Introduction. Drug transporters, such as ABCB1, hOCT1, and ABCG2, control both intracellular and systemic plasma concentrations of BCR-ABL inhibitors (TKIs). Our group previously reported that the hOCT1 c.480C>G polymorphism conditions higher rates of adverse events and shorter event-free survival (EFS) for imatinib. Even if nilotinib has less substrate affinity than imatinib for these transmembrane transporters, they could have a role on efficacy and/or toxicity of nilotinib. 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 95 CML patients receiving nilotinib as first-line therapy in 7 Italian Centers. Lack of CCyR at 12 months, stop of treatment for any cause, loss of MR3 or CCyR, appearance of mutations were all included as events in the EFS computation. The following polymorphisms were assessed: hOCT1: rs683369[c.480C>G]; ABCB1: rs1128503 [c.1236C>T], rs2032582[c.2677G>T/A], and rs1045642[c.3435C>T]. Results. Fifty-five patients were male and 40 female; the median age was 47 years (range, 18-79); Sokal score was low in 30%, intermediate in 40%, and high in 30% of cases; EUTOS was high in 30%. Efficacy: 96% of patients were in CHR at 3 months; 74% achieved the EMR, 94% the CCyR at 6 months, 95% the CCyR, and 75% the MR3 at 12 months. With a median follow-up of 42 months, 76% achieved a deep molecular response, and only 2.5% failed the MR3. All patients are still alive; with a median time of 49 months, 24% of patients stopped nilotinib, and 21% received <600 mg/day. The 3-year EFS was 77%. Patients were grouped according to the absence or the presence (heterozygous or polymorphic homozygous) of at least one polymorphic allele. We found that ABCB1 and hOCT1 polymorphisms did not condition the achievement of CHR, CCyR, MR3, or DMR. Time to the MR3 was 6 months longer for patients with polymorphic hOCT1 (13 months vs 7; p=0.01); nevertheless, EFS did not differ between the same groups. Toxicities were observed in 43% of cases, with 40% of them of grade 3 WHO; ABCB1 and hOCT1 polymorphisms did not condition toxicities or nilotinib discontinuation. Interestingly, time to the hematological toxicity was longer for heterozygous or polymorphic homozygous than for wild-type cases (19.0 vs 4.4 months; p=0.05). Conclusions. Our previous studies showed that polymorphic hOCT1 [c.480C>G] did negatively impact on CCyR and EFS during imatinib treatment, and that the combination of ABCB1 and hOCT1 polymorphisms conditioned higher levels of toxicity. On the contrary, the present study demonstrated that the same polymorphisms did not condition efficacy or toxicity when patients received nilotinib as first-line treatment, hence suggesting that the high efficacy of this second-generation TKI confirmed also in our series is independent from the transmembrane transporters.

The HOCT1/ABCB1 polymorphisms don’t condition the cytogenetic and molecular response or tolerability to first-line nilotinib in chronic myeloid leukemia patients / S. Galimberti, C. Bucelli, E. Arrigoni, C. Baratè, F. Ricci, F. Guerrini, S. Grassi, E. Ciabatti, C. Fava, A. D’Avolio, G. Fontanelli, G. Rege-Cambrin, A. Isidori, F. Loscocco, G. Caocci, M. Greco, M. Bocchia, L. Aprile, A. Gozzini, B. Scappini, D. Cattaneo, G. La Nasa, A. Bosi, M. Petrini, P. Leoni, R. Danesi, G. Saglio, G. Visani, A. Cortelezzi, A. Scortechini, A. Iurlo, A. Di Paolo. - In: HAEMATOLOGICA. - ISSN 0390-6078. - 101:suppl. 3(2016), pp. S101-S102. (Intervento presentato al 14. convegno Congress of the Italian Society of Experimental Hematology tenutosi a Rimini nel 2016).

The HOCT1/ABCB1 polymorphisms don’t condition the cytogenetic and molecular response or tolerability to first-line nilotinib in chronic myeloid leukemia patients

D. Cattaneo;R. Danesi;A. Cortelezzi;
2016

Abstract

Introduction. Drug transporters, such as ABCB1, hOCT1, and ABCG2, control both intracellular and systemic plasma concentrations of BCR-ABL inhibitors (TKIs). Our group previously reported that the hOCT1 c.480C>G polymorphism conditions higher rates of adverse events and shorter event-free survival (EFS) for imatinib. Even if nilotinib has less substrate affinity than imatinib for these transmembrane transporters, they could have a role on efficacy and/or toxicity of nilotinib. 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 95 CML patients receiving nilotinib as first-line therapy in 7 Italian Centers. Lack of CCyR at 12 months, stop of treatment for any cause, loss of MR3 or CCyR, appearance of mutations were all included as events in the EFS computation. The following polymorphisms were assessed: hOCT1: rs683369[c.480C>G]; ABCB1: rs1128503 [c.1236C>T], rs2032582[c.2677G>T/A], and rs1045642[c.3435C>T]. Results. Fifty-five patients were male and 40 female; the median age was 47 years (range, 18-79); Sokal score was low in 30%, intermediate in 40%, and high in 30% of cases; EUTOS was high in 30%. Efficacy: 96% of patients were in CHR at 3 months; 74% achieved the EMR, 94% the CCyR at 6 months, 95% the CCyR, and 75% the MR3 at 12 months. With a median follow-up of 42 months, 76% achieved a deep molecular response, and only 2.5% failed the MR3. All patients are still alive; with a median time of 49 months, 24% of patients stopped nilotinib, and 21% received <600 mg/day. The 3-year EFS was 77%. Patients were grouped according to the absence or the presence (heterozygous or polymorphic homozygous) of at least one polymorphic allele. We found that ABCB1 and hOCT1 polymorphisms did not condition the achievement of CHR, CCyR, MR3, or DMR. Time to the MR3 was 6 months longer for patients with polymorphic hOCT1 (13 months vs 7; p=0.01); nevertheless, EFS did not differ between the same groups. Toxicities were observed in 43% of cases, with 40% of them of grade 3 WHO; ABCB1 and hOCT1 polymorphisms did not condition toxicities or nilotinib discontinuation. Interestingly, time to the hematological toxicity was longer for heterozygous or polymorphic homozygous than for wild-type cases (19.0 vs 4.4 months; p=0.05). Conclusions. Our previous studies showed that polymorphic hOCT1 [c.480C>G] did negatively impact on CCyR and EFS during imatinib treatment, and that the combination of ABCB1 and hOCT1 polymorphisms conditioned higher levels of toxicity. On the contrary, the present study demonstrated that the same polymorphisms did not condition efficacy or toxicity when patients received nilotinib as first-line treatment, hence suggesting that the high efficacy of this second-generation TKI confirmed also in our series is independent from the transmembrane transporters.
Settore MED/15 - Malattie del Sangue
2016
https://haematologica.org/article/download/7926/51942
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/914454
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