To estimate the risk of secondary
leukemias after treatment with
etoposide (VP-16), we evaluated subjects treated for
Langerhans' cell histiocytosis (LCH) according to cooperative protocols in Italy or in Austria, Germany, Holland and Switzerland (AGDS). For each subject, information was collected on the cumulative dosages of
chemotherapy and
radiotherapy received, vital status and occurrence of secondary
leukemia. The expected number of
leukemias was estimated using age-specific incidence rates from the
cancer registries in Italy and Germany. Standardized incidence ratios (SIR) were used to measure the risk of secondary
leukemia among LCH patients. Five
leukemias occurred among the 241 Italian study patients (SIR 520), whereas no cases were reported among the 363 AGDS patients. Interestingly, and in contrast to previous descriptions of
epipodophyllotoxin-related
leukemias which are mostly FAB M4 or M5, these
leukemias showed typical FAB M3 features, and received a dose of
VP-16 > 4,000 mg/m2. Among the AGDS cohort, very few subjects were exposed to high doses of
VP-16. The risk of secondary acute non-
lymphoblastic leukemia (s-
ANLL) among the Italian subjects exposed to
VP-16 was more than 1,000 times greater than expected. The study suggests that high doses of
VP-16 appear to increase the risk of s-
ANLL in LCH patients. The fact that all the
leukemias described in the Italian LCH cohort were promyelocytic, and evidence of a higher incidence of promyelocytic
leukemias among Italians and Latinos, suggest that high doses of
etoposide in subjects of Latino origin may lead to aberrations on chromosomes 15 and 17.