Journal of Clinical Oncology, Vol 12, 1063-1073, Copyright © 1994 by American Society of Clinical Oncology

ARTICLES

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

FE van Leeuwen, AM Chorus, AW van den Belt-Dusebout, A Hagenbeek, R Noyon, EH van Kerkhoff, HM Pinedo and R Somers
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam.

PURPOSE: The development of leukemia is one of the most serious long- term complications of modern treatment for Hodgkin's disease (HD). This study was undertaken to examine the relation between risk of leukemia and various treatment factors (including cumulative dose of cytostatic drugs and interaction with radiotherapy [RT]), while also assessing the effect of treatment-induced bone marrow damage. PATIENTS AND METHODS: We conducted a case-control study in a cohort of 1,939 patients treated for HD between 1966 and 1986 in the Netherlands. Detailed information from the medical records was obtained for 44 cases of leukemia and 124 matched controls, in whom leukemia had not developed. RESULTS: The cumulative dose of mechlorethamine was the most important factor in determining leukemia risk. As compared with patients who received RT alone, patients treated with six or fewer cycles of combinations including nitrogen mustard (mechlorethamine) and procarbazine had an eightfold increased risk of developing leukemia (P = .08), while patients who received more than six of such cycles had a greater than 40-fold excess risk (P < .001). Treatment with lomustine or a combination of teniposide and cyclophosphamide also significantly increased the risk of leukemia. Patients who had received chemotherapy (CT) during two or more time periods had a nearly 40-fold increased risk of leukemia as compared with patients treated only once. The extent of RT did not further increase leukemia risk among patients who also received CT. A significantly increased risk of leukemia was found among patients with low platelet counts, both in response to initial therapy and during follow-up. Patients who experienced 2 or more half- year periods with platelet counts less than 75 x 10(6)/mL had an approximately fivefold risk of developing leukemia, and a similar risk increase was found for patients who responded to initial treatment with a > or = 70% decrease of platelet counts (as compared with patients who had a < or = 50% decrease). CONCLUSION: In addition to mechlorethamine, lomustine and teniposide combinations were also linked to an elevated risk of developing leukemia. Since the number of CT episodes was found to be a strong determinant of leukemia risk, it is important that new therapies for HD continue to yield high initial cure rates. Further studies are warranted to investigate whether patients at high risk for developing leukemia may be identified from the response of their platelets to initial therapy for HD.

This article has been cited by other articles:

				V. Pavone, U. Ricardi, S. Luminari, P. Gobbi, M. Federico, L. Baldini, E. Iannitto, G. Ucci, L. Marcheselli, L. Orsucci, et al. ABVD plus radiotherapy versus EVE plus radiotherapy in unfavorable stage IA and IIA Hodgkin's lymphoma: results from an Intergruppo Italiano Linfomi randomized study Ann. Onc., April 1, 2008; 19(4): 763 - 768. [Abstract] [Full Text] [PDF]

				A. K. Ng Second Cancers after Hodgkin's Lymphoma: Long-term Risks ASCO Educational Book, January 1, 2008; 2008(1): 418 - 422. [Abstract] [Full Text] [PDF]

				B. Barlogie, G. Tricot, J. Haessler, F. van Rhee, M. Cottler-Fox, E. Anaissie, J. Waldron, M. Pineda-Roman, R. Thertulien, M. Zangari, et al. Cytogenetically defined myelodysplasia after melphalan-based autotransplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: the Arkansas experience in more than 3000 patients treated since 1989 Blood, January 1, 2008; 111(1): 94 - 100. [Abstract] [Full Text] [PDF]

				C. K. Tebbi, W. B. London, D. Friedman, D. Villaluna, P. A. De Alarcon, L. S. Constine, N. P. Mendenhall, R. Sposto, A. Chauvenet, and C. L. Schwartz Dexrazoxane-Associated Risk for Acute Myeloid Leukemia/Myelodysplastic Syndrome and Other Secondary Malignancies in Pediatric Hodgkin's Disease J. Clin. Oncol., February 10, 2007; 25(5): 493 - 500. [Abstract] [Full Text] [PDF]

				G Sanna, K Lorizzo, N Rotmensz, V Bagnardi, S Cinieri, M Colleoni, F Nole, and A Goldhirsch Breast cancer in Hodgkin's disease and non-Hodgkin's lymphoma survivors Ann. Onc., February 1, 2007; 18(2): 288 - 292. [Abstract] [Full Text] [PDF]

				S. Bhatia, M. D. Krailo, Z. Chen, L. Burden, F. B. Askin, P. S. Dickman, H. E. Grier, M. P. Link, P. A. Meyers, E. J. Perlman, et al. Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: a report from the Children's Oncology Group Blood, January 1, 2007; 109(1): 46 - 51. [Abstract] [Full Text] [PDF]

