Abstract 2040: Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in patients with chronic myeloid leukemia

Abstract

Abstract Introduction: Genetic polymorphisms in the genes coding for imatinib transporters & metabolizing enzymes might be responsible for marked inter-individual pharmacokinetic variability seen with imatinib & might result in altered therapeutic response. Methodology: Newly diagnosed patients with chronic phase CML started on imatinib therapy were enrolled & followed up for 24 months. The following single nucleotide polymorphisms (SNPs) were genotyped - C1236T, C3435T, G2677T & G2677A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method & validated by direct gene sequencing. Plasma trough levels of imatinib were measured using LC-MS/MS. Patients who attained complete cytogenetic response by 12 months after imatinib therapy were called responders while those who failed to do so were called non-responders. Molecular response was assessed by quantitative RTPCR using international scale. Results: A total of 173 chronic phase CML patients were included in this study, out of which 71 were responders. Mean age at diagnosis was 35.9±14.3 years. All the alleles, except those for MDR1-C1236T, followed Hardy-Weinberg equilibrium. Marked variability in trough levels of imatinib was seen in patients with different genotypes (table1). The frequency of GG genotype for CYP3A5-A6986G and TT genotype for MDR1-C1236T, C3435T & G2677T/A was higher in responders; while the frequency of AA genotype for CYP3A5-A6986G, CC genotype for MDR1-C1236T & C3435T and GG genotype for MDR1-G2677T/A was higher in non-responders (table1). Conclusions: Genetic polymorphisms in MDR1 & CYP3A5 genes have a significant role in determining imatinib levels & therapeutic response in patients with CML. Genotyping of CPY3A5 & MDR1 genes may be considered in patients with CML to individualize the therapy & optimize the outcomes. Table 1:Trough levels of Imatinib in patients with different genotypes and frequency of different genotypes in imatinib responders and non-respondersSNPGenotypeTrough levels (mean±SD) of Imatinib (ng/mL)P valueImatinib responseP valueResponders (n = 71)Non-responders (n = 102)CYP3A5-A6986GAA1415.1 ± 1036.30.0164 (19%)17 (81%)< 0.001AG1610 ± 1161.120 (28%)51 (72%)GG2229 ± 1524.647 (58%)34 (42%)MDR1-C1236TCC1559.8 ± 990.40.2014 (21%)15 (79%)0.005CT1819.6 ± 1450.242 (37%)71 (63%)TT2178.4 ± 1246.725 (61%)16 (39%)MDR1-C3435TCC1418 ± 865.90.0133 (16%)16 (84%)< 0.001CT1695 ± 1318.928 (32%)60 (68%)TT2249.6 ± 1470.140 (61%)26 (39%)MDR1-G2677T/AGG1570.8 ± 1181.20.2974 (22%)14 (78%)0.019GT1726.5 ± 1489.323 (31%)51 (69%)TT2133.7 ± 1338.437 (54%)32 (46%)TA1840.5 ± 754.26 (60%)4 (40%)GA1450.2 ± 743.51 (50%)1 (50%) Citation Format: Natarajan Harivenkatesh, Lalit Kumar, Sameer Bakhshi, Atul Sharma, Madhulika Kabra, Thirumurthy Velpandian, Ajay Gogia, Shivaram Shastri, Yogendra Kumar Gupta. Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in patients with chronic myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2040.