Blood, 15 July 2002, Vol. 100, No. 2, pp. 704-706
BRIEF REPORT
High-dose cyclophosphamide for refractory autoimmune
hemolytic anemia
Victor M. Moyo,
Douglas Smith,
Isadore Brodsky,
Pamela Crilley,
Richard J. Jones, and
Robert A. Brodsky
From the Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins, Baltimore, MD; and Medical College of Pennsylvania,
Hahnemann University, Philadelphia, PA.
 |
Abstract |
High-dose cyclophosphamide, without stem cell rescue, has been used
successfully to treat aplastic anemia and other autoimmune disorders.
To determine the safety and efficacy of high-dose cyclophosphamide among patients with severe refractory autoimmune hemolytic anemia, we
treated 9 patients with cyclophosphamide (50 mg · kg
1 · d1 for 4 days) who had
failed a median of 3 (range, 1-7) other treatments. The median
hemoglobin before treatment was 6.7 g/dL (range, 5-10 g/dL). The median
time to reach an absolute neutrophil count of 500/µL or greater was
16 days (range, 12-18 days). Six patients achieved complete remission
(normal untransfused hemoglobin for age and sex), and none have
relapsed after a median follow-up of 15 months (range, 4-29 months).
Three patients achieved and continue in partial remission (hemoglobin
at least 10 g/dL without transfusion support). High-dose
cyclophosphamide was well tolerated and induced durable remissions in
patients with severe refractory autoimmune hemolytic anemia.
(Blood. 2002;100:704-706)
© 2002 by The American Society of Hematology.
| |
Introduction |
High-dose cyclophosphamide was initially
chosen as conditioning for allogeneic bone marrow transplantation
because of its potent immunosuppressive properties.1,2
Lymphocytes are highly sensitive to cyclophosphamide, but primitive
hematopoietic progenitors are resistant to its cytotoxic effects
because they contain high levels of aldehyde dehydrogenase, an enzyme
that confers resistance to cyclophosphamide.3 We and
others showed that high-dose cyclophosphamide without stem cell
transplantation induces durable treatment-free remissions in patients
with severe aplastic anemia.4-6 This approach also has
activity in a variety of other refractory autoimmune conditions7-9 and can eliminate
alloantibodies.10 Moreover, it avoids the risk of
reinfusing autoreactive effector cells with the autograft during stem
cell transplantation, a potential source of relapse.
Autoimmune hemolytic anemia (AIHA) has a prevalence of 1 per 100 000
and may be life-threatening.11 The disease is classified as primary (idiopathic) or secondary if there is an underlying disorder. The associated antibody that causes hemolysis is either a
warm antibody or a cold agglutinin.11 Treatment with
glucocorticoids results in improvement in the majority of cases, but
relapse is common.12 For patients whose disease becomes
refractory or who do not respond to glucocorticoids, splenectomy is
often employed as a second-line treatment.12 Subsequent
salvage treatments include intravenous immunoglobulin,
danazol,13 and a variety of immunomodulating agents
including low-dose cyclophosphamide, azathioprine, cyclosporine, and
vincristine.12 Unfortunately, many patients become
refractory to multiple therapeutic approaches and develop complications
of chronic high-dose steroid therapy. Cold agglutinin autoimmune
hemolytic anemia is particularly refractory to treatment. Because of
its success in other severe autoimmune disorders, high-dose
cyclophosphamide was studied in patients with severe AIHA that was
refractory to standard therapies.
| |
Study design |
All patients gave informed consent for study
participation as approved by the institutional review boards at Johns
Hopkins Hospital and Johns Hopkins University (JHH) and at Medical
College of Pennsylvania, Hahnemann University (MCPH). Between November 1998 and June 2001, 9 patients (JHH 6; MCPH 3) with severe refractory AIHA were treated with high-dose cyclophosphamide (50 mg/kg ideal body
weight per day) intravenously for 4 consecutive days. Mesna (sodium 2-mercaptoethanesulfonate) 10 mg/kg was given at 3, 6, and 8 hours following each cyclophosphamide dose. Granulocyte colony-stimulating factor at 5 µg/kg was initiated 6 days after the
completion of treatment with high-dose cyclophosphamide and continued
until an absolute neutrophil count (ANC) of 1000/µL or greater was
attained. Patients had to be 70 years of age or younger and were
required to have severe AIHA that had failed standard therapy (at least
2 standard therapies for primary AIHA and at least 1 standard therapy
for secondary AIHA). Patients were also required to be steroid
dependent by the criterion of inability to taper the prednisone dose to
less than 10 mg/d. Other inclusion criteria were cardiac ejection
fraction greater than 40%, serum creatinine value less than 2.5 mg/dL,
and pulmonary function tests showing forced vital capacity, forced
expiratory volume, and carbon monoxide diffusion in the lung at
least 50% of predicted values.