				J Franklin, A Pluetschow, M Paus, L Specht, A-P Anselmo, A Aviles, G Biti, T Bogatyreva, G Bonadonna, C Brillant, et al. Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials Ann. Onc., December 1, 2006; 17(12): 1749 - 1760. [Abstract] [Full Text] [PDF]

				L. B. Travis The Epidemiology of Second Primary Cancers Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2020 - 2026. [Abstract] [Full Text] [PDF]

				C. Ferme, N. Mounier, O. Casasnovas, P. Brice, M. Divine, A. Sonet, F. Bouafia, A. Bastard-Stamatoullas, D. Bordessoule, L. Voillat, et al. Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Blood, June 15, 2006; 107(12): 4636 - 4642. [Abstract] [Full Text] [PDF]

				S. J. Schonfeld, E. S. Gilbert, G. M. Dores, C. F. Lynch, D. C. Hodgson, P. Hall, H. Storm, A. Andersen, E. Pukkala, E. Holowaty, et al. Acute Myeloid Leukemia Following Hodgkin Lymphoma: A Population-Based Study of 35 511 Patients J Natl Cancer Inst, February 1, 2006; 98(3): 215 - 218. [Abstract] [Full Text] [PDF]

				H. Sill, W. Olipitz, and M. G. Schimek Therapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia After Autologous Bone Marrow Transplantation: Dosis Facit Venenum? J. Clin. Oncol., November 1, 2005; 23(31): 8120 - 8121. [Full Text] [PDF]

				J. Czyz, R. Dziadziuszko, W. Knopinska-Postuszuy, A. Hellmann, L. Kachel, J. Holowiecki, J. Gozdzik, J. Hansz, A. Avigdor, A. Nagler, et al. Outcome and prognostic factors in advanced Hodgkin's disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients Ann. Onc., August 1, 2004; 15(8): 1222 - 1230. [Abstract] [Full Text] [PDF]

				K. Behringer, A. Josting, P. Schiller, H. T. Eich, H. Bredenfeld, V. Diehl, and A. Engert Solid tumors in patients treated for Hodgkin's disease: a report from the German Hodgkin Lymphoma Study Group Ann. Onc., July 1, 2004; 15(7): 1079 - 1085. [Abstract] [Full Text] [PDF]

				M. Andre, N. Mounier, X. Leleu, A. Sonet, P. Brice, M. Henry-Amar, H. Tilly, B. Coiffier, A. Bosly, P. Morel, et al. Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients Blood, February 15, 2004; 103(4): 1222 - 1228. [Abstract] [Full Text] [PDF]

				A. K. Ng, S. Li, D. Neuberg, B. Silver, M. A. Stevenson, D. C. Fisher, and P. M. Mauch Comparison of MOPP versus ABVD as salvage therapy in patients who relapse after radiation therapy alone for Hodgkin's disease Ann. Onc., February 1, 2004; 15(2): 270 - 275. [Abstract] [Full Text] [PDF]

				A. Josting, S. Wiedenmann, J. Franklin, M. May, M. Sieber, J. Wolf, A. Engert, and V. Diehl 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., September 15, 2003; 21(18): 3440 - 3446. [Abstract] [Full Text] [PDF]

				B. M.P. Aleman, A. W. van den Belt-Dusebout, W. J. Klokman, M. B. van't Veer, H. Bartelink, and F. E. van Leeuwen Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin's Disease J. Clin. Oncol., September 15, 2003; 21(18): 3431 - 3439. [Abstract] [Full Text] [PDF]

				D. A. Persons, E. R. Allay, N. Sawai, P. W. Hargrove, T. P. Brent, H. Hanawa, A. W. Nienhuis, and B. P. Sorrentino Successful treatment of murine {beta}-thalassemia using in vivo selection of genetically modified, drug-resistant hematopoietic stem cells Blood, July 15, 2003; 102(2): 506 - 513. [Abstract] [Full Text] [PDF]

				V. Diehl, J. Franklin, M. Pfreundschuh, B. Lathan, U. Paulus, D. Hasenclever, H. Tesch, R. Herrmann, B. Dorken, H.-K. Muller-Hermelink, et al. Standard and Increased-Dose BEACOPP Chemotherapy Compared with COPP-ABVD for Advanced Hodgkin's Disease N. Engl. J. Med., June 12, 2003; 348(24): 2386 - 2395. [Abstract] [Full Text] [PDF]

