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

Marc Delord, Philippe Rousselot, Jean Michel Cayuela, François Sigaux, Joëlle Guilhot, Claude Preudhomme, François Guilhot, Pascale Loiseau, Emmanuel Raffoux, Daniela Geromin, Emmanuelle Génin, Fabien Calvo, Heriberto Bruzzoni-Giovanelli, Marc Delord, Philippe Rousselot, Jean Michel Cayuela, François Sigaux, Joëlle Guilhot, Claude Preudhomme, François Guilhot, Pascale Loiseau, Emmanuel Raffoux, Daniela Geromin, Emmanuelle Génin, Fabien Calvo, Heriberto Bruzzoni-Giovanelli

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 identified 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 identified an ABCG2 haplotype (define as G-G, rs12505410 and rs2725252) as associated with significantly 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 that patients randomized in the imatinib 600 mg/d arm. Our results suggest that response to imatinib may be influenced 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.

Trial registration: ClinicalTrials.gov NCT00219739.

Figures

Figure 1. Cumulative incidence of MMR (CI-MMR)…
Figure 1. Cumulative incidence of MMR (CI-MMR) according to Sokal score and treatment arms
A) 18 months CI-MMR was estimated with respect to Sokal score (n = 312). A Fine and Gray model showed that time to MMR was related to Sokal status and that the coefficient of regression within the first 18 months decreased by 36% (95% confidence interval (CI), 47% to 22%) on average when Sokal increased (P < 0.001). CI-MMR was 70% for the low Sokal score, 57% for the intermediate Sokal score and 39% for high Sokal score. B) CI-MMR was estimated in the exploratory cohort (SLEC) and compared to both treatment arms of the validation cohort (SVC). CI-MMR was comparable between the SLEC and the 400 mg/d arm of SVC (n = 237, P = 0.700), but significantly different between the SLEC and the 600 mg/d arm of SVC (n = 212, P = 0.003). HR was 1.71% (95% CI, 1.20% to 2.44%) in the latter (n = 212, P = 0.003). CI-MMR was 49% for the exploratory cohort, 49% and 67% for the 400 and the 600 mg/d arm of the SVC, respectively.
Figure 2. Frequencies and cumulative incidence of…
Figure 2. Frequencies and cumulative incidence of MMR relative to ABCG2 haplotypes
A) Distribution of haplotype frequencies in the SLEC, SVC and the CEU populations. Haplotypes were distributed homogeneously over the different populations. B) Cumulative incidence at 18-months of major molecular response (CI-MMR) was calculated in the SLEC according to ABCG2 haplotypes G-G. CI-MMR of patients with at least one copy of haplotype G-G was 69%. CI-MMR for other patients was 34%. C) CI-MMR at 18-months in all SVC patients with haplotype G-G was 63% and 47% for other patients (P = 0.006). D) CI-MMR in SVC patients treated with 400 mg/d was 57% and 36% for G-G haplotype carriers and other haplotype carriers respectively (P = 0.005). E) CI-MMR in SVC patients treated with 600 mg/d was 74% and 58% for G-G haplotype carriers and other patients respectively (P = 0.185). F) CI-MMR was not significantly different between in SVC patients with haplotype G-G receiving 400 mg/d and those with other haplotypes receiving 600 mg/d (57% vs 58% respectively, P = 0.950).

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