The incidence of hypersensitivity reactions (HSRs) to PEG-asparaginase (PEG-ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP-BFM ALL 2009 study. Patients with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) were stratified as standard-risk/medium-risk (MR)/high-risk (HR) and those with T-ALL as non-High/HR. PEG-ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG-ASNase doses in induction; thereafter non-HR versus HR patients received 1 versus 6 PEG-ASNase doses, respectively. After the single regular dose of PEG-ASNase at the beginning of delayed intensification, BCP-ALL-MR patients were randomized to receive 9 additional PEG-ASNase doses every 2 weeks (experimental arm [EA]) versus none (standard arm [SA]); HR patients were randomized to receive, in consolidation, 4 weekly PEG-ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T-non- HR/BCP-Standard-Risk, BCP-MR-SA, BCP-MR-EA, HR-SA and HR-EA patients had 1-year-CI-HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG-ASNase did not significantly impact on HSR incidence in BCP-MR patients (1-y-CI-HSR 3.8% [0.8] versus 3.2% [0.6] in MR-EA versus MR-SA; P = 0.55), while impacted significantly in HR patients (1-y-CI-HSR 6.4% [1.3] versus 17.9% [1.8] in HR-EA and HR-SA, respectively; P < 0.001). The CI-HSR was comparable among non-HR groups and was not increased by a substantial intensification of PEG-ASNase in the BCP-MR-EA group whilst it was markedly higher in HR-SA than in HR-EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG-ASNase reduces the risk of developing an HSR.

Bicocca Center of Bioinformatics Biostatistics and Bioimaging School of Medicine and Surgery University of Milan Bicocca Monza Italy

Cancer Centre for Children Sydney Children's Hospital Network Westmead NSW Australia

Department of Onco Hematology and Cell and Gene Therapy Bambino Gesù Children's Hospital IRCCS Rome Italy

Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS Laboratory of Cancer Pharmacology Milano Italy

Department of Pediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology Charité and Rudolf Virchow Hospital Berlin Germany

Department of Pediatric Hematology and Oncology St Anna Children's Hospital Medical University of Vienna Austria

Department of Pediatric Hematology and Oncology University Childrens' Hospital of Münster Germany

Department of Pediatric Hematology Oncology Hannover Medical School Hannover Germany

Department of Pediatrics 1 Pediatric Hematology Oncology ALL BFM Study Group Christian Albrechts University Kiel and University Hospital Schleswig Holstein Campus Kiel Germany

Department of Pediatrics IRCCS San Gerardo dei Tintori Foundation Monza Italy; Department of Medicine and Surgery University of MIlano Bicocca Milano Italy

Pediatric Hematology Oncology Schneider Children's Medical Center Petah Tikva and Sackler Faculty of Medicine Tel Aviv University Petah Tikva Israel

St Anna Children's Cancer Research Institute Vienna Austria

University Children's Hospital Zurich Switzerland

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