The hOCT1 and ABCB1 Polymorphisms Don't Condition the Efficacy and Toxicity of Nilotinib As First-Line Treatment: An Italian Multicentric Experience
Authors: Galimberti Sara , Bucelli Cristina , Arrigoni Elena , Baratè Claudia , Grassi Susanna , Ricci Federica , Guerrini Francesca , Ciabatti Elena , Fava Carmen , D'Avolio Antonio , Fontanelli Giulia , Rege Cambrin Giovanna , Isidori Alessandro , Loscocco Federica , Caocci Giovanni , Greco Marianna , Bocchia Monica , Aprile Lara , Gozzini Antonella , Scappini Barbara , Cattaneo Daniele , La Nasa Giorgio , Bosi Alberto , Petrini Mario , Leoni Pietro , Danesi Romano , Saglio Giuseppe , Visani Giuseppe , Cortellezzi Agostino , Scortechini Anna Rita , Iurlo Alessandra , Di Paolo Antonello 
Published: October 2019

Abstract
Introduction. Drug transporters, such as ABCB1, hOCT1, and ABCG2, control both intracellular and systemic plasma concentrations of BCR-ABL1 inhibitors. Our group previously reported that the hOCT1 c.480C>G polymorphism significantly correlated with higher rates of adverse events and shorter event-free survival (EFS) of patients receiving imatinib. Even if nilotinib has less affinity than imatinib for the transmembrane transporters, no definitive data about the possible role of their polymorphisms are available from the "real life".
Methods. Through an approach similar to the one previously used for imatinib, we investigated any possible influence of ABCB1 and hOCT1 polymorphisms on the nilotinib efficacy and toxicity in a series of 78 CML patients receiving nilotinib as first-line therapy in 8 Italian Centers from June 2012 to June 2016. Lack of CCyR at 12 months, stop of treatment for any cause, loss of MR3 or CCyR, appearance of mutations were computed as events in the EFS assessment. The following polymorphisms were tested by real-time PCR: hOCT1: rs683369[c.480C>G]; ABCB1: rs1128503 [c.1236C>T], rs2032582[c.2677G>T/A], and rs1045642[c.3435C>T].
Results. Forty-six patients were male and 32 female; the median age was 47 years (range, 18-79); Sokal score was low in 44%, intermediate in 37%, and high in 19% of cases; EUTOS was high in 30%. Efficacy: 97% of patients were in CHR and 82% in early molecular response (EMR) at 3 months; 85% achieved the CCyR at 6 months, and 88% the MR3 with a median time of 6.1 months; 78% achieved a deep molecular response (DMR), with 14% of MR5, with a median time of 26 months.With a median follow-up of 36 months, no patient lost CCyR and 9% lost MR3. All patients are still alive; 23% of patients stopped nilotinib (one third of them because of failure), and half of them reduced to<600 mg/day at least once; 3-year EFS was 90%.Patients were grouped according to the absence or the presence of at least one polymorphic allele (heterozygous or polymorphic homozygous): concerning c.3435C>T SNP, 56% of patients were heterozigous and 22% omozigous polymorphic; for the c1236 C>T SNP, 54% of patients were heterozigous and 12% omozigous polymorphic; finally, for the hOCT1 c.480 C>G, 41% of patients were heterozigous and 10% omozigous polymorphic.We found that ABCB1 and hOCT1 polymorphisms did not condition the achievement of CHR, CCyR, or MR3. Nevertheless, polymorphism of ABCB1 (c.3435C>T) was associated with a higher probability of achieving DMR (90% vs 65%; p=0.04).A longer 3-year EFS was conditioned by the achievement of EMR (90% vs 75%; p=0.012) and of MR3 (90% vs 65%: p=0.04). We found that polymorphic or wild-type status of transporters did not impact on EFS.Toxicities were observed in 41% of cases, with 40% of grade 3 or 4; ABCB1 and hOCT1 polymorphisms did not condition toxicities or nilotinib discontinuation.
Conclusions. Our previous studies showed that polymorphic hOCT1 negatively conditioned CCyR and EFS during imatinib treatment, and that the combination of ABCB1 and hOCT1 polymorphisms were related to higher levels of toxicity.On the contrary, the present study demonstrated that the same polymorphisms did not condition toxicity when patients received nilotinib as first-line treatment. About efficacy, even if in a multicentric "real life" setting, it resulted superimposable to that reported in literature. We found that hOCT1 polymorphism did not have any impact on the quality of response; on the contrary, the ABCB1 c.3435C>T polymorphism (that induces a lower efflux from the leukemic cell and lower intestinal and renal excretion) was associated to a high rate of deep molecular response.On the basis of these results, we demonstrated that hOCT1 and ABCB1 polymorphisms, differently from the imatinib setting, are not relevant in patients receiving nilotinib, and that patients polymorphic for ABCB1 can even receive an advantage on DMR.

Disclosures
Saglio: Ariad: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy.