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. Rich; Paul Scheet; Sima Jeha; Ching Hon Pui; William E. Evans; Meenakshi Devidas; Mary V. Relling

doi:10.1182/blood-2014-03-563742

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

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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.

Original language	English
Pages (from-to)	1266-1276
Number of pages	11
Journal	Blood
Volume	124
Issue number	8
DOIs	https://doi.org/10.1182/blood-2014-03-563742
State	Published - 21 Aug 2014
Externally published	Yes

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Fernandez, C. A., Smith, C., Yang, W., Daté, M., Bashford, D., Larsen, E., Bowman, W. P., Liu, C., Ramsey, L. B., Chang, T., Turner, V., Loh, M. L., Raetz, E. A., Winick, N. J., Hunger, S. P., Carroll, W. L., Onengut-Gumuscu, S., Chen, W. M., Concannon, P., ... 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

@article{706450d8d92244c4b329248aaf66f7cd,

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

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.",

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

year = "2014",

month = aug,

day = "21",

doi = "10.1182/blood-2014-03-563742",

language = "English",

volume = "124",

pages = "1266--1276",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

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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

TY - JOUR

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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U2 - 10.1182/blood-2014-03-563742

DO - 10.1182/blood-2014-03-563742

M3 - Article

C2 - 24970932

AN - SCOPUS:84907363522

SN - 0006-4971

VL - 124

SP - 1266

EP - 1276

JO - Blood

JF - Blood

IS - 8

ER -

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

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