Polymorphisms in MDR1 (ABCB1) gene are associated with worse response to imatinib in patients with chronic myeloid leukemia from Argentina.

WEICH N; FERRI C; BENGIÓ R; LARRIPA IB; FUNDIA AF

Philadelphia

Congreso; 16th Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy; 2014

European School of Haematology

The human multidrug resistance gene (MDR1, ABCB1) codes the efflux pump P-glycoprotein (P-gp) that affects the pharmacokinetics of many drugs, including Imatinib (IM). MDR1 gene is polymorphic and functional variation in this gene could explain at least in part variable responses to IM. Polymorphisms in MDR1 gene exhibit interethnic differences, but data are lacking in Argentina. We evaluated the relationship between MDR1 polymorphisms and the response to IM treatment in patients with chronic myeloid leukemia (CML) over a long period of follow up (mean 67.6 months of IM therapy). Genomic DNA from peripheral blood of 60 treated patients (median age 50.0 ± 2.0 years, 32 female and 28 male) without molecular or cytogenetic responses (during two consecutives studies) were evaluated. Simultaneous genotyping of MDR1 polymorphisms (c.1236C>T; c.3435C>T and c.2677G>T/A) was performed by multiplex allele-specific PCR. BCR/ABL1 transcript level was analyzed using RT-PCR and ABL1 mutations were identified by RT-PCR and sequencing. The association between each SNP and the time to treatment failure was determined considering the change of treatment as an event because of either unsatisfactory response or intolerance to IM. The log-rank test was used and Kaplan-Meier curves were generated. The incidences of null, minimal and minor molecular responses (41.4%, 22.4% and 36.2% respectively) indicates that these cases had no response to IM. Different type of ABL1 mutations were detected in 22 patients. The overall frequencies of MDR1 1236 CC, CT, and TT genotypes were 21.6%, 46.7%, and 31.7%, respectively. The overall frequency of MDR1 3435 CC, CT, and TT genotypes were 32.8%, 43.1%, and 24.1%, respectively. The frequencies of MDR1 2677 AA, AG, AT, GG, TG and TT genotypes were 6.9%, 5.2%, 1.7%, 32.7%, 34.5% and 19%, respectively. Individual analysis of each SNP revealed that patients with homozygous 1236TT or 3435TT genotypes had a shorter time to treatment failure respect to CC/CT genotypes (p=0.017; p=0.0046 respectively). No association was observed for 2677 genotypes. The combined analysis demonstrated that the mean time of treatment failure was 14.47 months for individuals carrying both homozygous variant genotypes (1236TT + 3435TT) comparing with others genotypes (35.93 months) (p=0.0043). These findings suggest that 1236TT and 3435TT genotypes are associated with a worse response to IM treatment and can be considered as useful biomarkers for therapy optimization. To our knowledge this is the first study that examined MDR1 polymorphisms in CML Argentinean patients. Further studies should validate the clinical importance of these results.