High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients

Abstract

Pharmacogenetic studies in chronic myelogenous leukemia (CML) typically use a candidate gene approach. In an alternative strategy, we analyzed the impact of single nucleotide polymorphisms (SNPs) in drug transporter genes on the molecular response to imatinib, using a DNA chip containing 857 SNPs covering 94 drug transporter genes. Two cohorts of CML patients treated with imatinib were evaluated: an exploratory cohort including 105 patients treated at 400 mg/d and a validation cohort including patients sampled from the 400 mg/d and 600 mg/d arms of the prospective SPIRIT trial (n=239). Twelve SNPs discriminating patients according to cumulative incidence of major molecular response (CI-MMR) were identifi ed within the exploratory cohort. Three of them, all located within the ABCG2 gene, were validated in patients included in the 400 mg/d arm of the SPIRIT trial. We identifi ed an ABCG2 haplotype (defi ne as G-G, rs12505410 and rs2725252) as associated with signifi cantly higher CI-MMR in patients treated at 400 mg/d. Interestingly, we found that patients carrying this ABCG2 "favorable" haplotype in the 400 mg arm reached similar CI-MMR rates thatpatients randomized in the imatinib 600 mg/d arm. Our results suggest that response to imatinib may be infl uenced by constitutive haplotypes in drug transporter genes. Lower response rates associated with "non- favorable" ABCG2 haplotypes may be overcome by increasing the imatinib daily dose up to 600 mg/d.