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 immune responses resulting in suboptimal drug exposure and a greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginase-induced 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 = 541) and the Children's Oncology Group (n = 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P = 7.5 × 10(-5), odds ratio [OR] = 1.64; P = 1.4 × 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 × 10(-4), OR = 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.

• Authors: 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
• Journal: Blood (Blood) Vol. 124 Issue 8 Pg. 1266-76 (Aug 21 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24970932 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• Antibodies
• Antineoplastic Agents
• Epitopes
• HLA-DRB1 Chains
• HLA-DRB1*07 antigen
• Asparaginase

Topics

• Adolescent
• Adult
• Alleles
• Antibodies (blood, immunology)
• Antineoplastic Agents (administration & dosage, adverse effects)
• Asparaginase (administration & dosage, adverse effects)
• Child
• Child, Preschool
• Drug Hypersensitivity (blood, genetics, immunology)
• Epitopes (blood, genetics, immunology)
• Female
• HLA-DRB1 Chains (genetics, immunology)
• Humans
• Infant
• Leukemia (drug therapy, genetics, immunology, pathology)
• Male
• Risk Factors