The hOCT1 and ABCB1 polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia

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// Sara Galimberti 1 , Cristina Bucelli 2 , Elena Arrigoni 3 , Claudia Baratè 1 , Susanna Grassi 1, 4 , Federica Ricci 1 , Francesca Guerrini 1 , Elena Ciabatti 1 , Carmen Fava 5 , Antonio D’Avolio 6 , Giulia Fontanelli 1 , Giovanna Rege Cambrin 7 , Alessandro Isidori 8 , Federica Loscocco 8 , Giovanni Caocci 9 , Marianna Greco 9 , Monica Bocchia 10 , Lara Aprile 10 , Antonella Gozzini 11 , Barbara Scappini 11 , Daniele Cattaneo 2 , Anna Rita Scortechini 12 , Giorgio La Nasa 9 , Alberto Bosi 11 , Pietro Leoni 12 , Romano Danesi 3 , Giuseppe Saglio 5 , Giuseppe Visani 8 , Agostino Cortelezzi 2 , Mario Petrini 1 , Alessandra Iurlo 2 and Antonello Di Paolo 3 1 Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy 2 Oncohematology Division, IRCCS Ca’ Granda, Maggiore Policlinico Hospital Foundation, University of Milan, Milano, Italy 3 Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Pisa, Pisa, Italy 4 GeNOMEC, University of Siena, Siena, Italy 5 Hematology Division, Ospedale Mauriziano, Torino, Italy 6 Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Torino, Torino, Italy 7 Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Torino, Italy 8 Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy 9 Department of Medical Sciences, University of Cagliari, Cagliari, Italy 10 Division of Hematology, Ospedale Le Scotte, University of Siena, Siena, Italy 11 Division of Hematology, AOU Careggi, University of Florence, Firenze, Italy 12 Division of Hematology, Marche Polytechnic University, Ancona, Italy Correspondence to: Sara Galimberti, email: sara.galimberti@med.unipi.it Keywords: nilotinib, ABC transporters, ABCB1, hOCT1, early molecular response Received: June 24, 2017 Accepted: August 29, 2017 Published: September 30, 2017 ABSTRACT First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of hOCT1 (rs683369 [c.480C>G]) and ABCB1 (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, hOCT1 and ABCB1 polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, i n contrast to data obtained in patients treated with imatinib, hOCT1 and ABCB1 polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.