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

// Marc Delord 1 , Philippe Rousselot 2 , Jean Michel Cayuela 3,4 , Francois Sigaux 1,3 , Joelle Guilhot 5 , Claude Preudhomme 6 , Francois Guilhot 5 , Pascale Loiseau 7 , Emmanuel Raffoux 8 , Daniela Geromin 9 , Emmanuelle Genin 10 , Fabien Calvo 11,12 and Heriberto Bruzzoni-Giovanelli 11,12 1 Plateforme de Bioinformatique et Biostatistique, Institut Universitaire d’Hematologie, Universite Paris Diderot, Sorbonne Paris Cite 2 Service d’Hematologie et d’Oncologie, Hopital Mignot, Universite Versailles Saint-Quentin-en-Yvelines 3 Laboratoire Central d’Hematologie, Hopital Saint Louis 4 EA3518, Universite Paris Diderot, Sorbonne Paris Cite 5 Inserm CIC 0802, CHU de Poitiers, Poitiers 6 Laboratoire d’Hematologie, Inserm, U837, CHRU et Universite de Lille Nord, Institut de Recherche sur le Cancer de Lille 7 Service d’Immunologie et Histocompatibilite et INSERM U940, Hopital Saint Louis 8 Service des Maladies du Sang, Hopital Saint Louis 9 Plateforme de Ressources Biologiques, Hopital Saint Louis, Paris 10 Inserm U1078, CHU Brest, Universite Bretagne Occidentale, Brest 11 Pharmacologie, Universite Paris Diderot, Sorbonne Paris Cite, Paris 12 Centre d’Investigations Cliniques 9504 INSERM-AP-HP, Hopital Saint-Louis, Paris, France. Correspondence: Heriberto Bruzzoni-Giovanelli, email: // Keywords : CML, Imatinib, SNPs, ABCG2, Pharmacogenetic, molecular response, BCR-ABL Received : June 6, 2013 Accepted : July 16, 2013 Published : July 18, 2013 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.