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

Sara Galimberti,Anna Rita Scortechini,Monica Bocchia,Romano Danesi,Alessandro Isidori,Alberto Bosi,Antonella Gozzini,Francesca Guerrini,Giuseppe Visani,Federica Ricci,Giovanni Caocci,Giulia Fontanelli,Federica Loscocco,Cristina Bucelli,Daniele Cattaneo,Alessandra Iurlo,Susanna Grassi,Barbara Scappini,Marianna Greco,Lara Aprile,Carmen Fava,Giuseppe Saglio,Pietro Leoni,Antonio D’Avolio,Giorgio La Nasa,Elena Ciabatti,Mario Petrini,Antonello Di Paolo,Giovanna Rege Cambrin,Agostino Cortelezzi,Claudia Baratè,E Arrigoni

doi:10.18632/oncotarget.21406

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, 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.

Highlights

After the introduction in the clinical practice of the tyrosine kinase inhibitors (TKIs), the outcome of patients affected by chronic myeloid leukemia (CML) has really improved, with 96% of them alive and free of progression at 3 years [1].Nilotinib was initially approved as a secondgeneration TKI for the treatment of patients resistant to imatinib, and since 2007 as a first-line option [2]
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
We investigated the possible correlation between single nucleotide polymorphisms of human organic cation transport member 1 (hOCT1) and ABCB1 and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice

Summary

Introduction

Nilotinib was initially approved as a secondgeneration TKI for the treatment of patients resistant to imatinib, and since 2007 as a first-line option [2]. Progressions occurred in 5 out of the 563 patients in the nilotinib arms (0.88%) in comparison to 12 out of 283 cases receiving imatinib (4.2%) [4]. The choice of nilotinib as first-line treatment significantly increases the probability of reaching the desired surrogate end-points at the correct time-points, and the probability of achieving a deep molecular response (DMR, by 5 years, 54% with nilotinib vs 31% for imatinib), which represents the basis for a further possible drug discontinuation. About 40% of patients discontinue nilotinib due to suboptimal response or toxicity [4]

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Conclusion