Lipidomic profiles associated with treatment related hepatotoxicity in children with acute lymphoblastic leukemia.
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INTRODUCTION: Treatment for childhood acute lymphoblastic leukemia (ALL) can result in hepatotoxicity. Despite being a common complication of ALL therapy, mechanisms and biomarkers of treatment-associated hepatotoxicity (TAH) are not well described. METHODS: We conducted lipidomic profiling to identify plasma lipids associated with TAH in children receiving ALL therapy utilizing a nested case-control framework. TAH was defined as (1) transaminitis: ALT/AST ≥ CTCAE grade 3, and/or (2) conjugated hyperbilirubinemia: > 3.0 mg/dL during induction therapy or > 2.0 mg/dL post induction. A total of 90 patients (45 matched pairs) treated at Texas Children's Hospital between 2012 and 2021 were selected for lipidomic profiling, with controls matched to cases based on the availability of samples collected at similar time points in therapy. Lipidomic profiling quantified 1056 lipids, with 751 retained after quality control. Associations with TAH were evaluated using multivariable conditional logistic regression controlling for age, diagnostic BMI z-score, race/ethnicity, and induction intensity. RESULTS: The cohort was 55% male, 50% Hispanic, with a mean diagnostic age of 5 years. We identified 110 lipids nominally associated with TAH post-sample collection (p < 0.05). Lipid classes phosphatidylcholines (PCs; Holm-p = 5 × 10-6) and sphingomyelins (SMs; Holm-p = 0.0009) were significantly enriched in cases. DISCUSSION: We identified plasma lipid profiles, characterized by elevated PCs and SMs with reduced triglycerides, associated with the incidence of TAH in children with ALL. Similar patterns have been linked to metabolic liver disease in adults and children. These findings suggest lipid dysregulation may contribute to TAH susceptibility and highlight candidate biomarkers for future validation in larger cohorts.