Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy

Abstract

open20siBackground Imatinib has so far been the first-choice treatment in chronic myeloid leukemia with excellent results. However, only a proportion of patients achieve major molecular response – hence the need to find biological predictors of outcome to select the optimal therapeutic strategy now that more potent inhibitors are available. Design and methods We investigated a panel of 20 polymorphisms in 7 genes, potentially associated with the pharmacogenetics of imatinib, in a subset of 189 newly diagnosed chronic myeloid leukemia patients enrolled in the TOPS trial. Included in this analysis were polymorphisms in the transporters hOCT1, MDR1, ABCG2, OCTN1, and OATP1A2, and in the metabolizing genes CYP3A4 and CYP3A5. Results In the overall population, the OCTN1 C allele (rs1050152), a simple combination of polymorphisms in the hOCT1 gene and in the genes involved in imatinib uptake were significantly associated with major molecular response. The combination of polymorphisms in imatinib uptake was also significantly associated with complete molecular response. Analyses restricted to Caucasians highlighted the significant association of MDR1 CC (rs60023214) genotype with complete molecular response. Conclusions We demonstrate the usefulness of a pharmacogenetic approach for stratification of chronic myeloid leukemia patients in terms of likelihood to achieve major or complete molecular response on imatinib. This represents an attractive opportunity for therapy optimization, worth testing in clinical trials.openAngelini S; Soverini S; Ravegnini G; Barnett M; Turrini E; Thornquist M; Pane F; Hughes TP; White DL; Radich J; Kim DW; Saglio G; Cilloni D; Iacobucci I; Perini G; Woodman R; Cantelli-Forti G; Baccarani M; Hrelia P; Martinelli GAngelini S; Soverini S; Ravegnini G; Barnett M; Turrini E; Thornquist M; Pane F; Hughes TP; White DL; Radich J; Kim DW; Saglio G; Cilloni D; Iacobucci I; Perini G; Woodman R; Cantelli-Forti G; Baccarani M; Hrelia P; Martinelli