Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins

Purpose: The incidence of secondary leukemia after epipodophyllotoxin treat ment and the relationship between epipodophyllotoxin cumulative dose and ri sk are not well characterised. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodoph yllotoxin treatment. Methods: Twelve NCl-supported cooperative group clinical trials were identi fied that use epipodophyllotoxins at low (< 1.5 g/m(2) etoposide), moderate (1.5 to 2.99 g/m(2) etoposide), or higher (greater than or equal to 3.0 g/ m2 etoposide) cumulative doses. Cases of secondary leukemia (including trea tment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby a llowing calculation of cumulative 6-year incidence rates of secondary leuke mia for each etoposide dose group. Results: The calculated cumulative 6-year risks for development of secondar y leukemia for the low, moderate, and higher cumulative dose groups were 3. 3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively. Conclusion: Within the context of the epipodophyllotoxin cumulative dose ra nge and schedules of administration encompassed by the monitoring plan regi mens, and within the context of multiagent chemotherapy regimens that inclu de alkylating agents, doxorubicin, and other agents, factors other than epi podophyllotoxin cumulative dose seem to be of primary importance in determi ning the risk of secondary leukemia. Data obtained by the CTEP secondary le ukemia monitoring plan support the relative safety of using epipodophylloto xins according to the therapeutic plans outlined in the monitored protocols . (C) 1999 by American Society of Clinical Oncology.