The risk of acute leukemia in patients treated for Hodgkin’s disease is significantly higher after combined modality programs than after chemotherapy alone and is correlated with the extent of radiotherapy and type and duration of chemotherapy: a case-control study

The risk of acute leukemia in patients treated for Hodgkin’s disease is significantly higher after combined modality programs than after chemotherapy alone and is correlated with the extent of radiotherapy and type and duration of chemotherapy: a case-control study ERCOLE BRUSAMOLINO,* ANNA PAOLA ANSELMO,° CATHERINE KLERSY,# MARIAQUILA SANTORO,@ ESTER ORLANDI,* GUIDO PAGNUCCO,* FRANCESCA LUNGHI,* RICCARDO MAURIZI-ENRICI,@ CARLO DAVID BARONI,^ MARIO LAZZARINO,* FRANCO MANDELLI,° CARLO BERNASCONI* *Istituto di Ematologia, Università di Pavia & Divisione di Ematologia, IRCCS Policlinico San Matteo, Pavia; °Ematologia, Dipartimento di Biopatologia Umana, Università "La Sapienza", Rome; #Unità di Biometria, Direzione Scientifica Policlinico San Matteo IRCCS, Pavia; @Istituto di Radiologia, Università "La Sapienza", Rome; ^Dipartimento di Medicina Sperimentale e Patologia, Università "La Sapienza", Rome, Italy Haematologica 1998; 83:812-823 original paper Correspondence: Ercole Brusamolino, M.D., Istituto di Ematologia, Università di Pavia, Divisione di Ematologia, IRCCS Policlinico San Matteo, piazzale Golgi 2, 27100 Pavia, Italy Phone: international +39-0382-503074 • Fax: international +390382-502250. Background and Objective. Patients treated for Hodgkin’s disease have an increased risk of developing subsequent acute leukemia. This coopoerative study was conducted to assess the relative risk associated with several candidate factors including age, splenectomy, combined modality therapy and cumulative drug dose including alkylating agents and nitrosurea derivatives. Design and Methods. This study evaluated the risk of acute leukemia according to pretreatment variables and therapy modalities among 1659 patients treated for Hodgkin's disease and followed for a median time of 10 years. Both case-control and actuarial risk studies were performed. Median age was 34 years (range: 12-83); 53% of patients were splenectomized. As to the overall therapy, 348 patients (21%) were given radiotherapy (RT) alone, 375 (23%) chemotherapy (CT) alone (including MOPP, MOPP+ABVD or MOPP+ ABVD+ lomustine); 936 (56%) received both CT and RT, either as primary or salvage treatment. Results. The overall 15-year actuarial risk of leukemia was 4.2%; the hazard function curve showed two peaks of risk at the 3th and the 8th year from the initiation of therapy and no leukemia beyond the 12th year of follow-up. Risk of leukemia was 0.3% after RT alone, 2.8% after CT alone (2.2% after MOPP; 4.4% after MOPP+ ABVD+ lomustine), and 5.4% in patients given combined modality therapy (10.2% for RT+ MOPP; 15.6% for RT+ MOPP+ lomustine). No leukemia occurred after ABVD alone and the risk was low (0.6%) when neither mechlorethamine nor lomustine were utilized. Patients who had received extended radiotherapy including abdomen and pelvis in addition to MOPP showed a significantly higher risk of leukemia compared to those given limited RT+MOPP (P = 0.01). Case-control analysis indicated advanced stage, type and duration (> 8 months) of CT and extension of RT as significant risk factors for leukemia. Compared to RT alone, the odds ratio was 5.9 after MOPP+extended RT, and 8 when a lomustine-containing regimen was used, as well. Neither age nor splenectomy were independent risk factors for leukemia; splenectomy was influential only when patients had been given MOPP chemotherapy, as well. Interpretations and Conclusions. Both case-control and actuarial analyses indicated that: a) combined modality therapy with MOPP and extensive RT (including abdomen and pelvis), and the use of lomustine added to the leukemogenic risk of MOPP alone; b) programs without mechlorethamine, procarbazine and lomustine were almost devoid of leukemogenic risk. ©1998, Ferrata Storti Foundation