Hypersensitivity to PEG-Asparaginase and Desensitization Strategies in Pediatric Acute Lymphoblastic Leukemia: A Narrative Review.

This narrative review synthesizes current evidence on incidence, the immunologic basis of hypersensitivity-including the recently clarified role of anti-PEG (rather than anti-protein) antibodies-genetic predisposition, differential diagnosis from asparaginase-associated hyperammonemia, therapeutic drug monitoring (TDM), and desensitization. Hypersensitivity to PEG-asparaginase is a frequent, clinically consequential complication of pediatric acute lymphoblastic leukemia therapy that can compromise treatment exposure and survival. Recombinant Erwinia asparaginase (crisantaspase) is now licensed in the United States (2021) and the European Union (2023) for hypersensitive patients; however, cost, reimbursement, and local availability continue to limit access in many settings. Therefore, strategies for the safe continuation of PEG-asparaginase remain clinically relevant for reasons other than supply shortages alone. Using Ponte di Legno Toxicity Working Group definitions, reactions are classified as clinical allergy, allergic-like reaction, or silent inactivation, each requiring a different response; TDM is central to making this distinction. Genetic susceptibility loci (HLA class II haplotypes, CNOT3, GRIA1) remain investigational, with moderate effect sizes and inconsistent replication, and are not yet suitable for clinical decision-making. An adapted multi-step desensitization protocol can preserve therapeutic enzyme activity in appropriately selected patients; however, tolerance is temporary and dose-specific and requires repeat TDM after every dose. Conclusion. A personalized, multidisciplinary approach-integrating TDM, realistic assessment of access to alternative formulations, and (where available) genetic data-is recommended to optimize treatment safety and antileukemic efficacy.