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Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 8120-8121 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.0643
Therapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia After Autologous Bone Marrow Transplantation: Dosis Facit Venenum?Division of Hematology, Medical University of Graz, Austria
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria To the Editor: In a recent article, Brown et al1 report increasing incidence of late secondary malignancies after autologous bone marrow transplantation (ABMT) for non-Hodgkin's lymphoma. At a median follow-up of 9.5 years, therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) were the most frequently observed secondary malignancies, representing 11% of the total patient population. The data presented in this article imply that high-dose chemoradiotherapy is a major factor involved in the pathogenesis of secondary neoplasias. However, with respect to t-MDS/t-AML there is clinical and laboratory evidence suggesting different mechanisms. It is well known that conventional chemo- and/or radiation therapy is also associated with an increased t-MDS/t-AML risk. The incidence of t-MDS/t-AML after conventional therapy for Hodgkin's disease and non-Hodgkin's lymphoma based on cohort study evidence ranges from less than 1% to 3% with up to 8% in selected subgroups. The main risk factors identified in these studies include the kind of antecedent chemotherapy, the extent of irradiation, and increasing age.2-6 Applying fluorescence in situ hybridization, Abruzzese et al7 and Lillington et al8 examined morphologically normal pretransplant marrow or stem-cell specimens of patients who developed t-MDS/t-AML after autologous stem-cell transplantation (ASCT). Both investigators were able to demonstrate that the same cytogenetic abnormality observed at the time of the t-MDS/t-AML diagnosis was already present in pre-ASCT specimens. These data strongly support the hypothesis that the stem-cell damage leading to leukemic transformation results from prior conventional chemotherapy. Finally, the fact that harvested autologous hematopoietic stem cells are never exposed to the conditioning regimen also argues against the role of high-dose chemoradiotherapy in the pathogenesis of t-MDS/t-AML. So why does a small but significant proportion of patients undergoing cytostatic therapy with or without ABMT/ASCT develop t-MDS/t-AML? Answers might be expected from molecular epidemiologic studies that explore the role of genetic risk factors predisposing to the development of t-MDS/t-AML. The most promising targets may thereby include polymorphisms within drug metabolizing enzymes and altered DNA repair mechanisms.9-11 Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Brown JR, Yeckes H, Friedberg JW, et al: Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 23:2208-2214, 2005
2. Lenz G, Dreyling M, Schiegnitz E, et al: Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem cell transplantation in patients with indolent lymphoma: Results of a prospective randomized trial of the German low grade lymphoma study group. J Clin Oncol 22:4926-4933, 2004
3. Josting A, Wiedenmann S, Franklin J, et al: Secondary myeloid leukemia and myelodysplastic syndromes in patients treated for Hodgkin's disease: A report from the German Hodgkin's lymphoma study group. J Clin Oncol 21:3440-3446, 2003
4. Andre M, Mounier N, Leleu X, et al: Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVP regimen: A GELA cohort study on 2837 patients. Blood 103:1222-1228, 2004
5. Valagussa P, Santora A, Fossati-Bellani F, et al: Second acute leukemia and other malignancies following treatment for Hodgkin's disease. J Clin Oncol 4:830-837, 1986
6. van Leeuwen FE, Chorus AMJ, van den Belt-Dusebout AW, et al: Leukemia risk following Hodgkin's disease: Relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage. J Clin Oncol 12:1063-1073, 1994
7. 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
8. Lillington DM, Micallef IN, Carpenter E, et al: Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin's lymphoma. J Clin Oncol 19:2472-2481, 2001
9. Allan JM, Wild CP, Rollinson S, et al: Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. Proc Natl Acad Sci U S A 98:11592-11597, 2001 [Erratum: Proc Natl Acad Sci U S A 98:15394, 2001]
10. Naoe T, Takeyama K, Yokozawa T, et al: Analysis of genetic polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy-related leukemia/myelodysplastic syndrome and de novo acute myeloid leukemia. Clin Cancer Res 6:4091-4095, 2000 11. Olipitz W, Hopfinger G, Aguiar RCT, et al: Defective DNA-mismatch repair: A potential mediator of leukemogenic susceptibility in therapy-related myelodysplasia and leukemia. Genes Chromosomes Cancer 34:243-248, 2002[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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