Class I HLA Alleles are associated with an increased risk of osimertinib-induced hypersensitivity.

IF 8.2 1区医学 Q1 ALLERGY Journal of Allergy and Clinical Immunology-In Practice Pub Date : 2024-11-04 DOI:10.1016/j.jaip.2024.10.027

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

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引用次数: 0

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 (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.

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I 类 HLA Alleles 与奥希替尼诱发超敏反应的风险增加有关。

背景奥希替尼是第三代表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI），具有卓越的肺癌疗效。然而，奥希替尼诱发的严重超敏反应，包括史蒂文斯-约翰逊综合征（Stevens-Johnson syndrome，SJS）/毒性表皮坏死（Toxic epidermal necrolysis，TEN），在亚洲人群中经常出现，阻碍了癌症治疗：我们研究了奥希替尼诱发超敏反应的遗传 HLA 易感性和免疫病理机制：我们招募了17名奥司替尼诱导的迟发性超敏反应患者（7名重度SJS/TEN患者和10名轻度斑丘疹性红斑[MPE]患者）、98名奥司替尼耐受受试者和2123名普通人群对照。研究人员进行了HLA基因分型、药物诱导淋巴细胞活化试验（LAT）和表面等离子体共振（SPR）测定：结果：83.3%的奥希替尼诱导的SJS/TEN患者体内存在HLA-B*51:02，但只有3.3%的普通人群对照组（P=2.8×10-7，Pc=6.9×10-6，比值比[OR]=146）和0%的奥希替尼耐受对照组（P=6.5×10-8，Pc=1.6×10-6，OR=707）存在HLA-B*51:02。HLA-B*51:01和HLA-A*24:02与奥希替尼诱导的MPE患者而非奥希替尼耐受的受试者相关（HLA-B*51:01的P=0.002，OR=15.7；HLA-A*24:02的P=0.003，OR=9.5），被确定为表型特异性相关。SJS/TEN患者血浆中的Granulysin--SJS/TEN特异性细胞毒性蛋白--明显更高（39.8±4.5 ng/ml，PConclusions.P=0.003）：HLA-B*51:02经常出现在亚洲人群中，并且与奥希替尼诱导的SJS/TEN密切相关。我们的研究结果表明，HLA-B*51:02筛查是减少奥希替尼诱导的严重超敏反应的先期检测方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Allergy and Clinical Immunology-In Practice ALLERGYIMMUNOLOGY-IMMUNOLOGY

CiteScore

11.10

自引率

9.60%

发文量

683

审稿时长

50 days

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.