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Genetic predisposition to PEG ‐asparaginase hypersensitivity in children treated according to NOPHO ALL 2008
Author(s) -
Højfeldt Sofie G.,
Wolthers Benjamin O.,
Tulstrup Morten,
Abrahamsson Jonas,
Gupta Ramneek,
HarilaSaari Arja,
Heyman Mats,
Henriksen Louise T.,
Jónsson Òlafur G.,
Lähteenmäki Päivi M.,
Lund Bendik,
Pruunsild Kaie,
Vaitkeviciene Goda,
Schmiegelow Kjeld,
Albertsen Birgitte K.
Publication year - 2019
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.15660
Subject(s) - asparaginase , medicine , peg ratio , immunology , allergy , acute lymphocytic leukemia , genetic predisposition , hematology , pharmacology , disease , leukemia , lymphoblastic leukemia , finance , economics
Summary 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 ALL 2008 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 CNOT 3 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 ‐ DQA 1 ( P = 9·37 × 10 −6 ) and TAP 2 ( P = 1·59 × 10 −5 ). This study associated variants in CNOT 3 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.