Biomarkers in the prediction of vincristine metabolism and neuropathy in pediatric acute lymphoblastic leukemia patients.

Abstract

9523 Background: This study evaluates the relationship between vinca alkaloid pharmacologic pathway genetic polymorphisms, demographic data, pharmacokinetics, and vincristine-induced peripheral neuropathy (VIPN) in pediatric acute lymphoblastic leukemia (ALL) patients. Pediatric ALL CYP3A5 expressers experience less VIPN and metabolize vincristine (VCR) into its major metabolite M1 at a greater rate than do the non- expressers but significant inter-individual variability remains. We hypothesize that multiple variables contribute to the metabolism of VCR into M1 and the development of VIPN in pediatric ALL patients. Methods: Patients 1-18 years old, with confirmed pre-B ALL diagnosis, who received VCR as part of their treatment regimen were eligible for this trial. Whole blood samples for DNA extraction were collected from enrolled patients (n=130). Subjects were genotyped for polymorphisms in CYP3A4, CYP3A5, MDR1, MAPT, MRP1, and MRP2. VIPN was assessed retrospectively via chart review and graded per the NCI Common Terminology Criteria for Adverse Events, version 3.0. VCR and M1 were quantified in plasma samples collected one hour after administration of VCR using LC-MS/MS. Variables associated with extent of VIPN and plasma concentration were determined using stepwise linear regression (lm) and linear mixed effects models (lme) in R. Results: Of the genotypes examined, the combination of CYP3A5 and MAPT C1428T genotypes best predicted cumulative VIPN over the first year of ALL therapy (p=0.031). MAPT C1428T homozygous variant CYP3A5 non-expressers had the highest cumulative VIPN scores. This combination with age was the most predictive of the proportion of treatment months patients experienced VIPN (p=0.004). M1 plasma concentration at 1 hour was predicted by age (p=0.002) and CYP3A5 genotype (p<0.001) with young CYP3A5 expressers producing the most M1. Conclusions: Age, CYP3A5 and MAPT genotype are important determinants of VIPN. CYP3A5 and age are determinants of M1 formation, indicating that variability in VCR metabolism may impact extent of VIPN. Further evaluation of other potential biomarkers and improvement in clinical assessment of VIPN are needed. No significant financial relationships to disclose.