Is There an Association Between Total-Body Irradiation and Secondary Acute Myelogenous Leukemia/Myelodysplastic Syndrome in Patients With Relapsed/Refractory Hodgkin’s Disease Treated With Autologous Stem-Cell Transplantation?
Authors: Henry C. Fung, Auayporn P. Nademanee, S. Bhatia, Stephen J. Forman, Anna Sureda, Eulogio Conde
Journal: Journal of Clinical Oncology (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.15.3585 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11481369 Is There an Association Between Total-Body Irradiation and Secondary Acute Myelogenous Leukemia/Myelodysplastic Syndrome in Patients With Relapsed/Refractory Hodgkin’s Disease Treated With Autologous Stem-Cell Transplantation? Henry C. FungxHenry C. FungSearch for articles by this author , Auayporn P. NademaneexAuayporn P. NademaneeSearch for articles by this author , S. BhatiaxS. BhatiaSearch for articles by this author , Stephen J. FormanxStephen J. FormanSearch for articles by this author Anna SuredaxAnna SuredaSearch for articles by this author , Eulogio CondexEulogio CondeSearch for articles by this author , For the Grupo Español de Linfomas/Transplante Autólogo de Médula Ósea Spanish Cooperative GroupxSearch for articles by this author Show More City of Hope National Medical Center, Duarte, CAHospital de la Santa Creu i Sant Pau, Barcelona, Spain https://doi.org/10.1200/JCO.2001.19.15.3585 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01082001In Reply:Fung et al have raised the outstanding concern of predisposing factors for secondary malignancies (SM) in patients with Hodgkin’s disease (HD) undergoing autologous stem-cell transplantation (ASCT). In our multicenter retrospective analysis, we found the use of total-body irradiation (TBI) within the conditioning regimen to be a significant predictive factor for developing an SM, namely a myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) after transplantation, along with an increased age (≥ 40 years) and the use of adjuvant radiotherapy (RT) pretransplantation.1 Although the proportion of patients receiving TBI is only 10% of the total series and the number of events after transplantation is rather low (16 SMs, 12 in the chemotherapy arm and four in the TBI arm), the administration of TBI increased more than four times the risk of developing an SM after transplantation (relative risk = 4.64; 95% confidence interval, 1.31 to 16.66; P = .01). It was not possible to obtain from participating centers the reason for using TBI as part of the conditioning regimen. Nevertheless, other questions pointed out by Fung et al have been addressed in this study; median follow-up between TBI and non-TBI treated patients is similar (32 [range, 0 to 139] months v 30 [range, 0 to 137] months; P = .62). The exact amount of alkylating agents or topoisomerase II inhibitors could not be evaluated because the information was not available in a significant proportion of patients, but in our hands, prior administration of nitrogen mustard was not a significant prognostic factor when included in the multivariate analysis. We also analyzed the impact of the number of treatment blocks received by the patients, considering the transplantation conditioning regimen as a treatment block in the development of SM after ASCT; in the multivariate analysis, there was a nonsignificant trend to develop an SM in patients receiving more than two treatment blocks with respect to those receiving one or two.MDS/secondary leukemia, a complication of HD treatment known to be associated with cumulative doses of alkylating agents and possibly further promoted by wide-field radiotherapy, is emerging as a major cause of morbidity and mortality in patients successfully treated with high-dose therapy and autografting. The crucial issue is whether the occurrence of MDS/secondary leukemia posttransplantation is due to the high-dose therapy per se or is merely indicative of the fact that patients who undergo transplantation have an increased risk because of their previous, often extensive, therapy. Several authors have addressed this issue, although the exact role of TBI is somewhat difficult to assess, probably because the vast majority of HD patients are autografted using chemotherapy protocols but not the combination of TBI and chemotherapy. In the series of Harrison et al,2 ASCT therapy did not have a significant impact on