A diagnosis of AIHA was made on the basis of severe anemia, a positive
direct antiglobulin test (DAT for IgG and C3b), or the presence of cold
agglutinin in the serum, and corroborating evidence of hemolysis
(unconjugated hyperbilirubinemia, elevated lactate dehydrogenase, low
serum haptoglobulin levels). Following treatment with high-dose
cyclophosphamide, patients were provided with supportive care as
described previously.5 A complete remission (CR) was
defined as achieving a normal untransfused hemoglobin for age and sex
while taking less than or equal to 10 mg/d prednisone and the
resolution of hemolysis; partial response (PR) was defined as achieving
a hemoglobin of 10 g/dL or greater following treatment and transfusion
independence.12,14
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Results and discussion |
The patient characteristics and response to treatment are shown in
Table 1. There were 5 males and 4 females
with a median age of 52 years (range, 7-64 years). Of the 9 patients, 7 had the warm-antibody variety of hemolytic anemia, 1 patient had a combination of both warm and cold antibodies, and 1 patient had purely
cold-agglutinin disease. Six patients had primary AIHA and 3 patients
had secondary AIHA. The underlying diseases in patients with secondary
AIHA included chronic lymphocytic leukemia, Castleman disease, and
graft-versus-host disease following allogeneic transplantation. The
patients had received a median of 3 (range, 1-7) treatment modalities;
splenectomy was performed in 3 patients. The median hemoglobin at the
time of treatment was 6.7 g/dL (range, 5-10 g/dL), and 8 patients
were erythrocyte transfusion dependent.
High-dose cyclophosphamide was well tolerated. Common side effects
included nausea, vomiting, transient alopecia, and neutropenic fever.
There were no deaths or documented fungal infections, although one
patient was treated empirically with amphotericin B for persistent neutropenic fever. The median number of hospital days was 21 (range, 15-25 days); however, 4 of the patients were hospitalized for complications of their AIHA before treatment with high-dose
cyclophosphamide. The median times to an ANC of 500/µL or greater and
to platelet-transfusion independence were 16 days (range, 12-18 days) and 15 days (range, 0-27 days), respectively. Patients became
independent of packed red blood cell transfusion after a median of
19 days (range, 15-31 days) following treatment.
All patients became transfusion independent in response to treatment.
Six patients went into CR, including 5 of 6 patients with primary AIHA,
and 1 patient with secondary AIHA. The remaining 3 patients
achieved a partial remission, including patient no. 1, who had both
cold and warm antibodies and in whom the warm antibody was eliminated.
The DAT became negative in 2 of the patients who achieved a CR.
At the time of treatment, patients required a median of 40 mg/d (range,
0-60 mg/d) of prednisone. At last follow-up, only one of the patients
in CR (patient no. 9) was receiving tapering doses of prednisone (5 mg
every other day) and one other patient in PR (patient no. 6) was still
taking dexamethasone at a low maintenance dose. All others had
discontinued steroids. None of the patients had experienced relapse at
a median follow-up of 15 months (range, 4-29 months).
For patients with AIHA in whom glucocorticoid treatment fails,
splenectomy is frequently offered as second-line
treatment.12,15 However, this approach is limited because
splenectomy is generally ineffective for cold-agglutinin
disease12 and may be less effective and have a higher
complication rate in secondary AIHA.16,17 Of the 6 patients with primary AIHA, 3 had splenectomy, 2 refused the procedure,
and 1 patient with cold-agglutinin disease was not offered the
procedure. Splenectomy was not performed in any of the patients with
secondary AIHA. There is little consensus on how to manage AIHA when
corticosteroid therapy fails and when splenectomy is ineffective or is
not an option.12 Treatments for these patients include
low-dose cytotoxic therapy,12,15 danazol,13
and intravenous immunoglobulin.18 Most of these treatments
are only partially successful, with many patients becoming dependent on
glucocorticoid maintenance therapy11,12 and eventually suffering the consequences of chronic steroid administration.
This small study suggests that treatment with "transplant doses" of
cyclophosphamide without stem cell rescue is well tolerated and
effective in patients with refractory AIHA. The majority of patients
achieved a durable CR, including 5 of 6 with primary AIHA and 2 of 3 who failed splenectomy. Although this approach is associated with
prolonged aplasia in patients with severe aplastic anemia,4,5 hematopoietic reconstitution is rapid in
patients with autoimmune disorders and normal bone marrow
function.7-9 Because autografting is not required, the
potential risk of relapse from reinfusing autoreactive effectors is
avoided. Thus, further study of this approach as treatment for
refractory AIHA is warranted.
| |
Footnotes |
Submitted January 14, 2002; accepted March 1, 2002.
Prepublished online
as Blood First Edition Paper, April 17, 2002; DOI
10.1182/blood-2002-01-0087.
Supported in part by National Institutes of Health grant CA 70970. R.A.B. is a Clinical Scholar of the Leukemia and Lymphoma Society of
America. V.M.M. is a Thomas E. Sanderfur Jr Fellow for Stem Cell
Research and an Amgen Clinical Fellow.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Robert A. Brodsky, Division of Hematological
Malignancies, Bunting-Blaustein Cancer Research Building, 1650 Orleans
St, Rm 242, Baltimore, MD 21231; e-mail: rbrodsky{at}jhmi.edu.
| |
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Abstract
Introduction
