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

TY - JOUR

T1 - High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients

AU - Delord, Marc

AU - Rousselot, Philippe

AU - Cayuela, Jean Michel

AU - Sigaux, François

AU - Guilhot, Joëlle

AU - Preudhomme, Claude

AU - Guilhot, François

AU - Loiseau, Pascale

AU - Raffoux, Emmanuel

AU - Geromin, Daniela

AU - Génin, Emmanuelle

AU - Calvo, Fabien

AU - Bruzzoni-Giovanelli, Heriberto

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - CML

KW - Imatinib

KW - SNPs

KW - ABCG2

KW - Pharmacogenetic

KW - molecular response

KW - BCR-ABL

U2 - 10.18632/oncotarget.1050

DO - 10.18632/oncotarget.1050

M3 - Article

C2 - 24123600

SN - 1949-2553

VL - 4

SP - 1582

EP - 1591

JO - Oncotarget

JF - Oncotarget

IS - 10

ER -