HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies

Christian A. Fernandez, Colton Smith, Wenjian Yang, Mihir Daté, Donald Bashford, Eric Larsen, W. Paul Bowman, Chengcheng Liu, Laura B. Ramsey, Tamara Chang, Victoria Turner, Mignon L. Loh, Elizabeth A. Raetz, Naomi J. Winick, Stephen P. Hunger, William L. Carroll, Suna Onengut-Gumuscu, Wei Min Chen, Patrick Concannon, Stephen S. RichPaul Scheet, Sima Jeha, Ching Hon Pui, William E. Evans, Meenakshi Devidas, Mary V. Relling

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immuneresponses resulting insuboptimal drug exposureanda greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginaseinduced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n 5 541) and the Children's Oncology Group (n 5 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P 5 7.5 3 10-5, odds ratio [OR] = 1.64; P = 1.4 x 10-5, OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 3 10-4, OR 5 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. These trials were registered at www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725.

Original languageEnglish
Pages (from-to)1266-1276
Number of pages11
JournalBlood
Volume124
Issue number8
DOIs
StatePublished - 21 Aug 2014

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Allergies
Asparaginase
HLA Antigens
Hypersensitivity
Alleles
Epitopes
Odds Ratio
Leukemia
Oncology
Consensus Sequence
Structural analysis
Anti-Idiotypic Antibodies
Lymphoma
Proteins
Amino Acids
Recurrence
Antibodies
Incidence
Enzymes
Research

Cite this

Fernandez, C. A., Smith, C., Yang, W., Daté, M., Bashford, D., Larsen, E., ... Relling, M. V. (2014). HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood, 124(8), 1266-1276. https://doi.org/10.1182/blood-2014-03-563742
Fernandez, Christian A. ; Smith, Colton ; Yang, Wenjian ; Daté, Mihir ; Bashford, Donald ; Larsen, Eric ; Bowman, W. Paul ; Liu, Chengcheng ; Ramsey, Laura B. ; Chang, Tamara ; Turner, Victoria ; Loh, Mignon L. ; Raetz, Elizabeth A. ; Winick, Naomi J. ; Hunger, Stephen P. ; Carroll, William L. ; Onengut-Gumuscu, Suna ; Chen, Wei Min ; Concannon, Patrick ; Rich, Stephen S. ; Scheet, Paul ; Jeha, Sima ; Pui, Ching Hon ; Evans, William E. ; Devidas, Meenakshi ; Relling, Mary V. / HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. In: Blood. 2014 ; Vol. 124, No. 8. pp. 1266-1276.
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abstract = "Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immuneresponses resulting insuboptimal drug exposureanda greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginaseinduced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n 5 541) and the Children's Oncology Group (n 5 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P 5 7.5 3 10-5, odds ratio [OR] = 1.64; P = 1.4 x 10-5, OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 3 10-4, OR 5 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. These trials were registered at www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725.",
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Fernandez, CA, Smith, C, Yang, W, Daté, M, Bashford, D, Larsen, E, Bowman, WP, Liu, C, Ramsey, LB, Chang, T, Turner, V, Loh, ML, Raetz, EA, Winick, NJ, Hunger, SP, Carroll, WL, Onengut-Gumuscu, S, Chen, WM, Concannon, P, Rich, SS, Scheet, P, Jeha, S, Pui, CH, Evans, WE, Devidas, M & Relling, MV 2014, 'HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies', Blood, vol. 124, no. 8, pp. 1266-1276. https://doi.org/10.1182/blood-2014-03-563742

HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. / Fernandez, Christian A.; Smith, Colton; Yang, Wenjian; Daté, Mihir; Bashford, Donald; Larsen, Eric; Bowman, W. Paul; Liu, Chengcheng; Ramsey, Laura B.; Chang, Tamara; Turner, Victoria; Loh, Mignon L.; Raetz, Elizabeth A.; Winick, Naomi J.; Hunger, Stephen P.; Carroll, William L.; Onengut-Gumuscu, Suna; Chen, Wei Min; Concannon, Patrick; Rich, Stephen S.; Scheet, Paul; Jeha, Sima; Pui, Ching Hon; Evans, William E.; Devidas, Meenakshi; Relling, Mary V.

In: Blood, Vol. 124, No. 8, 21.08.2014, p. 1266-1276.

Research output: Contribution to journalArticle

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T1 - HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies

AU - Fernandez, Christian A.

AU - Smith, Colton

AU - Yang, Wenjian

AU - Daté, Mihir

AU - Bashford, Donald

AU - Larsen, Eric

AU - Bowman, W. Paul

AU - Liu, Chengcheng

AU - Ramsey, Laura B.

AU - Chang, Tamara

AU - Turner, Victoria

AU - Loh, Mignon L.

AU - Raetz, Elizabeth A.

AU - Winick, Naomi J.

AU - Hunger, Stephen P.

AU - Carroll, William L.

AU - Onengut-Gumuscu, Suna

AU - Chen, Wei Min

AU - Concannon, Patrick

AU - Rich, Stephen S.

AU - Scheet, Paul

AU - Jeha, Sima

AU - Pui, Ching Hon

AU - Evans, William E.

AU - Devidas, Meenakshi

AU - Relling, Mary V.

PY - 2014/8/21

Y1 - 2014/8/21

N2 - Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immuneresponses resulting insuboptimal drug exposureanda greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginaseinduced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n 5 541) and the Children's Oncology Group (n 5 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P 5 7.5 3 10-5, odds ratio [OR] = 1.64; P = 1.4 x 10-5, OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 3 10-4, OR 5 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. These trials were registered at www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725.

AB - Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immuneresponses resulting insuboptimal drug exposureanda greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginaseinduced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n 5 541) and the Children's Oncology Group (n 5 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P 5 7.5 3 10-5, odds ratio [OR] = 1.64; P = 1.4 x 10-5, OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 3 10-4, OR 5 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. These trials were registered at www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725.

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Fernandez CA, Smith C, Yang W, Daté M, Bashford D, Larsen E et al. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood. 2014 Aug 21;124(8):1266-1276. https://doi.org/10.1182/blood-2014-03-563742