The journal of allergy and clinical immunology. In practice · 2024
Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Chen Chun-Bing, Wang Chuang-Wei, Lu Chun-Wei, Chen Wei-Ti, Zhou Bing-Rong, Chu Chia-Yu, 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
Аннотация
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.
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.