Diagnostic BMI and Induction Therapy Weight Change Associated With Hepatotoxicity in Pediatric Patients With Acute Lymphoblastic Leukemia

BACKGROUND: Hepatotoxicity is a common treatment-related complication in pediatric acute lymphoblastic leukemia (ALL). Excess adiposity at diagnosis has been identified as a risk factor, but the impact of weight change during therapy has not been examined. METHODS: We included patients aged 2-20 years newly diagnosed with ALL between 2005 and 2021. Hepatotoxicity was defined as: (1) transaminitis (ALT/AST > 10× the upper limit of normal), or (2) conjugated hyperbilirubinemia (cbili; > 3.0 mg/dL during induction/> 2.0 mg/dL post-induction). Youden's J was used to identify optimal BMI z-score thresholds. Cox proportional hazards regression was used to assess associations between hepatotoxicity during treatment and diagnostic BMI and post-induction hepatotoxicity and weight change during induction. Associations were adjusted for age, race, ethnicity, and treatment risk stratification. Patients were censored at qualifying event or 1200 days post-diagnosis. RESULTS: Among 1070 patients (median age 6 years), 45.8% developed transaminitis and 7.6% cbili. Optimal BMI z-score cut points were -1.5 and 1.5 for transaminitis and 1.5 for cbili. A BMI z-score ≤ -1.5 was associated with reduced transaminitis (HR = 0.58, 95% CI: 0.39-0.86; p = 0.006), while a z-score ≥ 1.5 was associated with increased transaminitis (HR = 1.32, 95% CI: 1.06-1.65; p = 0.01). A BMI z-score ≥ 1.5 was also associated with increased cbili (HR = 1.97, 95% CI: 1.23-3.18; p = 0.01). Weight change was not associated with transaminitis, but weight loss during induction was associated with an increase in hazard of post-induction cbili (HR = 1.08, 95% CI: 1.04-1.11; p < 0.0001). CONCLUSION: Diagnostic BMI z-score and weight loss during induction were associated with increased hepatotoxicity risk, highlighting potential targets for improved risk stratification and hepatoprotective interventions.