Effects of age, obesity, and body surface area on asparaginase-associated toxicities during acute lymphoblastic leukemia induction therapy: A report from the Children’s Oncology Group.
Authors: Orgel Etan , Militano Olga , Chen Zhiguo , Devidas Meenakshi , Maese Luke Devon , Rau Rachel E. , Angiolillo Anne L. , McNeer Jennifer Lynn , Schore Reuven J. , Raetz Elizabeth A. , Silverman Lewis B. , Winick Naomi J. , Larsen Eric , Carroll William L. , Winter Stuart S , Dunsmore Kimberley , Hunger Stephen , Loh Mignon L. 
Published: June 2022

7000 Background: Asparaginase is integral to pediatric-inspired regimens (PIR) to treat acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA). However, asparaginase-associated toxicities (AAT) often preclude delivery of planned therapy. Older age, obesity and/or large body surface area (BSA) have been associated with higher risk of AAT in PIR, but data are conflicting, and the impact of dose modification based on these factors is unknown. Methods: We examined induction toxicity data from patients ages 1-30 years enrolled in the frontline Children’s Oncology Group (COG) trials for high-risk B-ALL (AALL0232, 2004-2011) and T-ALL (AALL0434, 2007-2014). During Induction, patients received pegaspargase (2,500 IU/m2 without prescribed dose-capping) plus daunorubicin, vincristine, and prednisone or dexamethasone. AAT were defined as CTCAE v4 hyperbilirubinemia (Grade ≥3), elevated alanine aminotransferase (ALT) (Grade ≥4), thrombosis (any), or pancreatitis (any, included consolidation phase). Obesity was classified using population norms as body mass index (BMI) ≥30 (or ≥95th percentile for age/sex). BSA was analyzed continuously and dichotomized at 1.5 m2 (equivalent to pegaspargase 3,750 IU, the threshold for permissible dose-capping in PIR). The association of AAT with end-Induction minimal residual disease (MRD) ≥0.01% was assessed. Results: Among 4,925 patients, 25% were ≥15 years, 39% had BSA >1.5m2, and 18% had obesity. Multivariable logistic analyses inclusive of BMI and BSA together found increased risk for any AAT in age groups ≥10 years (10-15y, odds ratio (OR) 2.0, 15-20y OR 2.2, ≥21 OR 3.3, p=0.002). Only patients with both obesity and high BSA (>1.5m2) were at additional risk (OR 3.3, p<0.0001). Similarly, risks for hyperbilirubinemia, ALT elevations, and thrombosis were increased in patients with both high BSA and obesity (OR 3.5, 95% confidence interval [CI] 2.2-5.7), OR 3.3, 95%CI 1.7-6.6, and OR 3.1 95%CI 1.5-6.5, respectively), but not in those with high BSA without obesity. The risk of hyperbilirubinemia was greater with increasing obesity (p<0.0001) and was also higher in all age groups ≥10 years (OR 6.3-7.9, p<0.0001). Age was not associated with thrombosis or ALT elevation; risk for pancreatitis was associated with Hispanic ethnicity, but not with age, BMI, or BSA. AAT were not associated with pooled trial MRD ≥0.01%. Conclusions: We report here the largest dataset of AAT in children and AYAs receiving ALL Induction therapy without routinely prescribed dose-capping of pegaspargase. Risk for AAT was increased in patients >10 years and in those with obesity, but not high BSA alone. Dose capping may not be necessary for children and AYAs with high BSA without obesity. Prospective studies of AAT pharmacogenomics and modifiable risk factors will support safer dosing in PIR. Clinical trial information: NCT00075725, NCT00408005.