				B. M.P. Aleman, J. M.M. Raemaekers, U. Tirelli, R. Bortolus, M. B. van 't Veer, M. L.M. Lybeert, J. J. Keuning, P. Carde, T. Girinsky, R. W.M. van der Maazen, et al. Involved-Field Radiotherapy for Advanced Hodgkin's Lymphoma N. Engl. J. Med., June 12, 2003; 348(24): 2396 - 2406. [Abstract] [Full Text] [PDF]

				C. Metayer, R. E. Curtis, J. Vose, K. A. Sobocinski, M. M. Horowitz, S. Bhatia, J. W. Fay, C. O. Freytes, S. C. Goldstein, R. H. Herzig, et al. Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study Blood, March 1, 2003; 101(5): 2015 - 2023. [Abstract] [Full Text] [PDF]

				A. K. Ng, M. V. P. Bernardo, E. Weller, K. Backstrand, B. Silver, K. C. Marcus, N. J. Tarbell, M. A. Stevenson, J. W. Friedberg, and P. M. Mauch Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors Blood, August 28, 2002; 100(6): 1989 - 1996. [Abstract] [Full Text] [PDF]

				S. L. Gerson Clinical Relevance of MGMT in the Treatment of Cancer J. Clin. Oncol., May 1, 2002; 20(9): 2388 - 2399. [Abstract] [Full Text] [PDF]

				L. B. Travis, M. Gospodarowicz, R. E. Curtis, E. Aileen Clarke, M. Andersson, B. Glimelius, T. Joensuu, C. F. Lynch, F. E. van Leeuwen, E. Holowaty, et al. Lung Cancer Following Chemotherapy and Radiotherapy for Hodgkin's Disease J Natl Cancer Inst, February 6, 2002; 94(3): 182 - 192. [Abstract] [Full Text] [PDF]

				H. C. Fung, A. P. Nademanee, S. Bhatia, S. J. Forman, A. Sureda, and E. Conde 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? J. Clin. Oncol., August 1, 2001; 19(15): 3585 - 3588. [Full Text]

				J. M. Connors, E. M. Noordijk, and S. J. Horning Hodgkin's Lymphoma: Basing the Treatment on the Evidence Hematology, January 1, 2001; 2001(1): 178 - 193. [Abstract] [Full Text] [PDF]

				J. Pedersen-Bjergaard, M. K. Andersen, and D. H. Christiansen Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation Blood, June 1, 2000; 95(11): 3273 - 3279. [Abstract] [Full Text] [PDF]

				A. Krishnan, S. Bhatia, M. L. Slovak, D. A. Arber, J. C. Niland, A. Nademanee, H. Fung, R. Bhatia, A. Kashyap, A. Molina, et al. Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors Blood, March 1, 2000; 95(5): 1588 - 1593. [Abstract] [Full Text] [PDF]

				D. C. Linch, R. G. Gosden, T. Tulandi, S.-L. Tan, and S. L. Hancock Hodgkin's Lymphoma: Choice of Therapy and Late Complications Hematology, January 1, 2000; 2000(1): 205 - 221. [Abstract] [Full Text] [PDF]

				A. C. Aisenberg Problems in Hodgkin's Disease Management Blood, February 1, 1999; 93(3): 761 - 779. [Full Text] [PDF]

				A. K. Ng, J. C. Weeks, P. M. Mauch, and K. M. Kuntz Laparotomy Versus No Laparotomy in the Management of Early-Stage, Favorable-Prognosis Hodgkin's Disease: A Decision Analysis J. Clin. Oncol., January 1, 1999; 17(1): 241 - 241. [Abstract] [Full Text] [PDF]

				M. Andre, M. Henry-Amar, D. Blaise, P. Colombat, J. Fleury, N. Milpied, J.-Y. Cahn, J.-L. Pico, Y. Bastion, M. Kuentz, et al. Treatment-Related Deaths and Second Cancer Risk After Autologous Stem-Cell Transplantation for Hodgkin's Disease Blood, September 15, 1998; 92(6): 1933 - 1940. [Abstract] [Full Text] [PDF]

				M. de Lima, S. S. Strom, M. Keating, H. Kantarjian, S. Pierce, S. O'Brien, E. Freireich, and E. Estey Implications of Potential Cure in Acute Myelogenous Leukemia: Development of Subsequent Cancer and Return to Work Blood, December 15, 1997; 90(12): 4719 - 4724. [Abstract] [Full Text] [PDF]

				J. G. Krikorian and D. E. Palmer-Toy Case 38-1997- Inflammation of the Ears, Anemia, and Fever 21 Years after Treatment for Hodgkin's Disease N. Engl. J. Med., December 11, 1997; 337(24): 1753 - 1760. [Full Text] [PDF]