In a previous study, we evaluated efficacy of repeated antilymphocyte globulin (ALG) treatment for patients with severe aplastic anemia not responding to an initial ALG treatment or relapsing after initial response to ALG. We now searched in the same cohort of patients for differences between patients who responded to treatment and remained free of complications and those who relapsed or developed a clonal complication. From 107 patients surviving for more than 1 year after immunosuppression, 34 remained free from complications after the first course of ALG, and 73 presented an event defined as relapse of aplastic anemia, development of a clonal complication such as paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome or leukemia, or appearance of a solid tumor. We compared these two groups for survival, clinical performance and blood counts during follow-up. Survival probability was 93% for the event-free patients, and 55% for the patients with a complication event (p = 0.0003). Event-free patients had a higher incidence of complete remission (71%), were more often free of immunosuppressive treatment (79%) and independent of transfusions (100%), and had a higher Karnofsky score (91% with a score ≥90%) as compared to the group with events (29, 37, 67, 48%; p ≤ 0.0002). At 1 and 3 years, event-free patients had significantly higher leukocyte and neutrophil counts, as compared to patients with a complication (p < 0.05). However, at 3 and 5 years, event-free patients had borderline higher platelet counts (p = 0.056, p = 0.078) and hemoglobin (p = 0.097, p = 0.061). The coefficient of variation as an expression of the variability of the results in each group was systematically lower at 3, 5 and 10 years in the group of event-free patients. Despite some differences between the two groups, our data support the hypothesis that patients with long-lasting remissions should not be considered as definitively cured of aplastic anemia.

Keywords:
Antilymphocyte globulin, Aplastic anemia, Immunosuppression, Relapse
1.
Bacigalupo A, Hows J, Gluckman E, Nissen C, Marsh JCW, Van Lint MT, Congiu M, De Planque MM, Ernst P, McCann S, Ragavashar A, Frickhofen N, Würsch A, Marmont AM, Gordon-Smith EC: Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia: A report of the EBMT SAA Working Party. Br J Haematol 1988;70:177–182.
2.
Doney K, Leisenring W, Storb R, Appelbaum FR: Primary treatment of acquired aplastic anemia: Outcomes with bone marrow transplantation and immunosuppressive therapy. Ann Intern Med 1997;126:107–115.
3.
Frickhofen N, Kaltwasser JP, Schrezenmeier H, Ragavashar A, Vogt HG, Herrmann F, Freund M, Meusers P, Salama A, Heimpel H: Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. N Engl J Med 1991;324:1297–1304.
4.
Paquette RL, Tebyani N, Frane M, Ireland P, Ho WG, Champlin RE, Nimer SD: Long-term outcome of aplastic anemia in adults treated with antithymocyte globulin: Comparison with bone marrow transplantation. Blood 1995;85:283–290.
5.
Passweg JR, Socié G, Hinterberger W, Bacigalupo A, Biggs JC, Camitta BM, Champlin RE, Gale RP, Gluckman E, Gordon-Smith EC, Hows JM, Klein JP, Nugent ML, Pasquini R, Rowlings PA, Speck B, Tichelli A, Zhang MJ, Horowitz MM, Bortin MM: Bone marrow transplantation for severe aplastic anemia: Has outcome improved? Blood 1997;90:858–864.
6.
Storb R, Leisenring W, Anasetti C, Appelbaum FR, Buckner CD, Bensinger WI, Chauncey T, Clift RA, Deeg HJ, Doney KC, Flowers MED, Hansen JA, Martin PJ, Sanders KM, Witherspoon RP: Long-term follow-up of allogeneic marrow transplants in patients with aplastic anemia conditioned by cyclophosphamide combined with antithymocyte globulin. Blood 1997;89:3890–3891.
7.
Nissen C, Gratwohl A, Tichelli A, Stebler C, Wursch A, Moser Y, dalle Carbonare V, Signer E, Buser M, Ritz R: Gender and response to antilymphocyte globulin (ALG) for severe aplastic anaemia. Br J Haematol 1993;83:319–325.
8.
De Planque MM, Kluin-Nelemans HC, Van Krieken HJM, Kluin PM, Brand A, Beverstock GC, Willemze R, Van Rood JJ: Evolution of acquired severe aplastic anaemia to myelodysplastic and subsequent leukaemia in adults. Br J Haematol 1988;70:55.
9.
De Planque MM, Kluin-Nelemans HC, van Krieken HJ, Kluin PM, Brand A, Beverstock GC, Willemze R, van Rood JJ: Evolution of acquired severe aplastic anaemia to myelodysplasia and subsequent leukaemia in adults. Br J Haematol 1988;70:55–62.
10.
Marsh JC, Geary CG: Is aplastic anaemia a pre-leukaemic disorder? (editorial). Br J Haematol 1991;77:447–452.
11.
