1. Healthcare

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Complete Remission in Severe Aplastic Anemia After High-Dose
Cyclophosphamide Without Bone Marrow Transplantation
By Robert A. Brodsky, Lyle L. Sensenbrenner, and Richard J. Jones
Severe aplastic anemia (SAA) can be successfully treated
with allogeneic bone marrow transplantation (BMT) or immunosuppressivetherapy.However,
themajority of patients with SAA are not eligible for BMT because they lack
an HLA-identicalsibling. Conventional immunosuppressive
therapy also has major limitations; many of its remissions
are incomplete and relapse or secondary clonal disease is
common. Cyclophosphamide is a potent immunosuppressive agent that is used in all BMT conditioning regimens
for patients with SAA. Preliminary evidence suggestedthat
high-dose cyclophosphamide, even without BMT, may be
beneficial t o patients with SAA. Therefore, 10 patients with
SAA and lacking an HLA-identical sibling were treated with
high-dosecyclophosphamide(45mg/kg/d) for4 consecutive
days with or without cyclosporine. A complete response (hemoglobin level, > l 3 g/dL; absolute neutrophil count, >1.5
x 109/L, and platelet count > 125 x 109/L)was achieved in
7 of the 10 patients. One of the complete responders died
from the acquired immunodeficiency syndrome 44 months
after treatment with high-dosecyclophosphamide.The 6 remaining patients are alive and in continuous complete remission, with a median follow-up of 10.8 years (range. 7.3
to 17.8 years). The mediantime t o last platelet transfusion
and time to 0.5 x lo9 neutrophils/L were 85 and 95 days,
respectively. None of
the complete responders has relapsed
or developed a clonal disease. These results suggest that
high-dose cyclophosphamide, even without BMT. may be
more effective than conventional immunosuppressive therapy in restoring normal hematopoiesis and preventing relapse or secondary clonal disorders. Hence, further studies
confirming the efficacy of this approach in SAA are indicated.
0 7 9 9 6 b y The American Society of Hematology.
A
for this study if they lacked an HLA-identical donor. No patient was
excluded from the study. However, between 1980 and1984. all
patients with SAA and without an HLA-identical donor were entered
on studies of either ALG followed by haploidentical BMT and androgens (15 patients)- or ATG alone (5 patients).I2These patients have
been previously r e p ~ r t e d . ’ ~The
, * ~last patient accrued to this study
was treated at Wayne State University. SAAwas diagnosed by
standard criteria2*:less than 25% marrow cellularity and depression
in two of three blood counts (reticulocytes, <40 X 10y/L;platelets,
c 2 0 X 109/L;and an ANC <0.5 X 10y/L).Aplastic anemia was
considered super severe if it met the criteria for severe disease and
the ANC was less than 0.2 X I O Y L All patients gave informed
consent for study participation approved by the institutional review
boards of Johns Hopkins University and Wayne State University.
Treatment schedule. After confirmation ofthe diagnosis, patients were randomized to receive cyclophosphamide at 45 mg/kg/d
intravenously (IV) on days 1 through 4, with or without cyclosporine.
Patients randomized to receive cyclosporine received 5 mg/kg IV
on days 4 through 9, 3.75 mg/kg/d IV on days 10 through 20, 2.5
mg/kg/d IV on days 21 through 27, and on days 28 through 32 both
1.5 mg/kg/d 1V and 5 mgkgld orally. The patients then received
cyclosporine at 10 mgkgld orally on days 33 through 56 and 7.5
mg/kg/d orally from days 57 through 100, after which the drug was
discontinued. All patients received only one course of therapy.
Response. A complete response required normalization of all
blood counts (ie, hemoglobin level, > 13 g/L; ANC > 1.5 X 10y/L;
and platelet count, > 125 X 10y/L).All others were classified as
CQUIRED SEVERE aplastic anemia (SAA) is a rare
hematopoietic disorder that can be successfully treated
by bone marrow transplantation (BMT) or immunosuppressive therapy.’ BMT leads to complete hematopoietic recovery and cure of the disease in 60%to 80% of patients, with
the major causes of failure being graft rejection and graftversus-host disease.’” However, the majority of patients with
SAA are not candidates for BMT because they lack an HLAidentical sibling. The majority (60%to 80%)of SAA patients
treated with immunosuppression recover hematopoiesis sufficiently to be transfusion-independent and free of infection,
although often not to completely normal blood counts.8“‘
The combination of antithymocyte globulin (or antilymphocyte globulin) and cyclosporine appears to be the most effective form of immunosuppressive
Patients with
super severe aplastic anemia (SSAA), ie, SAA patients with
an absolute neutrophil count (ANC) of less than 0.2 X lo9/
L at diagnosis, have a poorer response to immunosuppression
than do patients with just SAA.9,” A major limitation of
immunosuppressive therapy is that up to 50% of successfully
treated patients either relapse or develop late clonal diseases
such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or acute
Cyclophosphamide is a potent immunosuppressive agent
and is used in all BMT conditioning regimens for patients
with SAA. After preparation with cyclophosphamide, most
allogeneic bone marrow grafts persist indefinitely; however,
in several cases, complete autologous hematologic recovery
has occurred.’’-’’ Case reports of 2 SAA patients achieving
a complete hematologic remission with moderately highdose cyclophosphamide (40 to 120 m a g ) without BMT
have also been des~ribed.’~.’~
These data suggest that cyclophosphamide, particularly in high doses, may be beneficial
to patients with SAA even without allogeneic BMT. We
treated 10 SAA patients lacking an HLA-identical sibling
donor with high-dose cyclophosphamide. A complete hematologic remission was achieved in 7 patients, and, with a
median follow-up of more than 10 years, no patient has
relapsed or developed secondary clonal disease.
