van de Ven C,
Ho W, Shen V, Buzby JS, Suen Y: Decreased endogenous circulating
steel factor (SLF) levels following allogeneic and autologous BMT:
Lack of an inverse correlation with post-BMT myeloid engraftment.
Bone Marrow Transplant 11 :l%, 1993
30. Haas R, Gericke G, Witt B, Cayeux S, Hunstein W: lncreased
serum levels of granulocyte colony-stimulating factor after autologous bone marrow or blood stem cell transplantation. Exp Hematol
21:109, 1993
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
1995 85: 3452-3456
Hematopoietic growth factors for graft failure after bone marrow
transplantation: a randomized trial of granulocyte-macrophage
colony- stimulating factor (GM-CSF) versus sequential GM-CSF plus
granulocyte- CSF
DJ Weisdorf, CM Verfaillie, SM Davies, AH Filipovich, JE Jr Wagner, JS Miller, J Burroughs, NK
Ramsay, JH Kersey and PB McGlave
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