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.
- Acute lymphoblastic leukemia
ASJC Scopus subject areas
- Cancer Research
- Pediatrics, Perinatology, and Child Health