Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity

Chun-Bing Chen; Chuang-Wei Wang; Chun-Wei Lu; Wei-Ti Chen; Bing-Rong Zhou; Chia-Yu Chu; Shang-Fu Hsu; Cheng-Ta Yang; John Wen-Cheng Chang; Chan-Keng Yang; Chih-Liang Wang; Yueh-Fu Fang; Ping-Chih Hsu; Chung-Ching Hua; Chiao-En Wu; How-Wen Ko; Kun-Chieh Chen; Yi-Chien Yang; Han-Chi Tseng; An-Yu Cheng; Li-Chuan Tseng; Feng-Ya Shih; Shuen-Iu Hung; Cheng-Yang Huang; Wen-Hung Chung

doi:10.1016/j.jaip.2024.10.027

Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity

J Allergy Clin Immunol Pract. 2024 Nov 4:S2213-2198(24)01110-3. doi: 10.1016/j.jaip.2024.10.027. Online ahead of print.

Authors

Chun-Bing Chen¹, Chuang-Wei Wang², Chun-Wei Lu³, Wei-Ti Chen⁴, Bing-Rong Zhou⁵, Chia-Yu Chu⁶, Shang-Fu Hsu⁷, Cheng-Ta Yang⁸, John Wen-Cheng Chang⁹, Chan-Keng Yang⁹, Chih-Liang Wang¹⁰, Yueh-Fu Fang⁸, Ping-Chih Hsu⁸, Chung-Ching Hua¹¹, Chiao-En Wu⁹, How-Wen Ko¹², Kun-Chieh Chen¹³, Yi-Chien Yang¹⁴, Han-Chi Tseng¹⁴, An-Yu Cheng¹⁴, Li-Chuan Tseng¹⁵, Feng-Ya Shih¹⁵, Shuen-Iu Hung¹⁶, Cheng-Yang Huang¹⁷, Wen-Hung Chung¹⁸

Affiliations

¹ Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan.
² Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
³ Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan.
⁴ Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China.
⁵ Department of Dermatology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
⁶ Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁷ Pulmonary and Critical Care Medicine, Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
⁸ College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Thoracic Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
⁹ College of Medicine, Chang Gung University, Taoyuan, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan.
¹⁰ Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
¹¹ Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung and Chang Gung University, Keelung, Taiwan.
¹² College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
¹³ Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
¹⁴ Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹⁵ Department of Oncology Case Management, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
¹⁶ Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
¹⁷ Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: [email protected].
¹⁸ Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; Department of Dermatology, Beijing Tsinghua Chang Gung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China; Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiao-tong University, Shanghai, China; Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan. Electronic address: [email protected].

PMID: 39505105
DOI: 10.1016/j.jaip.2024.10.027

Abstract

Background: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), shows superior lung cancer treatment efficacy. However, osimertinib-induced severe hypersensitivity, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), is frequently observed in Asian populations and hinders cancer treatment.

Objective: We investigated the genetic HLA predisposition and immune pathomechanism of osimertinib-induced hypersensitivity.

Methods: We enrolled 17 patients with osimertinib-induced delayed hypersensitivity (seven with severe SJS/TEN and 10 with mild maculopapular exanthema), 98 osimertinib-tolerant subjects, and 2,123 general population controls. We performed HLA genotyping, drug-induced lymphocyte activation test, and surface plasmon resonance assay.

Results: HLA-B∗51:02 was present in 83.3% of osimertinib-induced SJS/TEN patients but in only 3.3% of the general population controls (P = 2.8 × 10^-7; corrected P = 6.9 × 10^-6; odds ratio [OR] = 146), and 0% of osimertinib-tolerant controls (P = 6.5 × 10^-8; corrected P = 1.6 × 10^-6; OR = 707). The association of HLA-B∗51:01 and HLA-A∗24:02 with osimertinib-induced maculopapular exanthema patients, rather than with osimertinib-tolerant subjects (P = .002, OR = 15.7 for HLA-B∗51:01; and P = .003, OR = 9.5 for HLA-A∗24:02), was identified as a phenotype-specific association. Granulysin, the SJS/TEN-specific cytotoxic protein, was significantly higher in plasma of SJS/TEN patients (39.8 ± 4.5 ng/mL; P < .001) and in in vitro lymphocyte activation test (sensitivity = 83.3%; P < .01) compared with tolerant controls. Patients with osimertinib-induced hypersensitivity appeared to tolerate alternative EGFR-TKIs. Surface plasmon resonance results also confirmed that HLA-B∗51:02 protein has a higher binding affinity for osimertinib and lower or no affinity for other EGFR-TKIs.

Conclusions: HLA-B∗51:02 frequently occurs in Asian populations and is strongly associated with osimertinib-induced SJS/TEN. Our findings suggest HLA-B∗51:02 screening as a preemptive test to reduce osimertinib-induced severe hypersensitivity.

Keywords: HLA-B∗51:02; Hypersensitivity; Osimertinib; Stevens-Johnson syndrome; Toxic epidermal necrolysis.