Chromosomal abnormalities in secondary MDS and AML. Relationship to drugs and radiation with specific emphasis on the balanced rearrangements

Abstract

BACKGROUND AND OBJECTIVE: In therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) balanced chromosome aberrations to bands 11q23 and 21q22 have been significantly related to previous chemotherapy with DNA topoisomerase II inhibitors. The purpose of the present study was to evaluate to what extent other balanced chromosome aberrations show the same association, and to evaluate a possible relationship to patient age and subgroups of drugs. DESIGN AND METHODS: All previously published cases of t-MDS and t-AML with any type of balanced aberration identified from Felix Mitelman's Catalog of Chromosome Aberrations in Cancer were analyzed for age and type of previous therapy, and the results were evaluated in univariate and multivariate analyses. RESULTS: A total of 422 cases were recorded, 328 had previously received well specified types of chemotherapy; 254 presented one out of five characteristic balanced aberrations, whereas 168 cases presented different uncharacteristic balanced aberrations. In univariate analysis cases with translocations to 11q23 had most often received DNA topoisomerase II inhibitors, whereas patients with the uncharacteristic balanced rearrangements most often had received alkylating agents (p < 0.00000001). Inv(16), t(15;17), and t(9;22) were likewise significantly associated with previous therapy with DNA topoisomerase II inhibitors and to almost the same extent as translocations to 21q22. Patients with translocations to 11q23 were significantly younger as compared to all other groups of patients. Translocations to 11q23 predominated following therapy with epipodophyllotoxins, whereas patients with translocations to 21q22, inv(16), t(15;17), and t(9;22) most often had received anthracyclines. In a multivariate analysis taking age into consideration, however, these drug-specific associations were no longer significant. INTERPRETATION AND CONCLUSIONS: Specific balanced chromosome aberrations in t-MDS and t-AML involving chromosome bands 11q23 and 21q22, inv(16), t(15;17), and t(9;22) are all significantly associated with previous therapy with DNA topoisomerase II inhibitors, as compared to the uncharacteristic balanced aberrations most commonly observed after therapy with alkylating agents. Younger age and not a specific type of DNA topoisomerase II inhibitor seems to predispose specifically to development of t-MDS and t-AML with translocations to chromosome band 11q23.