Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia

Importance Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Hepatotoxic effects, including hyperbilirubinemia and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, are common during all phases of therapy and are linked to several chemotherapeutic agents, including asparaginase, mercaptopurine, and methotrexate. Objective To determine which genetic variants were associated with hyperbilirubinemia and elevated ALT and AST levels in children, adolescents, and young adults treated for ALL. Design, Setting, and Participants This retrospective analysis of a multiethnic genome-wide association study was conducted between January 1, 2019, and April 15, 2022, including patients treated as part of Children's Oncology Group (COG) trials with centers in the United States, Canada, and Australia, which accrued data from December 29, 2003, to January 21, 2011 (AALL0232), and from January 22, 2007, to July 24, 2014 (AALL0434). Germline genotypes were interrogated using genome-wide arrays and imputed using a National Institutes of Health TOPMed Imputation server. Mixed-effects logistic regressions were used to account for multiple episodes for an individual patient. Genotype x treatment phase interaction was tested to uncover phase-specific genetic risk factors. Exposures Total duration of multiagent protocol chemotherapy ranging from 2.5 to 3.5 years. Main Outcomes and Measures The primary outcomes were National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) hyperbilirubinemia of grade 3 or higher and elevated liver ALT and AST levels. Results A total of 3557 participants were included in the analysis (2179 [61.3%] male; median age, 11.1 [range, 1-30] years). Among 576 known variants associated with these liver function test results in the general population, UGT1A1 variant rs887829 and PNPLA3 variant rs738409 were associated with increased risk of hyperbilirubinemia (odds ratio [OR], 2.18 [95% CI, 1.89-2.53]; P=6.7 x 10(-27)) and ALT and AST levels (OR, 1.27 [95% CI, 1.15-1.40]; P=3.7 x 10(-7)), respectively, during treatment for ALL. Corresponding polygenic risk scores were associated with hepatotoxic effects across all therapy phases and were largely driven by UGT1A1 and PNPLA3 variants. Genome-wide association analysis revealed an age-specific variant near the CPT1A gene that was only associated with elevated ALT and AST levels among patients younger than 10 years (OR, 1.28 [95% CI, 1.18-1.39]; P=8.7 x 10(-10)). Conclusions and Relevance These results suggest a strong genetic basis for interpatient variability in hyperbilirubinemia and aminotransferase level elevations during leukemia chemotherapy.

Automated summary

This study aimed to determine the genetic variants associated with hyperbilirubinemia and elevated ALT and AST levels in children, adolescents, and young adults treated for ALL. The results showed that UGT1A1 variant rs887829 and PNPLA3 variant rs738409 were associated with an increased risk of hyperbilirubinemia and elevated ALT and AST levels during ALL treatment.