The hOCT1 and ABCB1 polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia
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Sara Galimberti1, Cristina Bucelli2, Elena Arrigoni3, Claudia Baratè1, Susanna Grassi1,4, Federica Ricci1, Francesca Guerrini1, Elena Ciabatti1, Carmen Fava5, Antonio D’Avolio6, Giulia Fontanelli1, Giovanna Rege Cambrin7, Alessandro Isidori8, Federica Loscocco8, Giovanni Caocci9, Marianna Greco9, Monica Bocchia10, Lara Aprile10, Antonella Gozzini11, Barbara Scappini11, Daniele Cattaneo2, Anna Rita Scortechini12, Giorgio La Nasa9, Alberto Bosi11, Pietro Leoni12, Romano Danesi3, Giuseppe Saglio5, Giuseppe Visani8, Agostino Cortelezzi2, Mario Petrini1, Alessandra Iurlo2 and Antonello Di Paolo3
1Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
2Oncohematology Division, IRCCS Ca’ Granda, Maggiore Policlinico Hospital Foundation, University of Milan, Milano, Italy
3Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Pisa, Pisa, Italy
4GeNOMEC, University of Siena, Siena, Italy
5Hematology Division, Ospedale Mauriziano, Torino, Italy
6Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Torino, Torino, Italy
7Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Torino, Italy
8Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy
9Department of Medical Sciences, University of Cagliari, Cagliari, Italy
10Division of Hematology, Ospedale Le Scotte, University of Siena, Siena, Italy
11Division of Hematology, AOU Careggi, University of Florence, Firenze, Italy
12Division of Hematology, Marche Polytechnic University, Ancona, Italy
Sara Galimberti, email: [email protected]
Keywords: nilotinib, ABC transporters, ABCB1, hOCT1, early molecular response
Received: June 24, 2017 Accepted: August 29, 2017 Published: September 30, 2017
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, in 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.
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