Incidence and Characteristics of Hypersensitivity Reactions to PEG-asparaginase Observed in 6136 Children With Acute Lymphoblastic Leukemia Enrolled in the AIEOP-BFM ALL 2009 Study Protocol
Carmelo Rizzari,
Anja Möricke,
Maria Grazia Valsecchi,
Valentino Conter,
Martin Zimmermann,
Daniela Silvestri,
Andishe Attarbaschi,
Felix Niggli,
Draga Barbaric,
Jan Stary,
Sarah Elitzur,
Gunnar Cario,
Luciana Vinti,
Joachim Boos,
Massimo Zucchetti,
Claudia Lanvers-Kaminsky,
Arend von Stackelberg,
Andrea Biondi,
Martin Schrappe
Affiliations
Carmelo Rizzari
1 Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
Anja Möricke
2 Department of Pediatrics I, Pediatric Hematology/Oncology, ALL-BFM Study Group, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Germany
Maria Grazia Valsecchi
1 Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
Valentino Conter
1 Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
Martin Zimmermann
4 Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany
Daniela Silvestri
1 Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
Andishe Attarbaschi
5 Department of Pediatric Hematology and Oncology, St. Anna Children’s Hospital, Medical University of Vienna, Austria
Felix Niggli
7 University Children’s Hospital, Zurich, Switzerland
Draga Barbaric
8 Cancer Centre for Children, Sydney Children’s Hospital Network, Westmead, NSW, Australia
Jan Stary
9 Department of Pediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Sarah Elitzur
10 Pediatric Hematology-Oncology, Schneider Children’s Medical Center, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel
Gunnar Cario
2 Department of Pediatrics I, Pediatric Hematology/Oncology, ALL-BFM Study Group, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Germany
Luciana Vinti
11 Department of Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Joachim Boos
12 Department of Pediatric Hematology and Oncology, University Childrens’ Hospital of Münster, Germany
Massimo Zucchetti
13 Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Laboratory of Cancer Pharmacology, Milano, Italy
Claudia Lanvers-Kaminsky
12 Department of Pediatric Hematology and Oncology, University Childrens’ Hospital of Münster, Germany
Arend von Stackelberg
14 Department of Pediatric Hematology and Oncology, Charité and Rudolf-Virchow-Hospital, Berlin, Germany
Andrea Biondi
1 Department of Pediatrics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; Department of Medicine and Surgery, University of MIlano-Bicocca, Milano, Italy
Martin Schrappe
2 Department of Pediatrics I, Pediatric Hematology/Oncology, ALL-BFM Study Group, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Germany
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.