MATERIALS AND METHODS
Patients. Patients referred to the Johns Hopkins Oncology Center for the treatment of SAA between 1977 and 1986 were eligible
Blood, Vol 87,
No 2 (January 151, 1996 pp 491-494
From the Johns Hopkins Oncology Center, Johns Hopkins Medical Institutions, Baltimore, MD; andthe Division of Hematology
and Oncology, Wayne State University School of Medicine, Detroit,
MI.
Submitted May 22, 1995; accepted September 1, 1995.
SupPofled in part by National Institutes of Health Grant No.
CA1.5396. R.J.J. is a Leukemia Sociezy of America Scholar.
Address reprint requests to Richard J. Jones, MD, Johns Hopkins
Oncology Center. Room 2-127, 600 N Wolfe St, Baltimore, MD
21287-8967.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1996 by The American Society of Hematology.
0006-4971/96/8702-0027$3.00/0
49 1
3/F
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JONES
492
BRODSKY, SENSENBRENNER,
AND
Table 1. Patient Characteristics
Pretreatment Blood Counts
Patient
No.
1
2
3
4
5
6
7
8
9
10
ANC
AgelSex
22/F
16/M
19/M
19/M
16/M
3O/F
Retics
CX~O~IL)
6
670
150
40
380
310
780
7/F
3WM
75
600
24/M
0
( X 10"L)
18
6
2
15
14
PltS
(x109ILl
Etiology
Previous Therapy
8
Benzene exposure
Androgens/steroids
None
None
None
None
None
None
Steroids
None
Androgenslsteroids
1
36
3
10
18
26
35
16
3
10
26
10
8
Idiopathic
Idiopathic
Benzene exposure
Idiopathic
Idiopathic
Idiopathic
Idiopathic
Idiopathic
Idiopathic
Duration of SAA
Before CY (wk)
52
4
2
2
3
16
4
40
3
8
Abbreviations: CY, cyclophosphamide; Retics, absolute reticulocyte count; Pits, platelet count,
nonresponders. Persistence of a transfusion requirement was evidence of no response.
RESULTS
Patient characteristics are shown in Table 1; no patients
were excluded from analysis. The median age (19 years;
range, 7 to 38 years) was similar to that of other studies of
SAA.7*'0,25
Of the 10 patients, 5 had SSAA and 5 had SAA.
Most of the patients were newly diagnosed; the median duration of disease before treatment with high-dose cyclophosphamide was 1 month (range, 2 weeks to l year), and only
3 patients had received any prior therapy for their SAA.
A complete response was achieved in 7 of the 10 patients;
the majority of patients with both SAA (4/5)and SSAA (3/
5) were complete responders (Table 1). An ANC of 0.5 X
109Lwas reached at a median of 95 days (range, 34 to 201
days), and the last platelet transfusion was at a median of
85 days (range, 35 to 151 days; Table 2). The use of
cyclosporine did not appear to influence whether the patients
were able to achieve a complete response, with 5 of 7 patients
treatedwith cyclophosphamide alone and 2 of 3 patients
treated with cyclophosphamide plus cyclosporine attaining
a complete response. None of the 7 complete responders has
relapsed or developed a clonal disease, with a median followupof 10.8 years (range, 7.3 to 17.8 years); 6 of the 7 are
alive and remain incomplete remission with completely normal blood counts, and 1 patient became infected with the
human immunodeficiency virus from a blood transfusion and
died of acquired immunodeficiency syndrome (AIDS) 44
months after treatment (Table 2). Only 1 patient (in remission for > 10 years) has an elevated mean corpuscular volume (MCV; 105 pm3; normal range, 80 to 100 pm'), which
has been reported to be predictive for the development of
late clonal disorders in SAA patients treated with immunosuppre~sion.'~
Dysplastic changes in the remission bone marrows (especially in the monocytic and megakaryocytic lineages) may also be associated with the development of late
clonal disorder^,'^ but were not present in any of the patients.
High-dose cyclophosphamide was generally well-tolerated, with toxicities similar to those seen with autologous
BMT. All acute side-effects resolved completely, with no
evidence of late sequelae (although gonadal function has not
been extensively evaluated). All patients developed febrile
neutropenia requiring combinations of antibiotics. Transient
Table 2. Hematologic Response to High-Dose Cyclophosphamide
Days to
Patient
No.
