Hepatotoxicity is a well-documented complication of induction chemotherapy for acute lymphoblastic leukemia (ALL), but our understanding of the biological mechanisms is limited. We identified 314 patients with ALL (age 1-19 years) treated at Texas Children's Hospital (2007-2018) with diagnostic bone marrow plasma available for metabolomic profiling: 234 for discovery and 80 for replication. Hepatotoxicity during induction therapy was defined as: 1) transaminitis: grade ≥3 AST or ALT, or 2) conjugated hyperbilirubinemia: conjugated bilirubin (c.bili) >3 mg/dL. Untargeted profiling detected 519 metabolites in both cohorts. Adjusted odds ratios (aORs) for each metabolite were calculated with logistic regression, accounting for sex, age, body mass index, race/ethnicity, and treatment intensity. The population was 56% Latino, 57% male, 92% B-cell ALL, 25% overweight/obese, and 57% NCI standard risk disease at a median age of 5 years. Transaminitis was observed in 34% of the discovery and 24% of the replication cohort. Seven instances of c.bili >3 mg/dL were observed in the discovery cohort, with none in the replication cohort. Twelve metabolites were associated with transaminitis (p3 mg/dL, including the top association of 1,2-dipalmitoyl-GPC (aOR = 5.76 95% CI: 2.20-23.16, p=0.002). We observed and replicated associations between phosphatidylcholine metabolites at ALL diagnosis and hepatotoxicity during induction therapy, suggesting a potential role for lipid dysregulation in the development of hepatotoxicity.
Mason et al. (Tue,) studied this question.