Hypersensitivity to Pegylated E.coli asparaginase as first-line treatment in contemporary paediatric acute lymphoblastic leukaemia protocols : a meta-analysis of the Ponte di Legno Toxicity working group

Background: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of inci-dence of allergic reactions to pegylated E.coli asparaginase (PEGasparaginase) across contem-porary paediatric acute lymphoblastic leukaemia (ALL) protocols is lacking. Method and patients: Questionnaires were sent to all members of the international ALL Ponte di Legno Toxicity Working Group. Meta-analyses were conducted to estimate the incidence of three types of hypersensitivity (allergy, allergic-like reaction and silent inactivation). Informa-tion on protocol level regarding PEGasparaginase dosing regimen, administration route and use of therapeutic drug monitoring was collected for risk analysis. Results: Newly diagnosed patients with ALL (n Z 5880), aged 1-24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The incidence of allergic reactions (sum of allergies and allergic-like reactions) [95% confidence in-terval] was 2% [1%; 3%] during induction and 8% [5%; 11%] during postinduction. Route of administration, number of doses, dosage and number of PEGasparaginase-free weeks did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis suggests that initiation of PEGasparaginase in postinduction and higher number of PEGasparaginase-free intervals increased the risk for allergic reactions. 9-16% and 23-29% of all hypersensitivities were allergic-like reactions and silent inactivation, respectively. Conclusion: The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared with that reported for E.coli asparaginase or PEGasparaginase after E.coli asparaginase. Postinduction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in postinduction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy.@ 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)