Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity
Journal
The Journal of Allergy and Clinical Immunology: In Practice
Journal Volume
13
Journal Issue
1
Start Page
143-154.e10
ISSN
2213-2198
Date Issued
2025-01
Author(s)
Chen, Chun-Bing
Wang, Chuang-Wei
Lu, Chun-Wei
Chen, Wei-Ti
Zhou, Bing-Rong
Hsu, Shang-Fu
Yang, Cheng-Ta
Wen-Cheng Chang, John
Yang, Chan-Keng
Wang, Chih-Liang
Fang, Yueh-Fu
Hsu, Ping-Chih
Hua, Chung-Ching
Wu, Chiao-En
Ko, How-Wen
Chen, Kun-Chieh
Yang, Yi-Chien
Tseng, Han-Chi
Cheng, An-Yu
Tseng, Li-Chuan
Shih, Feng-Ya
Hung, Shuen-Iu
Huang, Cheng-Yang
Chung, Wen-Hung
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.
Subjects
HLA-B∗51:02
Hypersensitivity
Osimertinib
Stevens-Johnson syndrome
Toxic epidermal necrolysis
SDGs
Publisher
Elsevier BV
Type
journal article