Effect of race on vincristine‐associated neurotoxicity in pediatric acute lymphoblastic leukemia patients

Abstract

Background This report examines the association between race and vincristine‐associated neurotoxicity in pediatric patients with precursor B cell acute lymphoblastic leukemia (preB ALL). Given that in vitro vincristine is metabolized more efficiently by cytochrome P450 (CYP) 3A5 than by CYP3A4 and that 70% African‐Americans (vs. 20% of Caucasians) express CYP3A5, one may hypothesize that African‐Americans metabolize vincristine more efficiently resulting in lower vincristine exposure and associated‐toxicity. Procedure A retrospective analysis of vincristine‐related side effects in pediatric patients treated for preB ALL was performed. Data were compared between Caucasians (n = 92) and African‐Americans (n = 21) to examine the relationship between race and vincristine‐associated neurotoxicity thus using race as a surrogate for CYP3A5 genotype. Race, age, gender, disease subtype, highest grade of vincristine‐associated neurotoxicity (per NIH Common Terminology Criteria for Adverse Events version 3.0), number of omitted and reduced vincristine doses, cumulative vincristine dose, and disease outcome were captured. Results 34.8% of Caucasians experienced symptoms consistent with vincristine‐related neurotoxicity compared to 4.8% of African‐Americans (P = 0.007). The average grade of neurotoxicity for Caucasians was 2.72 versus grade 1 neurotoxicity in the African‐American (P < 0.0001). Four percent of total doses administered to Caucasian patients were reduced due to vincristine‐related neurotoxicity compared to 0.1% given to African‐Americans (P < 0.0001). 1.2% of all protocol‐indicated doses for Caucasians were held due to severe vincristine‐associated toxicity compared to 0.1% of doses for African‐Americans (P < 0.01). Conclusions The data support the hypothesis pharmacogenetic polymorphisms in CYP3A5 expression contribute to variability in vincristine metabolism and neurotoxicity. Pediatr Blood Cancer 2008;50:769–771.