Blood, 15 March 2003, Vol. 101, No. 6, pp. 2156-2158
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Brief report
Antithymocyte globulin has limited efficacy and
substantial toxicity in unselected anemic patients with
myelodysplastic syndrome
David P. Steensma,
Angela Dispenzieri,
S.
Breanndan Moore,
Georgene Schroeder, and
Ayalew Tefferi
From the Division of Hematology, Department of Internal
Medicine, Mayo Clinic, Rochester, MN; Tissue Typing Laboratory,
Division of Transfusion Medicine, Department of Laboratory Medicine and
Pathology, Mayo Clinic, Rochester, MN; and Division of Biostatistics,
Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
 |
Abstract |
Antithymocyte globulin (ATG) has recently been popularized as an
effective treatment in myelodysplastic syndrome (MDS). We treated 8 anemic MDS patients (refractory anemia [RA] and refractory anemia
with excess blasts [RAEB-1]) with ATG (40 mg/kg/d for 4 days) and
prednisone in a phase 2 trial. The study was stopped early according to
a preset termination rule because of lack of efficacy. There were no
salutary responses. Toxicities included serum sickness (in all
patients), transient neutropenia and thrombocytopenia, diarrhea,
vomiting, and syncope with a generalized seizure. At least 3 patients
had the HLA-DR15 (DR2) allele. We conclude that the risk-benefit ratio
of ATG in an unselected population of MDS patients may be unfavorable,
and more work is needed to define the subset of patients who will
respond to ATG before its widespread use can be recommended.
(Blood. 2003;101:2156-2158)
© 2003 by The American Society of Hematology.
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Introduction |
The myelodysplastic syndrome (MDS) includes a
heterogeneous group of marrow disorders characterized by ineffective
hematopoiesis and a variable risk of leukemic transformation. Because
most patients with MDS are diagnosed after the age of 60 years, therapy
is often limited to supportive care with transfusions and hematopoietic growth factors. A subset of younger patients may benefit from hematopoietic stem cell transplantation, but new, nontoxic treatments are sorely needed.
Suppression of hematopoiesis by cytotoxic T cells may contribute
to anemia in some patients with MDS.1 MDS can be
associated with vasculitides, T-cell large granular lymphocytic
disease, and autoimmune conditions, suggesting the presence of immune
dysregulation in at least a subset of MDS sufferers and implying
that immunomodulation might provide palliative benefit.2,3
Antithymocyte globulin (ATG), derived from immunization of horses or
other animals with human thoracic duct lymphocytes, has complex
activity within the human hematopoietic milieu. ATG suppresses cytotoxic and potentially inhibitory T lymphocytes, may indirectly stimulate hematopoiesis via augmentation of hematopoietic growth factor
release by T cells and stromal cells, and promotes cellular differentiation.4-6 ATG has long enjoyed a
well-established clinical role in the transplantation setting and in
the treatment of aplastic anemia.7 More recently, 34% of
patients with MDS have been reported to achieve red cell transfusion
independence after 4 days of ATG treatment; platelet responses were
observed in 48% of patients with severe thrombocytopenia, and
neutrophil responses were observed in 55% of patients.8
Based on an earlier encouraging report from that cohort, we conducted a
nonrandomized, single-institution, single-arm phase 2 trial of ATG in
MDS.9
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Study design |
Eight anemic (hemoglobin less than 9 g/dL [90 g/L])
MDS patients (5 women; ages 62 to 74 years) with refractory anemia (RA) (2 patients) and refractory anemia with excess blasts (RAEB-1) (6 patients) were recruited from the Mayo Clinic hematology practice between 1998 and 2002. Patient characteristics are given in Table 1. Patients with refractory anemia with
ringed sideroblasts (RARS) were excluded because of lack of response to
ATG in the study that prompted this trial.9 Patients with
secondary (therapy-related) MDS, poor liver or renal function
(bilirubin more than 2 mg/dL [34.2 µM] or creatinine more than 2 mg/dL [176.8 µM]), HIV infection, active nonmyeloid malignancy, or
poor performance status (Eastern Cooperative Oncology Group
[ECOG] 3 or 4) were also excluded. All patients gave informed consent
prior to enrollment, and the Mayo Clinic Institutional Review Board
approved the study.
ATG (ATGAM; Pharmacia, Peapack, NJ) was administered
intravenously at a dose of 40 mg/kg/d for 4 days. Oral prednisone was given at a dose of 1 mg/kg/d and then rapidly tapered unless persistent rash and/or serum sickness prohibited this.
All patients had 10% or fewer marrow blasts at trial enrollment.
