{"title":"I 类 HLA Alleles 与奥希替尼诱发超敏反应的风险增加有关。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>We investigated the genetic HLA predisposition and immune pathomechanism of osimertinib-induced hypersensitivity.</p><p><strong>Methods: </strong>We enrolled 17 patients with osimertinib-induced delayed hypersensitivity (7 with severe SJS/TEN and 10 with mild maculopapular exanthema [MPE]), 98 osimertinib-tolerant subjects, and 2123 general population controls. HLA genotyping, drug-induced lymphocyte activation test (LAT), and surface plasmon resonance (SPR) assay were performed.</p><p><strong>Results: </strong>HLA-B*51:02 was present in 83.3% of osimertinib-induced SJS/TEN patients but only in 3.3% of the general population controls (P = 2.8×10<sup>-7</sup>, Pc=6.9×10<sup>-6</sup>, odds ratio [OR]=146), and 0% of osimertinib-tolerant controls (P = 6.5×10<sup>-8</sup>, Pc=1.6×10<sup>-6</sup>, OR=707). The association of HLA-B*51:01 and HLA-A*24:02 with osimertinib-induced MPE patients, rather than with osimertinib-tolerant subjects (P = 0.002, OR=15.7 for HLA-B*51:01; P = 0.003, 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 SJS/TEN patients' plasma (39.8±4.5 ng/ml, P<0.001) and in in vitro LAT (sensitivity=83.3%, P<0.01) compared to the tolerant controls. Patients with osimertinib-induced hypersensitivity appeared to tolerate alternative EGFR-TKIs. SPR 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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":51323,"journal":{"name":"Journal of Allergy and Clinical Immunology-In Practice","volume":" ","pages":""},"PeriodicalIF":8.2000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Class I HLA Alleles are associated with an increased risk of osimertinib-induced hypersensitivity.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>We investigated the genetic HLA predisposition and immune pathomechanism of osimertinib-induced hypersensitivity.</p><p><strong>Methods: </strong>We enrolled 17 patients with osimertinib-induced delayed hypersensitivity (7 with severe SJS/TEN and 10 with mild maculopapular exanthema [MPE]), 98 osimertinib-tolerant subjects, and 2123 general population controls. HLA genotyping, drug-induced lymphocyte activation test (LAT), and surface plasmon resonance (SPR) assay were performed.</p><p><strong>Results: </strong>HLA-B*51:02 was present in 83.3% of osimertinib-induced SJS/TEN patients but only in 3.3% of the general population controls (P = 2.8×10<sup>-7</sup>, Pc=6.9×10<sup>-6</sup>, odds ratio [OR]=146), and 0% of osimertinib-tolerant controls (P = 6.5×10<sup>-8</sup>, Pc=1.6×10<sup>-6</sup>, OR=707). The association of HLA-B*51:01 and HLA-A*24:02 with osimertinib-induced MPE patients, rather than with osimertinib-tolerant subjects (P = 0.002, OR=15.7 for HLA-B*51:01; P = 0.003, 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 SJS/TEN patients' plasma (39.8±4.5 ng/ml, P<0.001) and in in vitro LAT (sensitivity=83.3%, P<0.01) compared to the tolerant controls. Patients with osimertinib-induced hypersensitivity appeared to tolerate alternative EGFR-TKIs. SPR 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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":51323,\"journal\":{\"name\":\"Journal of Allergy and Clinical Immunology-In Practice\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2024-11-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Allergy and Clinical Immunology-In Practice\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jaip.2024.10.027\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ALLERGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology-In Practice","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jaip.2024.10.027","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
Class I HLA Alleles are associated with an increased risk of osimertinib-induced hypersensitivity.
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 (7 with severe SJS/TEN and 10 with mild maculopapular exanthema [MPE]), 98 osimertinib-tolerant subjects, and 2123 general population controls. HLA genotyping, drug-induced lymphocyte activation test (LAT), and surface plasmon resonance (SPR) assay were performed.
Results: HLA-B*51:02 was present in 83.3% of osimertinib-induced SJS/TEN patients but only in 3.3% of the general population controls (P = 2.8×10-7, Pc=6.9×10-6, odds ratio [OR]=146), and 0% of osimertinib-tolerant controls (P = 6.5×10-8, Pc=1.6×10-6, OR=707). The association of HLA-B*51:01 and HLA-A*24:02 with osimertinib-induced MPE patients, rather than with osimertinib-tolerant subjects (P = 0.002, OR=15.7 for HLA-B*51:01; P = 0.003, 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 SJS/TEN patients' plasma (39.8±4.5 ng/ml, P<0.001) and in in vitro LAT (sensitivity=83.3%, P<0.01) compared to the tolerant controls. Patients with osimertinib-induced hypersensitivity appeared to tolerate alternative EGFR-TKIs. SPR 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.
期刊介绍：
JACI: In Practice is an official publication of the American Academy of Allergy, Asthma & Immunology (AAAAI). It is a companion title to The Journal of Allergy and Clinical Immunology, and it aims to provide timely clinical papers, case reports, and management recommendations to clinical allergists and other physicians dealing with allergic and immunologic diseases in their practice. The mission of JACI: In Practice is to offer valid and impactful information that supports evidence-based clinical decisions in the diagnosis and management of asthma, allergies, immunologic conditions, and related diseases.
This journal publishes articles on various conditions treated by allergist-immunologists, including food allergy, respiratory disorders (such as asthma, rhinitis, nasal polyps, sinusitis, cough, ABPA, and hypersensitivity pneumonitis), drug allergy, insect sting allergy, anaphylaxis, dermatologic disorders (such as atopic dermatitis, contact dermatitis, urticaria, angioedema, and HAE), immunodeficiency, autoinflammatory syndromes, eosinophilic disorders, and mast cell disorders.
The focus of the journal is on providing cutting-edge clinical information that practitioners can use in their everyday practice or to acquire new knowledge and skills for the benefit of their patients. However, mechanistic or translational studies without immediate or near future clinical relevance, as well as animal studies, are not within the scope of the journal.
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