ASPO Abstracts
Ethnic disparities in methotrexate neurotoxicity among children and adolescents with acute lymphoblastic leukemia
Category: Cancer Health Disparities
Conference Year: 2021
Abstract Body:
Purpose of study: To identify factors related to the increased risk of neurotoxicity in children with
acute lymphoblastic leukemia (ALL) after treatment with the antifolate agent methotrexate
(MTX), a critical component of curative protocols.Methods: We analyzed the incidence of and
factors associated with acute MTX neurotoxicity (neurologic episode within 14d of dose that
resulted in treatment modification) in a multi-site study of 280 (48% Latino) newly diagnosed
(between 2012-2017) patients treated on recent pediatric ALL protocols. We examined the
effects of genetic ancestry and single nucleotide variants in a subset of 190 patients with
genotype data. Results: MTX neurotoxicity occurred in 22% of Latino compared to 7% of non-
Latino patients; a nearly 2.5-fold increased risk after accounting for other clinical and
demographic factors. Patients with neurotoxicity received fewer total MTX doses, and their risk
for relapse was 2-fold higher than patients who did not experience neurotoxicity. We also found
that 42% of our Latino patients who experienced a first neurotoxic event went on to have
additional events, compared to only 21% of non-Latino patients. The proportion of genetic
variation that co-segregates with Native American ancestry was overrepresented in individuals
with MTX-related neurotoxicity (mean=35%) vs without neurotoxicity (mean=23%, p=0.025). In
multivariable models accounting for sex, age at diagnosis, and treatment risk group, every 10%
increase in the proportion of Native American genetic ancestry was associated with a 16%
increase in neurotoxicity incidence (HR=1.16; 95% CI: 1.02-1.32). Our data also suggest that
Latinos are at higher risk for first (OR=3.51, p=0.02) and subsequent (OR=6.10, p=0.04)
neurotoxic events associated with a missense variant in TCF12, which is more common in
admixed Latino (23%) compared to European (3%) or African (<1%) populations. Conclusions:
MTX neurotoxicity is more common among Latino children and adolescents with ALL,
compromises treatment efficacy, and may contribute to disparities in ALL relapse and survival.
Our findings to date highlight that differences in inherited genetic variation, which segregate
with ancestry, likely contribute to disparities in the incidence of treatment-related neurotoxicity.
Keywords: pediatric, leukemia, treatment toxicity