According to the International Prognostic Scoring System (IPSS), 5 patients fit into the intermediate-1 (INT-1) risk group and 3 were
INT-2.10 The bone marrow was hypocellular in 2 patients (both had normal flow cytometric testing for a paroxysmal nocturnal hemoglobinopathy clone [CD59, CD14, and fluorescently labeled inactive
variant of aerolysin (FLAER)]), normocellular in 1 patient, and hypercellular in 5 patients. Bone marrow karyotypes are listed in
Table 1. Peripheral blood T-cell gene rearrangement studies were
done in 7 of 8 patients and failed to demonstrate a clonal T-cell population.
After this study was initiated, reports appeared of an increased
frequency of HLA-DR15 (DR2) in MDS patients and positive predictive
value of this allele with regard to response to immunosuppressive therapies such as ATG.11 To study the class II HLA profile
of patients in this trial, DNA was extracted from methanol-glacial acetic acid-fixed cells that had been preserved at the time of initial
marrow cytogenetic studies using the High Pure PCR Template Preparation
Kit (Roche Molecular Biochemicals, Indianapolis, IN). Class II
HLA DNA was amplified via polymerase chain reaction (PCR) and typed
according to established PCR with sequence-specific primers (SSP) technique.
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Results and discussion |
Unfortunately, there were no hematologic responses to ATG
and prednisone in the dose and schedule used in this study, and transfusion needs were unaffected. Enrollment of 20 patients was planned, but the study was terminated early due to a predetermined stopping rule.
Systemic toxicity potentially attributable to the drug included classic
serum sickness and/or rash in all 8 patients (7 fever, 4 rash, 4 myalgias/arthralgias), diarrhea (2 patients), nausea/vomiting (1 patient), syncope with a generalized tonic-clonic seizure
in a patient with no seizure history (1 patient, during the first day
of therapy), and reactivation of oral herpes simplex virus (HSV) (1 patient). All toxicities eventually resolved.
Transient hematopoietic toxicity was observed but did not lead to any
complications. These toxicities included worsening of neutropenia in 1 of 4 already neutropenic patients, new neutropenia in an additional
patient, worsening of pre-existing thrombocytopenia in 6 patients, and new, mild thrombocytopenia in the 2 patients who had a normal platelet
count at trial enrollment (platelet count of 253 × 109/L fell to 60 × 109/L, and 412 × 109/L fell to 145 × 109/L). The nadir
platelet count occurred on day 5 of therapy in 6 of 8 patients, and
recovery to pretreatment values was rapid.
A sufficient quantity of DNA for HLA typing (range, 47.2 to 70.3 µg) was obtained from 7 of 8 patient samples. In 5 patients, this DNA was of high enough quality to allow successful amplification and HLA class II typing; the other 2 patients are deceased, so additional genetic material is unavailable. In 3 of 5 patients (60%),
HLA-DR15 (DR2) was detected; the expected frequency of HLA-DR15 (DR2)
in North Americans is 15% to 21%.11
With 0 hematopoietic responses in 8 patients, the 95% confidence
interval for the true response rate to ATG and prednisone in a similar
population of MDS patients is 0% to 37%. Although this does not
statistically exclude the 34% red cell response rate seen in the study
by Molldrem et al, the response rate in this cohort was
disappointing.8
It is possible that the lack of response occurred by chance alone, but
the group enrolled in this study might actually have been expected to
have a higher probability of including ATG-responding patients than a
more typical consecutive series of MDS patients seen in clinical
practice. There were 2 patients in this cohort with a
hypocellular marrow (hypocellular MDS may have pathophysiologic overlap with aplastic anemia, which often responds to
ATG,12 and 38% of patients in the series reported by
Molldrem et al were hypocellular9
more than in most
general MDS series), no patients had more than 10% blasts, patients
with secondary MDS (which is typically more refractory to treatment
than is de novo disease) were excluded, only 2 enrolled patients had an
IPSS high-risk karyotype, at least 3 were HLA-DR15 (DR2)-positive, and
6 of 8 patients were thrombocytopenic at trial enrollment (a low
platelet count predicted ATG response in the study by Molldrem et
al8).
Although there may be a subset of MDS patients who will respond
to therapy with ATG, we believe this population is not yet clearly
defined. HLA-DR15 (DR2) typing alone is not of sufficient predictive value.
In conclusion, in the dose and schedule used in the trial, ATG
had no efficacy in a population of patients with intermediate-risk RA
and RAEB-1. Given the toxicity observed and the substantial cost of
therapy (the direct drug acquisition cost of the 4-day ATG regimen for
a typical 70-kg patient is approximately $13,60013), further research is needed before this drug might be widely recommended in MDS.
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Acknowledgments |
We thank Terra Reeder, Cynthia Kroning, and Jack Spurbeck for their
valuable technical assistance.
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Footnotes |
Submitted September 19, 2002; accepted October 20, 2002.
Prepublished online as Blood First Edition Paper, October
31, 2002; DOI 10.1182/blood-2002-09-2867.
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: David P. Steensma, Mayo Clinic, 200 First
St, SW, Rochester, MN 55905; e-mail:
steensma.david{at}mayo.edu.
| |
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Abstract
Introduction
