Genetic polymorphisms in ABCB1 and CEP72 genes as pharmacogenetic markers in patients receiving vincristine-based chemotherapy: a preliminary Indian context exploratory study.

INTRODUCTION: Vincristine is limited by its adverse effect of peripheral neuropathy with only a few inconclusive reports of its genetic occurrence. Therefore, the present research work was intended to identify the distribution of rs1045642 polymorphism in ABCB1 gene and rs924607 polymorphism in CEP72 gene, and their association with clinically documented neurological adverse drug reactions to vincristine.

METHODS: Seventy-five children below 18 years diagnosed with acute lymphoblastic leukemia receiving vincristine were followed for 6 months and analyzed for correlation with vincristine-associated neuropathy.

RESULTS: Twenty of 75 patients were homozygous for the risk allele (TT at rs924607) of CEP72 genotype and 25 of 75 patients were homozygous for the risk allele (TT at rs1045642) of ABCB1 genotype. Among patients with the high-risk ABCB1 genotype (TT at rs1045642), 13 of 25 (52%) developed at least one episode of grade 1-3 neuropathy, and had a statistically significant 4.3 times risk of developing neurotoxicity in comparison to patients with the ABCB1 CC or CT genotypes [10 of 50 (20%) patients, odds ratio: 4.3, 95% confidence interval: 1.5-12.3; P = 0.0060]. The patients receiving average dose of vincristine of greater than or equal to 2 mg/m 2 (58.3%) when compared to those receiving an average dose of less than 2 mg/m 2 (25.4%) had 4.1 times risk of developing neurotoxicity (odds ratio: 4.1, 95% confidence interval: 1.1-14.8; P = 0.0304).

CONCLUSION: This study emphasizes the significant association of ABCB1 genotype (TT at rs1045642) with vincristine-associated neuropathy and highlights the relevance of higher average doses of vincristine in causing neurotoxicity.