Biomarkers of vincristine neuropathy in Kenyan children.

Abstract

2601 Background: In a U.S. population, cytochrome P450 (CYP) 3A5 high-expressers metabolize vincristine (VCR) more efficiently than low-expressers and vincristine-induced peripheral neuropathy (VIPN) is less common in African-Americans than Caucasians. We test the hypothesis that more children in Kenya are CYP3A5 high-expressers compared to U.S. children and as such experience less VIPN. Methods: This study was conducted in Kenyan children with cancer (n=78) being treated with VCR at Moi University AMPATH Oncology Institute in partnership with Indiana University. Saliva Oragene kits for DNA extraction and genotyping were obtained. Whole blood was collected via finger stick on Whatman protein saver dried blood spot cards for analysis of VCR concentrations. VIPN was assessed prospectively using two neuropathy assessment tools (Modified Total Neuropathy Score (TNS) and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0). Results: Compared to 14% in the U.S. sample, 94% of Kenyan subjects are CYP3A5 high-expressers (p<2.2x10-16). Kenyan children have significantly lower VCR plasma concentrations (11.15ng/ml/mg ± 1.051) compared to US (primarily Caucasian) children (13.26ng/ml/mg ± 2.897) one hour following the administration of VCR (p=0.011). By TNS VIPN assessment, 71% of Kenyan children developed VIPN compared to 100% of U.S. children (p=8.8x10-7). CYP3A5 high-expresser genotype is associated with lower TNS VIPN severity scores than low-expresser genotypes (p=0.006). TNS VIPN assessments show that height is positively correlated with severity of VIPN (p=0.025). CTCAE VIPN assessments also showed a positive correlation with height (p=0.036), but did not show any association with CYP3A5 genotype. Conclusions: Kenyan children are more likely to be CYP3A5 high-expressers than U.S. children and as such may metabolize VCR more efficiently. Supporting these data is that Kenyan children experience significantly less VIPN than U.S. children. CYP3A5 genotype and height are independent predictors of VIPN in Kenyan children with cancer. The CTCAE may lack sufficient sensitivity to detect VIPN for use in future studies aimed at optimizing VCR dosing strategies.