Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours

• Published in: The Lancet (British edition) 1991-08, Vol.338 (8763), p.359-363
• Main Authors: Pedersen-Bjergaard, J., Daugaard, G., Hansen, S.W., Rørth, M., Philip, P., Larsen, S.O.
• Format: Article
• Language: English
• Subjects: Acute Disease; Acute myeloid leukemia; Adult; Alkylating agents; Alkylation; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biological and medical sciences; Bleomycin; Bleomycin - administration & dosage; Chemotherapy; Chromosome Aberrations; Chromosome translocations; Cisplatin; Cisplatin - administration & dosage; Cohort Studies; Cytostatic agents; Deoxyribonucleic acid; DNA; DNA topoisomerase (ATP-hydrolysing); DNA Topoisomerases, Type II - drug effects; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Drugs; Etoposide; Etoposide - administration & dosage; Etoposide - adverse effects; Female; Humans; Leukemia; Leukemia, Myeloid - chemically induced; Leukemia, Myeloid - genetics; Male; Medical research; Medical sciences; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - chemically induced; Myelodysplastic Syndromes - genetics; Neoplasms, Germ Cell and Embryonal - drug therapy; Patients; Pharmacology. Drug treatments; Risk; Risk Factors; Toxicity: blood; Tumors; Vinblastine
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/0140-6736(91)90490-G

Among the cytostatic drugs only the alkylating agents have been firmly established as being leukaemogenic. This report describes 4 cases of acute myeloid leukaemia and 1 of myelodysplasia occurring in a cohort of 212 patients with germ-cell tumours treated with etoposide, cisplatin, and bleomycin. The mean cumulative risk of leukaemic complications was 4·7% (SE 2·3) 5·7 years after start of etoposide-containing chemotherapy, and, compared with the risk in the general population, the relative risk of overt leukaemia was 336 (95% Cl 92-861). No leukaemias were detected in a previous cohort of 127 patients with germ-cell tumours treated with cisplatin, bleomycin, and vinblastine. The increased risk of leukaemia was most probably due to etoposide alone or in combination with cisplatin or bleomycin, since other published work has also not revealed an excess of leukaemias among patients with germ-cell tumours treated with only cisplatin, bleomycin, and vinblastine. The risk of leukaemia was dose related since all 5 patients with leukaemic complications were among the 82 who had received a cumulative dose of more than 2000 mg/m2 etoposide, whereas no leukaemias were observed among 130 patients who had received up to 2000 mg/m2 (p=0·004). 3 of the leukaemic patients had balanced chromosome translocations affecting bands 11q23 and 21q22. These translocations, and perhaps also other balanced aberrations, seem to be characteristic of myelodysplasia and acute leukaemia occurring after therapy with cytostatic agents acting on DNA-topoisomerase II.