the development of SM after transplantation, but TBI as part of the conditioning regimen was not evaluated because almost all patients were conditioned with the BEAM protocol (carmustine 300 mg/m2 intravenously [IV] on day 1, etoposide 200 mg/m2 IV on days 2 through 5, cytarabine 200 mg/m2 twice daily on days 2 through 5, and melphalan 140 mg/m2 IV on day 6). In their nested case-controlled study including a group of 218 patients with HD,3 the City of Hope group found that priming with etoposide (relative risk = 8.3; 95% confidence interval, 1.6 to 43.9; P < .05) was the only significant prognostic factor for developing an MDS/secondary leukemia after transplantation. However, the number of patients who received TBI in the conditioning regimen was not specified. Moreover, the impact of priming with etoposide on the incidence of MDS/secondary leukemia in this series has probably obscured a possibly deleterious effect of previous chemotherapy treatments or even the effect of the conditioning regimen.TBI has been specifically considered as a contributing factor to the development of MDS/secondary leukemia after ASCT. Darrington et al4 found an increased risk of secondary MDS in non-Hodgkin’s lymphoma patients ≥ 40 years of age who received TBI in the conditioning regimen; Milligan et al5 in a retrospective analysis from the European Bone Marrow Transplantation Group also found that TBI was a significant prognostic factor for the development of a secondary myelodysplasia. Interestingly, TBI was also a weak risk factor in the multivariate analysis for HD patients until the time interval between diagnosis and ASCT was included in the model. This may suggest that more heavily pretreated HD patients were selected for TBI conditioning. In our study, time interval between diagnosis and transplantation was only a weak factor that lost its significance after including conditioning regimen in the protocol; moreover, as stated above, the number of treatment blocks received before transplantation had only a marginal impact on the incidence of myelodysplasia after ASCT in our study.In conclusion, there are no definitive data in the literature to ascertain the real impact of pretransplantation chemotherapy or conditioning regimen in the development of SM after ASCT. In a significant proportion of patients with HD, the use of TBI is precluded because of prior radiation therapy. Although the use of TBI has demonstrated its efficacy in terms of disease-free survival and overall survival in some subgroups of patients,6,7 on the basis of the results of our study, we would not recommend the routine use of TBI outside of specific clinical trials.1. Sureda A, Arranz R, Iriondo A, et al: Autologous stem cell transplantation for Hodgkin’s disease: Results and prognostic factors in 494 patients from the Grupo Español de Linfomas/Transplante Autólogo de Médula Ósea Spanish Cooperative Group. J Clin Oncol 19:: 1395,2001-1404, Link, Google Scholar2. Harrison CN, Gregory W, Vaughan Hudson G, et al: High-dose BEAM chemotherapy with autologous haemopoietic stem cell transplantation for Hodgkin’s disease is unlikely to be associated with a major increased risk of secondary MDS/AML. Br J Cancer 81:: 476,1999-483, Crossref, Medline, Google Scholar3. Krishnan A, Bhatia S, Slovak ML, et al: Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: An assessment of risk factors. Blood 95:: 1588,2000-1593, Crossref, Medline, Google Scholar4. 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:: 2527,1994-2534, Link, Google Scholar5. Milligan DW, Ruiz de Elvira C, Kolb H-J, et al: Secondary leukaemia and myelodysplasia after autografting for lymphoma: Results from the EBMT. Br J Haematol 106:: 1020,1999-1026, Crossref, Medline, Google Scholar6. Fung H, Nademanee A, Vora N, et al: Autologous stem cell transplantation for patients with poor risk Hodgkin’s disease treated with a total body irradiation based preparative regimen with or without involved field irradiation: The impact of FTBI & IF-RT on the transplant outcome. Blood 92:: 461a,,1998 (abstr) Google Scholar7. Stiff PJ, Unger J, Fisher RI, et al: Single fraction high dose chemotherapy with or without total body irradiation and an autologous bone marrow transplant for patients with relapsed/refractory Hodgkin’s disease: High survival rate in chemoresistant disease. Blood 88:: 485a,,1996 (abstr) Google Scholar