Pharmacogenomic Determinants of Asparaginase‐Induced Hypersensitivity, Pancreatitis, Thrombosis, and Hepatotoxicity in Children: A Systematic Review

Asparaginase is a common treatment for childhood hematological malignancies, but its use may be limited by toxicities including hypersensitivity, pancreatitis, thrombosis, and hepatotoxicity. Pharmacogenomic testing may identify children who are genetically predisposed to these toxicities, thus enabling personalized treatment. We performed a systematic review to synthesize and critically appraise available evidence for pharmacogenomic associations with asparaginase-induced toxicities in pediatric oncology patients. Literature searches of MEDLINE, Embase, and Web of Science were performed to identify studies investigating genetic associations with asparaginase-induced hypersensitivity, pancreatitis, thrombosis, or hepatotoxicity in children. Data extraction and risk of bias assessment using the Q-GENIE tool were performed independently by two reviewers. Forty studies met inclusion criteria. Evidence was the strongest for hypersensitivity, with consistent replication of associations involving HLA class II alleles, particularly the HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02 haplotype, although risk alleles differed by ancestry. For hepatotoxicity, evidence was limited to three studies, but PNPLA3 rs738409 was identified and independently replicated. Associations with pancreatitis and thrombosis were heterogeneous, with numerous candidate loci reported but limited validation across independent cohorts. The overall evidence base was highly heterogeneous, characterized by varying toxicity definitions, inconsistent reporting of statistical power, and limited replication. Current evidence supports HLA class II alleles and PNPLA3 as the most promising pharmacogenomic markers of asparaginase hypersensitivity and hepatotoxicity respectively, but larger, ancestrally diverse studies with standardized toxicity definitions and independent validation are required before routine clinical implementation.