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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-02-0494.
BRIEF REPORT
From the Hematology Branch, National Heart, Lung, and
Blood Institute, National Institutes of Health, Bethesda, MD.
High-dose cyclophosphamide (Cy) has been promoted as curative
therapy for severe aplastic anemia (SAA). However, our randomized trial
comparing antithymocyte globulin (ATG) and Cy was terminated early
because of excess morbidity/early mortality in the Cy arm. We now
report analysis of secondary endpoints at a median of 38 months.
Relapse occurred in 6 (46%) of 13 responders in the ATG arm versus 2 (25%) of 8 in the Cy arm (P = .38). Five (31%) of 16 patients in the ATG arm and 4 (27%) of 15 patients in the Cy arm had
evidence of paroxysmal nocturnal hemoglobinuria (PNH) at
diagnosis, with no substantial change in the overall percentage of glycophosphatidyl inositol (GPI)-anchored protein-deficient neutrophils over extended follow-up in individual patients in either
arm. Bone marrow cytogenetic abnormalities have been observed among
surviving patients in both arms (2 of 14 ATG versus 1 of 12 Cy,
P = .70). High-dose Cy does not prevent relapse or clonal evolution in SAA.
(Blood. 2002;100:4668-4670) Immunosuppression with antithymocyte globulin (ATG)
and cyclosporine (CSA) results in long-term survival in patients with severe aplastic anemia (SAA), comparable to that achieved by allogeneic bone marrow transplantation from a histocompatible sibling
donor,1 yet problems, including incomplete hematologic
recovery, relapse, and the appearance of clonal hematopoietic
disorders, complicate long-term management.2 High-dose
cyclophosphamide has been proposed as an alternative immunosuppressive
agent for the treatment of aplastic anemia, based on encouraging
results in 2 uncontrolled trials3,4: in contrast to the
experience with antithymocyte globulin (ATG)-based treatments, neither
relapse nor clonal disease were reported. We initiated a phase III
randomized trial to compare response rates to immunosuppression with
either ATG or high-dose cyclophosphamide (Cy), both combined with CSA.
Secondary endpoints included relapse and clonal evolution. Although
primary response rates were not significantly different at 6 months,
our trial was terminated early because of excess morbidity and early
mortality in the Cy arm.5 We now report analysis of
secondary endpoints after extended follow-up at a median of 38 months.
The protocol was approved by the Institutional Scientific Review
Committee and the Institutional Review Board of the National Heart,
Lung, and Blood Institute, and all patients gave written informed
consent. A sample size of 91 patients per treatment arm was planned to
allow comparison of the response proportions conducted at the 0.05 significance level, but the trial was terminated after accrual of only
31 patients.5 Secondary endpoints included relapse, the appearance of clonal hematologic disorders, and overall and event-free survival. All endpoints were assessed at scheduled follow-up visits at 6 months, 12 months, and yearly thereafter. Patients were considered responders if they experienced an improvement in blood counts sufficient to no longer meet criteria for severe disease, criteria that correlate with eventual transfusion
independence.6 To better assess the quality of hematologic
recovery, response was further classified with ordered, mutually
exclusive criteria as partial response with transfusion dependence
(PRd), partial response with transfusion independence (PRi), and
complete response (CR; normal or near normal blood
counts).5 Patients meeting criteria for sustained response
of more than 3 months who subsequently experienced a fall in counts
sufficient to require reinstitution of immunosuppressive drugs were
considered to have relapsed. Peripheral blood samples were analyzed by
flow cytometry for the presence of glycophosphatidyl inositol
(GPI)-anchored protein-deficient granulocytes at presentation and at
each scheduled follow-up; detection at 1.0% or greater on 2 or more
evaluations was considered evidence for expansion of a clonal
population of paroxysmal nocturnal hemoglobinuria cells (PNH).
Evolution to myelodysplastic syndrome (MDS) was defined by the
characteristic marrow morphology or the presence of a consistent
chromosomal abnormality; cytogenetic examination of bone marrow samples
was performed at presentation, at 6-month follow-up, and yearly thereafter.
