High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients
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Marc Delord1, Philippe Rousselot2, Jean Michel Cayuela3,4, François Sigaux1,3, Joëlle Guilhot5, Claude Preudhomme6, François Guilhot5, Pascale Loiseau7, Emmanuel Raffoux8, Daniela Geromin9, Emmanuelle Génin10, Fabien Calvo11,12 and Heriberto Bruzzoni-Giovanelli11,12
1 Plateforme de Bioinformatique et Biostatistique, Institut Universitaire d’Hématologie, Université Paris Diderot, Sorbonne Paris Cité
2 Service d’Hématologie et d’Oncologie, Hôpital Mignot, Université Versailles Saint-Quentin-en-Yvelines
3 Laboratoire Central d’Hématologie, Hôpital Saint Louis
4 EA3518, Université Paris Diderot, Sorbonne Paris Cité
5 Inserm CIC 0802, CHU de Poitiers, Poitiers
6 Laboratoire d’Hématologie, Inserm, U837, CHRU et Université de Lille Nord, Institut de Recherche sur le Cancer de Lille
7 Service d’Immunologie et Histocompatibilité et INSERM U940, Hôpital Saint Louis
8 Service des Maladies du Sang, Hôpital Saint Louis
9 Plateforme de Ressources Biologiques, Hôpital Saint Louis, Paris
10 Inserm U1078, CHU Brest, Université Bretagne Occidentale, Brest
11 Pharmacologie, Université Paris Diderot, Sorbonne Paris Cité, Paris
12 Centre d’Investigations Cliniques 9504 INSERM-AP-HP, Hôpital Saint-Louis, Paris, France.
Keywords: CML, Imatinib, SNPs, ABCG2, Pharmacogenetic, molecular response, BCR-ABL
Received: June 6, 2013 Accepted: July 16, 2013 Published: July 18, 2013
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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