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© 2000 American Society for Clinical Oncology
Myelodysplasia and Acute Leukemia After Autologous Bone Marrow TransplantationUniversity of Nebraska Medical Center , Omaha, NE MYELODYSPLASIA AND acute leukemia have been known to be complications of cytotoxic cancer therapy for many years.1 The risk of this complication is not equal for all chemotherapeutic agents, with alkylating agents and etoposide being particularly associated.2,3 The acute leukemias that develop in this setting have characteristic chromosomal abnormalities. With alkylating agents, the abnormalities most commonly involve chromosomes 5 and 7, whereas 11q23 abnormalities are usually seen after etoposide therapy. Local radiotherapy in association with certain chemotherapeutic regimens, such as mechlorethamine, vincristine, procarbazine, and prednisone, is associated with an increased risk for leukemia.4,5 Low-dose total-body radiotherapy that was once popular for use in low-grade non-Hodgkin’s lymphomas6 and total-body radiotherapy associated with nuclear explosions7 or occupational radiation exposure8,9 are also associated with an increased risk of developing acute leukemia. The cytogenetic abnormalities of the acute leukemias that follow exposure to radiation are less likely to involve chromosomes 5 and 7 than alkylating agent therapy.2 The first successful bone marrow transplants were predominantly allogeneic transplants done for leukemia and were not associated with an apparent increase in posttreatment myelodysplasia/acute leukemia, despite the use of total-body radiotherapy. This was once thought to be explained by total destruction of host cells by the relatively high doses of total-body radiotherapy. However, allogeneic bone marrow transplantation using donor marrow depleted of T cells was shown to often lead to mixed chimeras, implying that host hematopoietic progenitor cells do survive high-dose therapy regimens, including total-body radiotherapy.10 It now seems that destruction of host hematopoietic cells is largely related to the allogeneic T cells of the marrow graft. Given these findings, it is not surprising that secondary myelodysplasia and acute leukemia occur after autologous bone marrow transplantation. However, it raises the question of the etiology of the myelodysplasia/acute leukemia, which could be due to exposure to cytotoxic agents before the autotransplant as well as hematopoietic injury from the high-dose regimen. As shown in the article by Micallef et al11 (in this issue), the problem is clinically important. Incidence rates of myelodysplasia/acute leukemia after autotransplantation for lymphoma have ranged from 7% to 15% in most, but not all, series, with some actuarial projections being even higher.11-17 The outcome for these patients has been dismal, even with attempts at salvage allogeneic bone marrow transplantation.11,18 The distinction between secondary myelodysplasia/acute leukemia caused by total-body radiotherapy as part of the high-dose preparative regimen versus previous therapy administered for the initial malignancy can only be addressed indirectly. The cytogenetic abnormalities found in posttransplant myelodysplasia/acute leukemia have often involved chromosomes 5 and 7.11,13,14 Analyses of the factors predisposing to the development of acute leukemia have identified older patient age, lower dose of hematopoietic progenitors infused, prior fludarabine therapy, prior radiotherapy, increased interval from diagnosis to transplantation, lower platelet count at/before transplantation, bone marrow involvement, type of lymphoma, slow platelet recovery, and lymphoma recurring after transplantation.11-16 Because most centers have used total-body radiotherapy exclusively in their transplant preparative regimens, it has been difficult to assess the impact of radiotherapy. Two reports in which radiotherapy was used for a proportion of patients did find that radiotherapy predisposed to the development of myelodysplasia/acute leukemia after transplantation.16,19 Also, St Bartholomew’s transplant team discontinued the use of total-body radiotherapy in their transplant preparative regimen after concerns were raised. Subsequent to that change, they observed no more cases of myelodysplasia/acute leukemia, although the follow-up was comparatively short.11 In two studies where patients had marrow cytogenetic studies performed before autologous transplantation, it was shown that a significant number of patients came to transplantation with previously acquired chromosomal abnormalities presumably related to previous chemotherapy.20,21 Studies at the University of Nebraska found that myelodysplasia/acute leukemia was seen in patients with Hodgkin’s disease who had received extensive previous alkylating agent therapy despite no total-body radiotherapy in the transplant preparative regimen.16 Thus, it is clear that myelodysplasia/acute leukemia can appear in patients who never receive total-body radiotherapy as part of their transplant preparative regimen but also that total-body radiotherapy increases the risk. At the present time, data supporting the association of total-body radiotherapy and the subsequent development of