Etoposide and secondary haematological malignancies: coincidence or causality?

Secondary haematological malignancies (SHM) induced by alkylating agents show cytogenetic abnormalities involving mainly chromosomes 5 and 7. Etoposide and other topoisomerase II inhibitors including anthracyclines induce secondary leukaemias with a short latency period, briefly preceded by a myelodysplastic phase, and frequently associated with balanced translocation characteristically involving the long arms of chromosomes 11 and 21.

Etoposide with doxorubicin containing chemotherapy was administered to 26 patients with Hodgkin's disease (HD), eight of whom received alkylating agents at relapse or progression, and to 59 patients with small-cell lung carcinoma (SCLC), thirty-three of whom received alkylating agents in the same combination.

Four of 85 patients developed SHM of the myelodysplastic or acute myeloid type at, respectively, 20, 30, 35 and 38 months after therapy. In 3 of them, chromosome abnormalities were observed: two balanced translocations, t(6;9)(p23;34) and t(11;19)(q23;p13), and one monosomy 7q due to t(1;7)(cen;cen) with trisomy 8. The cumulative risk estimate of SHM is 12% (95% confidence interval (CI): 3%-46%) at 5 years for patients with HD and 18% (95% CI: 5%-49%) at 3 years for patients with SCLC.

Our observations lend further support to the existence of SHM induced by topoisomerase II inhibitors that present early after initial treatment with balanced translocations to 11q23 and 21q22. However, other defects such as unbalanced abnormalities of chromosomes 5 and 7 can occur and may be related to the combination of topoisomerase II inhibitors with alkylating agents. Balanced t(6;9) was observed for the first time in SHM. A synergism between epipodophyllotoxins, anthracyclines, alkylating agents, cisplatin and radiotherapy is suggested, given the observed high risk of SHM.