title: 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 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.
authors.affiliation: Plateforme de Bioinformatique et Biostatistique, Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité.
authors.forename: Marc
authors.initials: M
authors.lastname: Delord
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Cayuela
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.forename: Joëlle
authors.initials: J
authors.lastname: Guilhot
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: François
authors.initials: F
authors.lastname: Guilhot
authors.forename: Pascale
authors.initials: P
authors.lastname: Loiseau
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.forename: Daniela
authors.initials: D
authors.lastname: Geromin
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Génin
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
authors.forename: Heriberto
authors.initials: H
authors.lastname: Bruzzoni-Giovanelli
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage*; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D010879:Piperazines / Q000008:administration & dosage*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate