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

• Published in: Oncotarget Vol. 4; no. 10; pp. 1582 - 1591
• Main Authors: Delord, Marc, Rousselot, Philippe, Cayuela, Jean Michel, Sigaux, François, Guilhot, Joëlle, Preudhomme, Claude, Guilhot, François, Loiseau, Pascale, Raffoux, Emmanuel, Geromin, Daniela, Génin, Emmanuelle, Calvo, Fabien, Bruzzoni-Giovanelli, Heriberto
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 01-10-2013
• Subjects: Antineoplastic Agents - administration & dosage; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; Benzamides - administration & dosage; Cohort Studies; DNA, Neoplasm - blood; DNA, Neoplasm - genetics; Female; Genotype; Haplotypes; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - blood; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Male; Middle Aged; Neoplasm Proteins - genetics; Oligonucleotide Array Sequence Analysis; Pharmacogenetics; Piperazines - administration & dosage; Polymorphism, Single Nucleotide; Prospective Studies; Pyrimidines - administration & dosage; Research Paper; Retrospective Studies; Treatment Outcome
• ISSN: 1949-2553; 1949-2553
• 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.