An Analysis of Diagnostic Metabolomic Profiles Associated with Hepatotoxicity During Childhood ALL Induction Therapy Open Access

• Children with obesity frequently experience hepatotoxicity during ALL induction therapy.

• Pretreatment lipid metabolites in the GPC pathway may identify patients at increased risk of hepatotoxicity.

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 (p<0.05) in the discovery cohort, including two that replicated (p<0.05): 1,2-dipalmitoyl-GPC (aOR-combined = 1.88 [95% CI: 1.26-2.79], p=0.002) and 1-(1-enyl-palmitoyl)-2-palmitoleoyl-GPC (aOR-combined = 1.56 [95% CI: 1.17-2.09], p=0.003). In the discovery cohort, 34 metabolites were associated with c.bili >3 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.