Toxicity from asparaginase during acute lymphoblastic leukemia induction: a report from the Children’s Oncology Group

ABSTRACT: Asparaginase-associated toxicities (AAT) often compromise therapy for acute lymphoblastic leukemia (ALL), affecting relapse risk and survival. There are conflicting data on the contributions of older age, obesity by body mass index (BMI), and/or large body surface area (BSA) to AAT. We examined the association of these risk factors with AAT and the impact of AAT on disease response. Induction data were examined from 4925 patients aged between 1 and 30 years enrolled in the Children's Oncology Group ALL trials AALL0232 and AALL0434, which included a single dose of pegaspargase (2500 IU/m2) without a maximum dose. The associations of age, BMI, and BSA with hyperbilirubinemia, elevated alanine aminotransferase (ALT), thrombosis, and pancreatitis were evaluated. The impact of AAT on minimal residual disease (MRD) positivity (≥0.01%) at the end of induction (EOI) was assessed. Increased risk of developing at least 1 AAT was observed in patients aged ≥10 years (P = .002) and in those with obesity and high BSA (P< .0001) but not with high BSA alone. Risks for hyperbilirubinemia, ALT elevations, and thrombosis were all increased in patients with obesity and high BSA (odds ratio [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). AAT were not associated with EOI MRD positivity. To our knowledge, we report the largest data set of AAT in children, adolescents, and young adults. Preventive strategies are indicated for older patients and for those with obesity and high BSA, but not with high BSA alone. These trials were registered at www.clinicaltrials.gov as NCT00075725 and NCT00408005.