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

Authors: Delord, M  Rousselot, P  Cayuela, JM  Sigaux, F  Guilhot, J  Preudhomme, C  Guilhot, F  Loiseau, P  Raffoux, E  Geromin, D  Genin, E  Calvo, F  Bruzzoni-Giovanelli, H 
Citation: Delord M, etal., Oncotarget. 2013 Oct;4(10):1582-91.
Pubmed: (View Article at PubMed) PMID:24123600
DOI: Full-text: DOI:10.18632/oncotarget.1050

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.


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CRRD Object Information
CRRD ID: 11081181
Created: 2016-05-31
Species: All species
Last Modified: 2016-05-31
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.