Thirteen (81%) of 16 patients randomly assigned to ATG and 8 (53%) of 15 patients randomly assigned to Cy showed a hematologic response (Table 1). All responding
patients, regardless of treatment allocation, eventually achieved
transfusion independence (no remaining PRds), as predicted from
previous results with standard immunosuppressive therapy.6
Complete responses were observed in 10 (63%) of 16 patients in the ATG
arm and 6 (40%) of 15 patients in the Cy arm (10 [77%] of 13 responders ATG, 6 [75%] of 8 responders Cy); there was no difference
in the overall or complete response rates between arms
(P = .12, P = .15, respectively, Fisher
exact test).
Relapse is the most frequent long-term complication following
immunosuppression with ATG-containing regimens,6,7 but it
was not observed in the early Cy-treated patients.3
Indeed, relapse occurred in 6 (46%) of 13 responders in the ATG arm,
but relapse was also observed in 2 (25%) of 8 responders in the Cy arm
(P = .38, Fisher exact test). Four of 6 patients in the
ATG arm and 1 of 2 patients in the Cy arm were retreated, based solely on a fall in the platelet count. Relapse in which blood counts again
met criteria for severe disease was observed in 1 patient in the ATG
arm and 1 patient in the Cy arm. Although the patient in the Cy arm
presented initially with counts just satisfying severity criteria,
relapse to supersevere disease occurred more than 2 years after
attaining a CR. All relapsed patients responded to reinstitution of
immunosuppression either with CSA or with ATG and CSA; 3 patients in
the ATG arm and 1 patient in the Cy arm required the addition of ATG.
The association between PNH and aplastic anemia is well
established; however, early studies suggesting evolution to PNH used the now outdated Ham test.8 Patients with clinical PNH
were excluded from our randomized trial; however, flow cytometric
methods now allow more sensitive detection of such clones in not only erythroid but also myeloid cells, increasing both sensitivity and
specificity, and the use of such techniques argues that PNH is a common
and early event in SAA.9,10 The simultaneous absence of 2 GPI-anchored proteins highly expressed on normal granulocytes, CD66b
and CD16, at levels above our threshold of 1.0% was used as criteria
for establishing evidence of PNH clonal expansion11; such
an expanded population was detected in 5 patients in the ATG arm and 4 patients in the Cy arm, at presentation. A GPI-anchored protein-deficient population just below our cutoff was detectable at
diagnosis in one additional patient in the ATG arm; one subsequent determination was just above the cutoff. Regardless of treatment allocation, the overall percentage of GPI-anchored protein-deficient granulocytes has not changed substantially over extended follow-up (Table 2). Further, treatment of a single
patient with clinical PNH with high-dose Cy by compassionate exemption
produced neither hematologic improvement nor a change in the percentage
of GPI-anchored protein-deficient granulocytes over time. Although
detection of the PNH phenotype among blood cells of patients with
aplastic anemia is relatively common, clinical PNH is less frequently
observed, and only one patient in each treatment arm subsequently has
developed evidence of intravascular hemolysis.
The late occurrence of MDS is the most dire complication observed in
patients with SAA and occurs in both successfully treated and
persistently cytopenic patients.12 Evolution to
myelodysplasia was not described in the 2 pilot series published to
date.3,4 In the current protocol, marrow cytogenetic
evaluation revealed the presence of abnormalities characteristic of MDS
not only in 2 patients in the ATG arm (trisomy 8, 9 of 20 metaphases at
6-month follow-up, increasing to 19 of 20 at 4-year follow-up; and
20q Although the early termination of our trial because of toxicity on the Cy arm does not permit a comparison of either response rates or long-term complications with adequate statistical power, the tempered enthusiasm for this approach we experienced as a result of the high degree of early toxicity is further dampened by our recent observations. Cy treatment does not prevent the familiar long-term complications experienced by patients treated with conventional immunosuppression for SAA, and, as such, the resulting early morbidity and mortality cannot be justified by their anticipated absence. The continued development of alternative immunosuppressive regimens that take into account both the late complications as well as early safety is thus warranted.
