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

Abstract

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. We investigated a panel of 20 polymorphisms in seven genes, potentially associated with the pharmacogenetics of imatinib, in a subset of 189 patients with newly diagnosed chronic myeloid leukemia enrolled in the TOPS trial. The analysis included polymorphisms in the transporters hOCT1, MDR1, ABCG2, OCTN1, and OATP1A2, and in the metabolizing genes CYP3A4 and CYP3A5. In the overall population, the OCTN1 C allele (rs1050152), a simple combination of polymorphisms in the hOCT1 gene and another combination 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. We demonstrate the usefulness of a pharmacogenetic approach for stratifying patients with chronic myeloid leukemia according to their likelihood of achieving a major or complete molecular response to imatinib. This represents an attractive opportunity for therapy optimization, worth testing in clinical trials.

Figure 1.

Rates of cytogenetic and molecular response to imatinib in the study population. Cumulative incidence of patients achieving major cytogenetic response (MCgR), complete cytogenetic response (CCgR), major molecular response (MMR) and complete molecular response (CMR) in the overall population (left panel) and in Caucasians (right panel).

Figure 2.

Molecular response by OCTN1 genotype. Cumulative incidence of patients achieving MMR and CMR according to OCTN1 rs1050152 genotype in the overall population (left panels) and in Caucasians (right panels). Given that the major allele is C and the minor allele is T, CC and CT carriers had significantly higher MMR and CMR rates with respect to TT carriers.

Figure 3.

Molecular response in Caucasians according to MDR1 and CYP3A4 genotypes. (A) Cumulative incidence of patients achieving CMR according to MDR1 rs60023214 genotype. Given that for rs60023214 the major allele is C and the minor allele is T, CC carriers had a significantly higher CMR rate with respect to CT and TT carriers. (B) Cumulative incidence of patients achieving MMR according to CYP3A4 rs2740574 genotype. Given that for rs2740574 the major allele is A and the minor allele is G, AA carriers had a significantly higher MMR rate with respect to AG carriers (no GG carriers were detected in our study population).