Page 150 - 2019_03-Haematologica-web

Acute Lymphoblastic Leukemia
Ferrata Storti Foundation
Haematologica 2019 Volume 104(3):556-563
Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte
di Legno toxicity working group report
Benjamin O. Wolthers,1 Thomas L. Frandsen,1 Chirag J. Patel,2 Rachid Abaji,3 Andishe Attarbaschi,4 Shlomit Barzilai,5 Antonella Colombini,6 Gabriele Escherich,7 Marie Grosjean,8 Maja Krajinovic,3,9 Eric Larsen,10 Der-Cherng Liang,11 Anja Möricke,12 Kirsten K. Rasmussen,1 Sujith Samarasinghe,13 Lewis B. Silverman,14 Inge M. van der Sluis,15 Martin Stanulla,16 Morten Tulstrup,1 Rachita Yadav,8,17 Wenjian Yang,18 Ester Zapotocka,19 Ramneek Gupta8 and Kjeld Schmiegelow1,20 on behalf of the Ponte di Legno toxicity working group
1Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; 2Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; 3CHU Sainte-Justine Research Center and Department of Pharmacology, University of Montreal, QC, Canada; 4Department of Pediatric Hematology and Oncology, St Anna Children's Hospital and Department of Pediatric and Adolescent Medicine, Medical University of Vienna, Austria; 5Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petah-Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Israel; 6Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy; 7University Medical Center Eppendorf, Clinic of Pediatric Hematology and Oncology, Hamburg, Germany; 8Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark; 9Department of Pediatrics, University of Montreal, QC, Canada; 10Maine Children's Cancer Program, Scarborough, ME, USA; 11Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan; 12Christian-Albrechts- University Kiel and University Medical Center Schleswig-Holstein, Department of Pediatrics, Kiel, Germany; 13Great Ormond Street Hospital for Children, London, UK; 14Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; 15Dutch Childhood Oncology Group, The Hague and Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; 16Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany; 17Molecular Neurogenetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; 18St. Jude Children's Research Hospital, Department of Pharmaceutical Sciences, Memphis, TN, USA; 19University Hospital Motol, Department of Pediatric Hematology/Oncology, Prague, Czech Republic and 20Institute of Clinical Medicine, University of Copenhagen, Denmark.
ABSTRACT
Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To eluci- date genetic predisposition and asparaginase-associated pancre- atitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0−17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 x upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2x10-8). Moreover, rs13228878 (OR=0.61; P=7.1x10-6) and rs10273639 (OR=0.62; P=1.1x10-5) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of
Correspondence:
KJELD SCHMIEGELOW
Kjeld.Schmiegelow@regionh.dk
Received: June 6, 2018.
Accepted: November 16, 2018. Pre-published: November 22, 2018.
doi:10.3324/haematol.2018.199356
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