title: Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours.
abstract: 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% CI 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.
authors.affiliation: Department of Haematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Pedersen-Bjergaard
authors.forename: G
authors.initials: G
authors.lastname: Daugaard
authors.forename: S W
authors.initials: SW
authors.lastname: Hansen
authors.forename: P
authors.initials: P
authors.lastname: Philip
authors.forename: S O
authors.initials: SO
authors.lastname: Larsen
authors.forename: M
authors.initials: M
authors.lastname: Rørth
mesh_terms: D000208:Acute Disease; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001761:Bleomycin / Q000008:administration & dosage; D002869:Chromosome Aberrations; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000235:genetics; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy*; D012307:Risk Factors
chemical_list: D001761:Bleomycin; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D002945:Cisplatin