1
2
3
4
5
6
7
8
9
10
Treatment (date1
Status
CY ( M 7 )
CY (ID81
CY (8/78)
CY (4184)
CYICSA (7184)
CYICSA (11/84)
CY (2185)
CYICSA W861
CY (5/86)
CY (9187)
CCR
CCR295
NR
CCR
CR*
CCR
CCR
NR
NR
CCR
ANC of
500/pL
9513.8
20114.6
-
Recent Blood Counts
Last Plt
WBC
Transfusion (xlO9/L)
(x103/L)
35
2.0
95
1.9
-
13.8 78 3.7
74
117
151
47 5.8
85
9613.8
135
2.6
167
5.7
5.9
-
ANC
MCVHgb
(g/dL)
322
-
-
7.2
4.2
5.4
-
-
-
3413.3
35
5.1
8.4
PltS
(x103/L)
2.3
2.8
15.1
14.6
-
-
Date
99
98
-
-
03/21/95
03/10/95
310
92
11111/94
140
166
182
1/87
94
105
46
-
-
0511
03/08/95
07/13/94
202
99
12/22/94
-
-
-
-
Abbreviations: CY, cyclophosphamide; CSA, cyclosporine; CCR, continuous complete remission; NR, no response; Plt, platelet; WBC, white
blood cell count; Hgb, hemoglobin.
* Died of acquired immunodeficiency syndrome 44 months after treatment.
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
CYCLOPHOSPHAMIDE FOR APLASTIC ANEMIA
493
to an ANC of 0.5 x 109/L and transfusion-independence in
this series (day 95 and 85, respectively) is comparable to
that seen with conventional immunosuppression," even
though no patient in our series received growth factor support.
HLA-identical sibling BMT is currently the treatment of
choice for young patients with SAA, primarily because of
the lower risk of relapse and late clonal disorders when
compared with patients treated with immunosuppression.
Our data suggest that high-dose cyclophosphamide without
BMT may also effectively restore normal hematopoiesis and
prevent relapse or secondary clonal disorders. Although the
beneficial effects of high-dose cyclophosphamide may just
be a consequence of its intensive immunosuppressive activity, it is likely that the potent cytotoxic properties of cyclophosphamide are also important; this could have important
DISCUSSION
implications regarding the pathophysiology of SAA. It is not
clear why aplastic anemia is a premalignant
We found that high-dose cyclophosphamide without BMT
Damage to hematopoietic stem cells may lead to an autoimproduced long-term survival and normal hematopoiesis in
mune response directed against the bone marrow.28In addipatients with SAA. The response rate in our series is compation, sublethal damage to a stem cell may produce genetic
rable with response rates seen after allogeneic BMT2-7or
mutations
that give it a growth advantage. Over time, an
conventional immunosuppressive therapy with antithymoabnormal
clone
arising from a slowly proliferating, transcyte globulin and cyclosporine.8-l' A previous report sugformed stem cell could become dominant. Cyclophosphagested a lower response rate for SAA to cyclophosphamide."
mide not only causes profound immunosuppression, but also
However, most patients in the previous report received relahas the potential to destroy a minor population of damaged
tively low doses of cyclophosphamide and the highest dose
stem cells with the capacity to develop into MDS, P M , or
was only two-thirds of the dose used in our study.*'
acute leukemia.
Like BMT, high-dose cyclophosphamide in our series proAlthough encouraging, these results remain preliminary.
duced complete hematopoietic recovery in all responders and
The
studywas small and the patients were all relatively
was notassociated with relapse or late clonal diseases despite
young. Hence, further studies with high-dose cyclophosphaat least 7 years of follow-up in all patients. In contrast,
mide need to be performed. Nevertheless, our data suggest
conventional immunosuppressive therapy frequently fails to
restore normal hematopoiesis and relapse is common.8.'03'1 that this approach should be considered as an alternative to
immunosuppressive therapy in patients who lack an HLAFurthermore, conventional immunosuppressive therapy is
identical sibling.
also associated with a significant risk of late clonal diseases.
Tichelli et a l l 7 reported a 42% cumulative risk of developing
ACKNOWLEDGMENT
PNH or MDS at 10 years after therapy with antilymphocyte
We thank Marie C. Moineau for assistancein manuscript preparaglobulin. The European Group for Bone Marrow Transof Americaforhelp with
tion,theAplasticAnemiaFoundation
plantation (EBMT) reported an 18.8% cumulative incidence
patientfollow-up, and DrsRobertStuart and MarkEdelsteinfor
of cancer at 10 years after immunosuppressive therapy16;
providing excellent patient care.
however, theydidnot include PNH in their definition of
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From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
1996 87: 491-494
Complete remission in severe aplastic anemia after high-dose
cyclophosphamide without bone marrow transplantation
RA Brodsky, LL Sensenbrenner and RJ Jones
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