Submitted February 15, 2002; accepted May 24, 2002.
Prepublished online as Blood First Edition Paper, June 28, 2002; DOI 10.1182/blood-2002-02-0494.
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: John F. Tisdale, Molecular and Clinical Hematology Branch, National Institute of Diabetes, Digestive, and Kidney Disorders, Building 10, Room 9N116, Bethesda, MD 20892; e-mail: johntis{at}intra.niddk.nih.gov.
1.
Bacigalupo A, Brand R, Oneto R, et al.
Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy
2.
Young NS, Barrett AJ.
The treatment of severe acquired aplastic anemia.
Blood.
1995;85:3367-3377
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Brodsky RA, Sensenbrenner LL, Jones RJ.
Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation.
Blood.
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Brodsky RA, Sensenbrenner LL, Smith BD, et al.
Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia.
Ann Intern Med.
2001;135:477-483 5. Tisdale JF, Dunn DE, Geller N, et al. High-dose cyclophosphamide in severe aplastic anaemia: a randomised trial. Lancet. 2000;356:1554-1559[CrossRef][Medline] [Order article via Infotrieve].
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Rosenfeld SJ, Kimball J, Vining D, Young NS.
Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia.
Blood.
1995;85:3058-3065 7. Schrezenmeier H, Marin P, Raghavachar A, et al. Relapse of aplastic anaemia after immunosuppressive treatment: a report from the European Bone Marrow Transplantation Group SAA Working Party. Br J Haematol. 1993;85:371-377[Medline] [Order article via Infotrieve].
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Griscelli-Bennaceur A, Gluckman E, Scrobohaci ML, et al.
Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link.
Blood.
1995;85:1354-1363 9. Schubert J, Alvarado M, Uciechowski P, et al. Diagnosis of paroxysmal nocturnal haemoglobinuria using immunophenotyping of peripheral blood cells. Br J Haematol. 1991;79:487-492[Medline] [Order article via Infotrieve].
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Dunn DE, Tanawattanacharoen P, Boccuni P, et al.
Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.
Ann Intern Med.
1999;131:401-408 11. Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS. Relationship between bone marrow failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clones. Br J Haematol. 2001;115:1015-1022[CrossRef][Medline] [Order article via Infotrieve]. 12. Socie G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A. Late clonal diseases of treated aplastic anemia. Semin Hematol. 2000;37:91-101[CrossRef][Medline] [Order article via Infotrieve].
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Mikhailova N, Sessarego M, Fugazza G, et al.
Cytogenetic abnormalities in patients with severe aplastic anemia.
Haematologica.
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Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia.
Blood.
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© 2002 by The American Society of Hematology.
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  N. S. Young, R. T. Calado, and P. Scheinberg Current concepts in the pathophysiology and treatment of aplastic anemia Blood, October 15, 2006; 108(8): 2509 - 2519. [Abstract] [Full Text] [PDF]
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 J. P. Maciejewski and A. M. Risitano Aplastic Anemia: Management of Adult Patients Hematology, January 1, 2005; 2005(1): 110 - 117. [Abstract] [Full Text] [PDF]
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G. C. Bagby, J. M. Lipton, E. M. Sloand, and C. A. Schiffer Marrow Failure Hematology, January 1, 2004; 2004(1): 318 - 336. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
, 9 of 50 metaphases at 3-year follow-up with 0 of 6 at 4-year
follow-up) but also in 1 patient in the Cy arm (trisomy 8, 4 of 20 metaphases at 1-year follow-up; P = .70, Fisher exact
test) despite a normal karyotype in all cases at presentation. These
cytogenetic abnormalities were noted, however, on routine marrow
samples among patients who remain in clinical remission and underscore
the importance of marrow sampling even among patients with stable,
recovered blood counts. Further, such chromosomal abnormalities do not
necessarily portend a poor prognosis in patients with
SAA.
The European Group for Blood and Marrow Transplantation experience.
Semin Hematol.
2000;37:69-80