Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols

Case reports have suggested that treatment with high-dose etoposide can result in development of a unique secondary leukemia.

This study was designed to estimate the risk of developing leukemia for patients receiving conventional doses of etoposide along with cisplatin and bleomycin.

We reviewed the records at Indiana University of all untreated patients entering clinical trials using etoposide at conventional doses (cumulative dose, 2000 mg/m2 or less) for germ cell cancer between 1982 and 1991. The records of all patients who received a chemotherapy regimen containing etoposide, ifosfamide, or cisplatin after failing to respond to primary chemotherapy were also reviewed.

Between 1982 and 1991, 538 patients entered serial clinical trials with planned cumulative etoposide doses of 1500-2000 mg/m2 in combination with cisplatin plus either ifosfamide or bleomycin. Of these 538 patients, 348 received an etoposide combination as initial chemotherapy and 190 received etoposide as part of salvage treatment. To date, 315 patients are alive, with median follow-up of 4.9 years, and 337 patients have had follow-up beyond 2 years. Two patients (0.37%) developed leukemia. One developed acute undifferentiated leukemia with a t(4;11) (q21;q23) cytogenetic abnormality 2.0 years after starting etoposide-based therapy, and one developed acute myelomonoblastic leukemia with no chromosome abnormalities 2.3 years after beginning chemotherapy. During this period, several hundred patients were treated with etoposide-based chemotherapy and did not enter clinical trials. Three of these patients are known to have developed hematologic abnormalities, including one patient with acute monoblastic leukemia with a t(11;19)(q13;p13) abnormality.

Secondary leukemia after treatment with a conventional dose of etoposide does occur, but the low incidence does not alter the risk-to-benefit ratio of etoposide-based chemotherapy in germ cell cancer.

The reports of leukemia associated with high doses of etoposide emphasize the need for diligent follow-up of patients and make careful risk-to-benefit analysis imperative.