Hispanic ethnicity and the rs4880 variant in SOD2 are associated with elevated liver enzymes and bilirubin levels in children receiving asparaginase-containing chemotherapy for acute lymphoblastic leukemia.

Abstract

Asparaginase is an integral component of acute lymphoblastic leukemia (ALL)3 treatment. Hepatotoxicity related to asparaginase is one of the most common treatment-related toxicities in ALL therapy. Hispanic children are at higher risk of developing ALL, and toxicities from ALL therapy. The rs4880 variant in the superoxide dismutase 2 (SOD2)4 gene, a critical mitochondrial enzyme that protects cells against oxidative stress, was found to be associated with increased incidence of asparaginase-related hepatotoxicity in adult cohort of largely White non-Hispanics patients with ALL. The risk genotype (rs4880-CC) is more frequent among adult Hispanic patients with ALL. To assess the prevalence of hepatotoxicity and risk genotype among pediatric patients with ALL, particularly of Hispanic ethnicity, we conducted a prospective study of 143 pediatric patients with ALL (62.2% Hispanic). Bilirubin and hepatic transaminase levels were collected at different times during multiagent therapy including asparaginase treatment. Germline DNA blood samples were genotyped for the SOD2 rs4880. We found that the frequency of hepatotoxicity and the rs4880-CC risk genotype are higher in Hispanic patients than non-Hispanic. Patients with the CC genotype exhibit higher bilirubin and hepatic transaminase levels compared with patients with the TT and CT genotypes. In a multivariate Cox analysis, Hispanic ethnicity was identified as a strong predictor of hepatotoxicity (hazard ratio [HR] = 1.9, 95% confidence interval [95% CI] 1.0–3.5, p = 0.05). Altogether, these findings demonstrate that hepatotoxicity is highly prevalent among Hispanic pediatric patients with ALL, and those with rs4880-CC genotype.