Novel Genetic Risk Factor Identified for L-Asparaginase-Induced Pancreatitis in Pediatric Patients With Cancer

L-asparaginase is a critical component in treatment protocols for pediatric acute lymphoblastic leukemia. Acute pancreatitis reactions can necessitate delays and, in some cases, discontinuation of L-asparaginase, which compromises outcomes.

Genome-wide analyses were conducted to identify significant associations between single-nucleotide polymorphisms and risk for L-asparaginase-induced pancreatitis in 1086 pediatric patients treated on acute lymphoblastic leukemia treatment protocols. Patients were randomly split 75/25 into independent Discovery (n = 824) and Replication (n = 262) cohorts. Cases experienced Common Terminology Criteria for Adverse Events v5.0 Grades 3-4 acute pancreatitis reactions due to L-asparaginase treatment. Controls received L-asparaginase but did not develop acute pancreatitis.

A significant association was observed between the rs149210846 variant and L-asparaginase-induced pancreatitis (odds ratio [OR] = 8.9; 95% confidence interval [CI]: 3.6-22.3; p = 1.8 × 10^-8) and was confirmed in the replication analysis (OR = 6.2; 95% CI: 1.1-35.0; p = 0.02). Carriers had 5.9-fold (95% CI: 1.9-16.3; p = 0.002) and 7.7-fold (95% CI: 1.3-29.3; p = 0.01) increased risk of severe Grade 3 and Grade 4 acute pancreatitis reactions, respectively, relative to non-carriers. Moreover, patients of Admixed-American (OR = 8.8; 95% CI: 2.4-34.6; p = 1.45 × 10^-3) and Asian (OR = 10.0; 95% CI: 1.9-53.6; p = 8.06 × 10^-3) genetic ancestries were at significantly higher risk.

These findings will allow clinicians to proactively conduct stricter monitoring of patients at higher risk for L-asparaginase-induced pancreatitis and inform future development of protective agents that can be used concomitantly to mitigate their risk.