Age but Not Adiposity Predicts Asparaginase-Induced Hepatotoxicity during Induction Therapy for Adolescent and Young Adults with Acute Lymphoblastic Leukemia

INTRODUCTION: Obesity is associated with increased treatment-related toxicity during therapy for acute lymphoblastic leukemia (ALL). During induction, hepatotoxicity due to L-asparaginase results in significant morbidity and chemotherapy delays/modifications. While hepatotoxicity is more common in older adolescent and young adult (AYA) patients, it cannot be predicted with high accuracy. Obesity defined by the surrogate marker of body mass index (BMI) has been shown to be a risk factor for hepatotoxicity; however, BMI does not accurately reflect body adiposity during ALL therapy due to concurrent muscle loss and adiposity gain. Because excess adiposity is generally believed to be responsible for most of the comorbidities of obesity, we hypothesized that body fat measured by direct assessment would be a better predictor of asparaginase-induced hepatotoxicity, and that non-obese patients with increased adiposity might be identified as an at-risk population which would not otherwise be recognized.

METHODS: We conducted an interim analysis of a prospective trial for an obesity intervention in pre-adolescent and AYA patients ≥10 years old newly diagnosed with B-ALL (NCT02708108). Whole-body dual-energy x-ray absorptiometry (DXA) performed at diagnosis and end of induction (EOI) directly quantified adiposity as total body fat percentage (TBF%) and fat mass (FM). Overweight or obesity (OW/OB) was defined using CDC-norms as a BMI percentile (BMI%) ≥85%. All patients were treated with Children's Oncology Group ALL regimens using a four-drug induction inclusive of glucocorticoids, daunorubicin, vincristine, and pegylated L-asparaginase. Obese and/or patients ≥15 years were considered at-risk for hepatotoxicity and thus eligible to receive exogenous supplementation with levocarnitine for hepatoprotection per provider discretion. The primary endpoint for the analysis was CTCAE Grade 3+ hepatotoxicity. Stepwise multivariable logistic regression models were constructed for the primary endpoint inclusive of TBF% and FM at diagnosis, change in FM during induction, and demographic candidate predictors. All tests were two-sided and significance was set at p<0.05.

RESULTS: We analyzed a cohort of 25 subjects enrolled on trial with DXA results at diagnosis. The cohort was divided equally by age ≥15 years (48%) and sex (44% female). The majority were of Hispanic ethnicity (64%) consistent with institutional demographics. Over half the cohort was OW/OB at diagnosis with mean TBF% of 39.5±1.3% and FM 31.7±2.5kg. In this AYA population, Grade 3+ hepatotoxicity occurred in 10/25 (40%) overall; all episodes included transaminitis (10/10) ± concurrent hyperbilirubinemia (2/10). Two of these patients met criteria for CTCAE Grade 4 hepatotoxicity (2/25, 8%); both were older, obese, with TBF% >40% at diagnosis. After accounting for age, radiographic measures of adiposity at diagnosis were not significant predictors of hepatotoxicity on multivariable analyses (FM at diagnosis p=0.299; TBF% at diagnosis p=0.599). Similarly, gain or loss of FM was not significantly associated with hepatotoxicity after adjusting for age or starting BMI category (p=0.818). Successful loss of fat due to the intervention occurred in 7/13 (54%) of OW/OB patients (mean loss -3.9±8.9kg) but was similarly not associated with decreased risk of hepatotoxicity (p=0.734). Only age ≥15 years was significantly associated with risk for Grade 3 hepatotoxicity across all models. Levocarnitine supplementation was prescribed by the primary providers to five of six eligible at-risk patients; no reported adverse events occurred. No severe, CTCAE Grade 4 hepatotoxicity occurred in the four patients adherent to levocarnitine supplementation.

CONCLUSION: Contrary to our hypothesis, neither directly measured adiposity at diagnosis nor changes in adiposity during ALL induction predicted hepatotoxicity for this AYA cohort. Older AYA patients were at significant risk for hepatotoxicity irrespective of level of adiposity. However, the potential impact of extreme obesity on hepatotoxicity requires further investigation. Validation of these results is necessary in a larger cohort; should they be confirmed, future trials targeting hepatotoxicity reduction from ALL induction should focus on age-related differences in drug metabolism and effects.