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


METHODS
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.
Renbarger
Jamie L
JL
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA. jarenbar@iupui.edu
McCammack
Kevin C
KC
Rouse
Caroline E
CE
Hall
Stephen D
SD
D001741:Black or African American; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D020258:Neurotoxicity Syndromes / Q000208:ethnology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D044469:Racial Groups / Q000208:ethnology*; D014750:Vincristine / Q000009:adverse effects*; D044465:White People
D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine