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Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 8121-8122 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.2292
In Reply:Department of Medical Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital; and Harvard Medical School, Boston, MA We appreciate the interest of Sill et al and their comments in response to our recently published article detailing the incidence of secondary malignancy following autologous bone marrow transplantation (AMBT) for non-Hodgkin's lymphoma (NHL). Sill et al present data suggesting that therapy-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are primarily induced by treatment received before autologous stem-cell transplantation (ASCT) and may be determined by genetic susceptibility. Our article was primarily focused on a discussion of the incidence and causes of secondary solid tumors, since we have previously reported on MDS/AML in this population.1,2 However, as discussed in the article, the causes of secondary neoplasia after ASCT are complex and, in the case of MDS/AML, likely include contributions from therapy given before ASCT, use of total-body irradiation for conditioning, and conditioning with high-dose alkylating agents. It is well established that conventional chemotherapy can induce secondary MDS/AML. However, following standard chemotherapy for NHL, recent data suggest that this risk is significantly lower than has been reported in long-term follow-up of phase II studies of ASCT.1,3,4 For example, the Groupe d’Etude des Lymphomes de l’Adulte group has reported a 0.4% absolute incidence of MDS/AML (standardized incidence ratios 5.65 for males, 19.9 for females) at 7 year follow-up in a large cohort of NHL patients treated with standard cyclophosphamide- and adriamycin-containing chemotherapy.5 In contrast, most reports of MDS/AML following ASCT have found a 5% to 15% absolute incidence at 5 to 10 years.1,3,4 In our study, 68 cases of MDS/AML were observed while only 0.27 cases would have been expected, and this incidence was not impacted by the extent of prior chemotherapy as assessed by transplant in first or later remission.6 Furthermore, recently published randomized trial data from both the German Low Grade Lymphoma Study Group and the Groupe Ouest-Est des Leucémies et Autres Maladies du Sang group confirm a significant increase in the risk of MDS/AML in indolent lymphoma patients randomized to early ASCT rather than interferon or standard chemotherapy maintenance.7,8 Thus, although prior therapy and reinfusion of damaged stem cells likely contribute to the high incidence of MDS/AML following ASCT, the conditioning involved in ASCT is also a likely contributor. Sill et al also point out that detection of cytogenetic abnormalities with fluorescent in situ hybridization (FISH) before ASCT suggests that prior therapy may be the primary cause of MDS/AML. However, although skewed X inactivation and clonal hematopoiesis before ASCT have been associated with subsequent development of MDS/AML,9 FISH analyses have largely been applied retrospectively to subjects who subsequently developed MDS/AML. The true incidence of pre-ASCT FISH abnormalities in subjects who do not develop MDS/AML remains largely unknown, although one study has reported a 12.5% incidence.10 Subjects with normal bone marrow by FISH before ASCT may nonetheless develop MDS/AML with characteristic cytogenetic abnormalities.11,12 Clonal cytogenetic abnormalities may also be identified in hematologically normal patients following ASCT2; the significance of these is unclear as they may disappear or remain stable for years without progressing to MDS.13,14 Although likely reflective of stem-cell damage and certainly concerning, the exact predictive value of clonal abnormalities before or following ASCT is yet to be fully clarified. Finally, although the impact of genetic polymorphisms on treatment response and toxicity is only beginning to be explored, we agree completely that an important goal of current and future research is to move toward an era of targeted therapy based on the unique genetic susceptibility of the host and unique tumor characteristics. Doing so will optimize our chances of offering our patients the most efficacious therapy with the least short- and long-term toxicity. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. 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
2. 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
3. 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
4. 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
5. Andre M, Mounier N, Leleu X, et al: Second cancers and late toxicities after treatment of aggressive non-Hodgkin's lymphoma with the ACVBP regimen: A GELA cohort study on 2,837 Patients. Blood 103:1222-1228, 2004
6. 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
7. Deconinck E, Foussard C, Milpied N, et al: High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: A randomized multicenter study by GOELAMS. Blood 105:3817-3823, 2005
8. 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
9. Mach-Pascual S, Legare RD, Lu D, et al: Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: A single institution study. Blood 91:4496-4503, 1998
10. 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 11. Howe R, Micallef IN, Inwards DJ, et al: Secondary myelodysplastic syndrome and acute myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma. Bone Marrow Transplant 32:317-324, 2003[CrossRef][Medline] 12. Nichols G, de Castro K, Wei LX, et al: Therapy-related myelodysplastic syndrome after autologous stem cell transplantation for breast cancer. Leukemia 16:1673-1679, 2002[CrossRef][Medline]
13. Traweek ST, Slovak ML, Nademanee 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 14. Martinez-Climent JA, Comes AM, Vizcarra E, et al: Chromosomal abnormalities in women with breast cancer after autologous stem cell transplantation are infrequent and may not predict development of therapy-related leukemia or myelodysplastic syndrome. Bone Marrow Transplant 25:1203-1208, 2000[CrossRef][Medline]
Related Correspondence
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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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