THERAPY-RELATED ACUTE MYELOID-LEUKEMIA FOLLOWING TREATMENT WITH EPIPODOPHYLLOTOXINS - ESTIMATING THE RISKS

In the past decade, therapy-related acute myeloid leukemia (t-AML) fol lowing treatment with regimens that include inhibitors of topoisomeras e-II (TOPO-II) has been reported with increasing frequency. These case s of t-AML generally have a shorter latency period than t-AML followin g alkylator therapy, are associated with chromosomal translocations (e specially involving chromosome band 11q23), and usually present as M4 or M5 FAB subtype. Although the epipodophyllotoxins (etoposide and ten iposide) have been most often implicated, similar cases of t-AML occur following therapy with other classes of Topo-II inhibitors (e.g., ant hracyclines). There is wide variation in published studies in the esti mates of risk of t-AML following epipodophyllotoxin therapy. These var ying estimates may reflect a number of factors, including: small sampl e size leading to large confidence intervals around risk estimates; va rying susceptibility of different patient populations; varying schedul es of epipodophyllotoxin administration; different cumulative doses of epipodophyllotoxins; and administration of epopodophyllotoxins with a dditional agents that may alter the leukemogenic effect of the epipodo phyllotoxins. Available data suggest that children with acute lymphocy tic leukemia (ALL) treated with high cumulative doses of epipodophyllo toxins using either weekly or twice-weekly schedules of administration have a relatively high risk of developing t-AML (5-12% cumulative ris k). On the other hand, germ cell patients treated with relatively low cumulative doses of etoposide (usually 1,500-2,500 mg/m2) appear to ha ve a low risk for developing t-AML. There is inadequate experience at this time with higher cumulative doses of etoposide (e.g., 4,000-5,000 Mg/M2 as used for pediatric solid tumors) given on a daily x 5 schedu le to allow estimates of risk to be developed for this schedule and cu mulative dose. The Cancer Therapy Evaluation Program (CTEP) of the Nat ional Cancer Institute (NCI) has developed a monitoring plan designed to obtain reliable estimates of the risk of t-AML following epipodophy llotoxin treatment. Twelve Cooperative Group clinical trials that use epipodophyllotoxins at either low (<1,500 mg/m2), moderate (1,500-3,99 9 mg/m2), or higher cumulative doses (>4,000 mg/m2) are being prospect ively monitored for cases of t-AML occurring among patients entered on to the trials. (C) 1994 Wiley-Liss, Inc.