Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008

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DOI

  • Sofie G Højfeldt
  • ,
  • Benjamin O Wolthers, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • ,
  • Morten Tulstrup, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • ,
  • Jonas Abrahamsson, University of Gothenburg
  • ,
  • Ramneek Gupta, DTU Bioinformatics, Department of Bio and Health Informatics, Technical University of Denmark, Kemitorvet, 2800 Kongens Lyngby, Denmark.
  • ,
  • Arja Harila-Saari, Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
  • ,
  • Mats Heyman, Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
  • ,
  • Louise T Henriksen
  • Òlafur G Jónsson, Children's Hospital Iceland, Landspitali University Hospital, Reykjavik, Iceland
  • ,
  • Päivi M Lähteenmäki, Department of Paediatric and Adolescent Medicine, Turku University Hospital and Turku University, Turku, Finland.
  • ,
  • Bendik Lund, Department of Paediatrics, St Olavs University Hospital, Trondheim, Norway.
  • ,
  • Kaie Pruunsild, Department of Oncology and Haematology, University Children's Hospital, Tallinn, Estonia.
  • ,
  • Goda Vaitkeviciene, Clinic of Children's Diseases, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
  • ,
  • Kjeld Schmiegelow, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • ,
  • Birgitte K Albertsen
  • Nordic Society of Paediatric Haematology Oncology (NOPHO) group

Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.

OriginalsprogEngelsk
TidsskriftBritish Journal of Haematology
Vol/bind184
Nummer3
Sider (fra-til)405-417
Antal sider13
ISSN0007-1048
DOI
StatusUdgivet - feb. 2019

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© 2018 British Society for Haematology and John Wiley & Sons Ltd.

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