HIGH-RISK OF LEUKEMIA AFTER SHORT-TERM DOSE-INTENSIVE CHEMOTHERAPY INYOUNG-PATIENTS WITH SOLID TUMORS

Purpose: To help fill the gap in knowledge about the risk of leukemia from repetitive high-dose use of alkylating agents and topoisomerase-I I inhibitors in young patients with solid tumors. Methods: Poor risk s olid tumors were treated with four courses of cyclophosphamide (4,200 mg/m(2))/doxorubicin (75 mg/m(2)), and three courses of ifosfamide (9, 000 mg/m(2))/etoposide (500 mg/m(2)). The cumulative incidence of trea tment-related myelodysplasia/leukemia (t-AML) was calculated using the method of competing risks. The expected number of leukemic events was calculated by applying national incidence rates to person-years class ified by age and sex. Results: Among 86 patients (median age, 17 years ) monitored for 6 to 88 months (median, 24), five cases of t-AML were detected at 10 to 37 months (median, 17). The expected number of leuke mic events in this cohort was .001. Clinical and cytogenetic findings implicated prior alkylator therapy in three cases and prior treatment with topoisomerase-II inhibitors in two. At 40 months, the cumulative incidence of t-AML was 8% (SE 7%). Conclusion: Repetitive high dose us e of alkylating agents given with topoisomerase-II inhibitors is stron gly leukemogenic, even with modest cumulative doses of each drug. This finding is notable for the following reasons: (1) it undermines predi ctions that limited use of high-dose chemotherapy might be minimally l eukemogenic, and (2) it contrasts strikingly with the previously repor ted low risk of t-AML following treatment of pediatric solid tumors wi th chemotherapy lacking the alkylator dose-intensity and prominence of etoposide that are hallmarks of current regimens, J Clin Oncol 16:301 6-3020. (C) 1998 by American Society of Clinical Oncology.