myelodysplasia/acute leukemia for patients with lymphoma undergoing autologous transplantation are compelling. Since attempts to compare the efficacy of high-dose chemotherapy regimens and those containing total-body radiotherapy have shown no advantage to receiving total-body radiotherapy,22 the prudent decision might be to eliminate the radiation from autologous transplant preparative regimens for patients with lymphoma. However, it is important to remember that the goal of therapy is the net effect of the treatment regimen. If total-body radiotherapy has higher toxicity but comparable survival, it is possible that it is the more effective antilymphoma therapy. Even so, until methods have been identified to eliminate its apparent leukeogenic potential, or a net gain in survival or quality of life has been shown using total-body radiotherapy, it is probably better avoided. REFERENCES 1. Levine EG, Bloomfield CD: Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure. Semin Oncol 19:47, 1992[Medline] 2. Kantarjian HM, Keating MJ, Walters RS, et al: Therapy-related leukemia and myelodysplastic syndrome: Clinical, cytogenetic, and prognostic features. J Clin Oncol 4:1748-1757, 1986[Abstract] 3. Karp JE, Smith MA: The molecular pathogenesis of treatment-induced (secondary) leukemias: Foundations for treatment and prevention. Semin Oncol 24:103-113, 1997[Medline]
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Valagussa P, Santoro A, Fossati-Bellarni F, et al: Second acute leukemia and other malignancies following treatment for Hodgkin’s disease. J Clin Oncol 4:830-837, 1986
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Greene MH, Young RC, Merrill JM, et al: Evidence of a treatment dose response in acute nonlymphocytic leukemias which occur after therapy of non-Hodgkin’s lymphoma. Cancer Res 43:1891-1898, 1983
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Travis LB, Weeks J, Curtis RE, et al: Leukemia following low-dose total body irradiation and chemotherapy for non-Hodgkin’s lymphoma. J Clin Oncol 14:565-571, 1996
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Heyssel R, Brill AB, Woodbury L, et al: Leukemia in Hiroshima atomic bomb survivors. Blood 15:313-331, 1960 8. Smith PG, Doll R: Mortality from cancer and all causes among British radiologists. Radiol 54:187-194, 1981 9. Wang JX, Inskip PD, Boice JD Jr, et al: Cancer incidence among medical diagnostic x-ray workers in China, 1950 to 1985. Cancer 45:889-895, 1990
10.
Bretagne S, Vidaud M, Kuentz M, et al: Mixed blood chimerism in T-cell depleted bone marrow transplant recipients: Evaluation using DNA polymorphisms. Blood 70:1692-1695, 1987
11.
Micallef INM, Lillington DM, Apostolidis J, et al: Therapy-related myelodysplasia and secondary acute myelogenous leukemia after high-dose therapy with autologous hematopoietic progenitor-cell support for lymphoid malignancies. J Clin Oncol 18:947-955, 2000 12. Pedersen-Bjergaard J, Pedersen M, Myhre J, et al: High risk of therapy-related leukemia after BEAM chemotherapy and autologous stem cell transplantation for previously treated lymphomas is mainly related to primary chemotherapy and not to the BEAM-transplantation procedure. Leukemia 11:1654-1660, 1997[Medline]
13.
Traweek ST, Slovak ML, Nadermanee AP, et al: Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin’s disease and non-Hodgkin’s lymphoma. Blood 84:957-963, 1994
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Darrington DL, Vose JM, Anderson JR, et al: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12:2527-2534, 1994
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Stone RM, Neuberg D, Soiffer R, et al: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 12:2535-2542, 1994
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Miller JS, Arthur DC, Litz CE, et al: Myelodysplastic syndrome after autologous bone marrow transplantation: An additional late complication of curative cancer therapy. Blood 83:3780-3786, 1994 17. Taylor PRA, Jackson GH, Lennard AL, et al: Low incidence of myelodysplastic syndrome following transplantation using autologous non-cryopreserved bone marrow. Leukemia 11:1650-1653, 1997[Medline]
18.
Friedberg JW, Neuberg D, Stone RM, et al: Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 17:3128-3135, 1999 19. Ketterer N, Salles G, Dumontet C, et al: Fludarabine may increase the toxicity of peripheral blood progenitor cell transplantation. Br J Haematol 102:204, 1998 (abstr) 20. Chao NJ, Nademanee AP, Long GD, et al: Importance of bone marrow cytogenetic evaluation before autologous bone marrow transplantation for Hodgkin’s disease. J Clin Oncol 9:1575-1579, 1991[Abstract]
21.
Abruzzese E, Radford JE, Miller JS, et al: Detection of abnormal pretransplant clones in progenitor cells of patients who developed myelodysplasia after autologous transplantation. Blood 94:1814-1819, 1999 22. Goldstone AH, McMillan AK, Chopra R: High-dose therapy for the treatment of non-Hodgkin’s lymphoma, in Armitage JO, Antman KH (eds): High-Dose Cancer Therapy: Pharmacology, Hematopoietins, Stem Cells (ed 2). Baltimore, MD,Williams & Wilkins, 1995, pp 757-779
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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