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

Sofie G. Højfeldt, Benjamin O. Wolthers, Morten Tulstrup, Jonas Abrahamsson, Ramneek Gupta, Arja Harila-Saari, Mats Heyman, Louise T. Henriksen, Òlafur G. Jónsson, Päivi M. Lähteenmäki, Bendik Lund, Kaie Pruunsild, Goda Vaitkeviciene, Kjeld Schmiegelow, Birgitte K. Albertsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.
Original languageEnglish
JournalBritish Journal of Haematology
Volume184
Issue number3
Pages (from-to)405-417
Number of pages13
ISSN0007-1048
DOIs
Publication statusPublished - 2019

Keywords

  • PEG-asparaginase
  • Genome-wide association study
  • Hypersensitivity
  • Paediatric acute lymphoblastic leukaemia

Cite this

Højfeldt, S. G., Wolthers, B. O., Tulstrup, M., Abrahamsson, J., Gupta, R., Harila-Saari, A., ... Albertsen, B. K. (2019). Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008. British Journal of Haematology, 184(3), 405-417. https://doi.org/10.1111/bjh.15660
Højfeldt, Sofie G. ; Wolthers, Benjamin O. ; Tulstrup, Morten ; Abrahamsson, Jonas ; Gupta, Ramneek ; Harila-Saari, Arja ; Heyman, Mats ; Henriksen, Louise T. ; Jónsson, Òlafur G. ; Lähteenmäki, Päivi M. ; Lund, Bendik ; Pruunsild, Kaie ; Vaitkeviciene, Goda ; Schmiegelow, Kjeld ; Albertsen, Birgitte K. / Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008. In: British Journal of Haematology. 2019 ; Vol. 184, No. 3. pp. 405-417.
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title = "Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008",
abstract = "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.",
keywords = "PEG-asparaginase, Genome-wide association study, Hypersensitivity, Paediatric acute lymphoblastic leukaemia",
author = "H{\o}jfeldt, {Sofie G.} and Wolthers, {Benjamin O.} and Morten Tulstrup and Jonas Abrahamsson and Ramneek Gupta and Arja Harila-Saari and Mats Heyman and Henriksen, {Louise T.} and J{\'o}nsson, {{\`O}lafur G.} and L{\"a}hteenm{\"a}ki, {P{\"a}ivi M.} and Bendik Lund and Kaie Pruunsild and Goda Vaitkeviciene and Kjeld Schmiegelow and Albertsen, {Birgitte K.}",
year = "2019",
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Højfeldt, SG, Wolthers, BO, Tulstrup, M, Abrahamsson, J, Gupta, R, Harila-Saari, A, Heyman, M, Henriksen, LT, Jónsson, ÒG, Lähteenmäki, PM, Lund, B, Pruunsild, K, Vaitkeviciene, G, Schmiegelow, K & Albertsen, BK 2019, 'Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008', British Journal of Haematology, vol. 184, no. 3, pp. 405-417. https://doi.org/10.1111/bjh.15660

Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008. / Højfeldt, Sofie G.; Wolthers, Benjamin O.; Tulstrup, Morten; Abrahamsson, Jonas; Gupta, Ramneek; Harila-Saari, Arja; Heyman, Mats; Henriksen, Louise T.; Jónsson, Òlafur G.; Lähteenmäki, Päivi M.; Lund, Bendik; Pruunsild, Kaie; Vaitkeviciene, Goda; Schmiegelow, Kjeld; Albertsen, Birgitte K.

In: British Journal of Haematology, Vol. 184, No. 3, 2019, p. 405-417.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008

AU - Højfeldt, Sofie G.

AU - Wolthers, Benjamin O.

AU - Tulstrup, Morten

AU - Abrahamsson, Jonas

AU - Gupta, Ramneek

AU - Harila-Saari, Arja

AU - Heyman, Mats

AU - Henriksen, Louise T.

AU - Jónsson, Òlafur G.

AU - Lähteenmäki, Päivi M.

AU - Lund, Bendik

AU - Pruunsild, Kaie

AU - Vaitkeviciene, Goda

AU - Schmiegelow, Kjeld

AU - Albertsen, Birgitte K.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - PEG-asparaginase

KW - Genome-wide association study

KW - Hypersensitivity

KW - Paediatric acute lymphoblastic leukaemia

U2 - 10.1111/bjh.15660

DO - 10.1111/bjh.15660

M3 - Journal article

VL - 184

SP - 405

EP - 417

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 3

ER -