Najean Y, Haguenauer O: Long-term (5 to 20 years) evolution of nongrafted aplastic anemias. The Cooperative Group for the Study of Aplastic and Refractory Anemias. Blood 1990;76:2222–2228.
12.
Narayanan MN, Geary CG, Freemont AJ, Kendra JR: Long-term follow-up of aplastic anaemia. Br J Haematol 1994;86:837–843.
13.
Socié G, Henry-Amar M, Bacigalupo A, Hows J, Tichelli A, Ljungman P, McCann SR, Frickhofen N, Van’t Veer-Korthof E, Gluckman E: Malignant tumors occurring after treatment of aplastic anemia. European Bone Marrow Transplantation-Severe Aplastic Anaemia Working Party. N Engl J Med 1993;329:1152–1157.
14.
Tichelli A, Gratwohl A, Würsch A, Nissen C, Speck B: Late haematological complications in severe aplastic anaemia. Br J Haematol 1988;69:413–418.
15.
Marsh JC, Gordon-Smith EC: Treatment of aplastic anaemia with antilymphocyte globulin and cyclosporin. Int J Hematol 1995;62:133–144.
16.
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.
17.
Schrezenmeier H, Hinterberger-Fischer M, Hows J, Ljungman P, Locascuilli A, Marin P, Marsh JC, McCann S, den Ottolander GJ, Ragavashar A, Socie G, Tichelli A, Van’t Veer-Korthof E, Bacigalupo A, for the EMBT SAA Working Party. Second immunosuppressive treatment of patients with aplastic anemia not responding to the first course of immunosuppression: A report from the Working Party on Severe Aplastic Anemia of the EBMT (abstract). Bone Marrow Transplant 1998;15(suppl 2):S10–S10.
18.
Means RT Jr, Krantz SB, Dessypris EN, Lukens JN, Niblack GD, Greer JP, Flexner JM, Stein RS: Re-treatment of aplastic anemia with antithymocyte globulin or antilymphocyte serum. Am J Med 1988;84:678–682.
19.
Marsh JC, Socie G, Schrezenmeier H, Tichelli A, Gluckman E, Ljungman P, McCann SR, Raghavachar A, Marin P, Hows JM: Haemopoietic growth factors in aplastic anaemia: A cautionary note. European Bone Marrow Transplant Working Party for Severe Aplastic Anaemia (see comments). Lancet 1994;344:172–173.
20.
Marsh JCW, Gordon-Smith EC: The role of antilymphocyte globulin in the treatment of chronic acquired bone marrow failure. Blood Rev 1988;2:141–148.
21.
Tichelli A, Passweg JR, Nissen C, Bargetzi M, Hoffmann T, Wodnar-Filipowicz A, Signer E, Speck B, Gratwohl A: Repeated treatment with horse antilymphocyte globulin for severe aplastic anaemia. Br J Haematol 1998;100:393–400.
22.
Camitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP, Rappeport JM, Storb R: Severe aplastic anemia: A prospective study of the effect of early marrow transplantation on acute mortality. Blood 1976;48:63–70.
23.
Speck B, Gratwohl A, Nissen C, Leibundgut U, Ruggero O, Osterwalder B, Burri HP, Cornu P, Jeannet M: Treatment of severe aplastic anaemia with antilymphocyte globuline or bone marrow transplantation. Br Med J 1981;282:860–863.
24.
Speck B, Gratwohl A, Nissen C, Osterwalder B, Würsch A, Tichelli A, Lori A, Reusser P, Jeannet M, Signer E: Treatment of severe aplastic anemia. Exp Hematol 1986;14:126–132.
25.
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481.
26.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br J Cancer 1977;35:1–39.
27.
Schrezenmeier H, Marin P, Raghavachar A, McCann S, Hows J, Gluckman E, Nissen C, van’t Veer-Korthof ET, Ljungman P, Hinterberger W, Van Lint MT, Frickhofen N, Bacigalupo A, for the EBMT SAA Working Party: 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.
28.
De Planque MM, Brand A, Kluin-Nelemans HC, Eernisse JG, van der Burgh F, Natarajan AT, Beverstock GC, Zwaan FE, Willemze R, van Rood JJ: Haematopoietic and immunologic abnormalities in severe aplastic anaemia patients treated with antithymocyte globulin. Br J Haematol 1989;71:421–430.
29.
Marsh JCW, Hows J, Bryett KA, Al-Hashimi S, Fairhead SM, Gordon-Smith EC: Survival after antithymocyte globulin therapy for aplastic anemia depends on disease severity. Blood 1987;70:1046–1052.
30.
Tichelli A, Gratwohl A, Nissen C, Signer E, Stebler Gysi Ch, Speck B: Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin. Blood 1992;80:337–345.
31.
Marsh JC, Chang J, Testa NG, Hows J, Dexter TM: The hematopoietic defect in aplastic anemia assessed by long-term marrow culture. Blood 1990;76:1–10.
© 2000 S. Karger AG, Basel
2000
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.