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

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^*

^*Corresponding author for this work

School of Medicine

Chang Gung Memorial Hospital
Chang Gung University
Xiamen Chang Gung Hospital
National Tsing Hua University
First Affiliated Hospital of Nanjing Medical University
National Taiwan University
Taipei Medical University
Veterans General Hospital-Taichung Taiwan
Chung Shan Medical University
Tsinghua University
Shanghai Jiao Tong University

Research output: Contribution to journal › Journal Article › peer-review

3 Scopus citations

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.

Original language	English
Pages (from-to)	143-154.e10
Journal	Journal of Allergy and Clinical Immunology: In Practice
Volume	13
Issue number	1
Early online date	04 11 2024
DOIs	https://doi.org/10.1016/j.jaip.2024.10.027
State	E-pub ahead of print - 04 11 2024

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

Access to Document

10.1016/j.jaip.2024.10.027

Cite this

Chen, C. B., Wang, C. W., Lu, C. W., Chen, W. T., Zhou, B. R., Chu, C. Y., Hsu, S. F., Yang, C. T., Wen-Cheng Chang, J., Yang, C. K., Wang, C. L., Fang, Y. F., Hsu, P. C., Hua, C. C., Wu, C. E., Ko, H. W., Chen, K. C., Yang, Y. C., Tseng, H. C., ... Chung, W. H. (2024). Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity. Journal of Allergy and Clinical Immunology: In Practice, 13(1), 143-154.e10. Advance online publication. https://doi.org/10.1016/j.jaip.2024.10.027

@article{052e7413536e4b84b6ee9edc3596a1ad,

title = "Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity",

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",

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

year = "2024",

month = nov,

day = "4",

doi = "10.1016/j.jaip.2024.10.027",

language = "英语",

volume = "13",

pages = "143--154.e10",

journal = "Journal of Allergy and Clinical Immunology: In Practice",

issn = "2213-2198",

publisher = "American Academy of Allergy, Asthma and Immunology",

number = "1",

}

Chen, CB, Wang, CW, Lu, CW, Chen, WT, Zhou, BR, Chu, CY, Hsu, SF, Yang, CT, Wen-Cheng Chang, J, Yang, CK, Wang, CL, Fang, YF, Hsu, PC, Hua, CC, Wu, CE, Ko, HW, Chen, KC, Yang, YC, Tseng, HC, Cheng, AY, Tseng, LC, Shih, FY, Hung, SI, Huang, CY & Chung, WH 2024, 'Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity', Journal of Allergy and Clinical Immunology: In Practice, vol. 13, no. 1, pp. 143-154.e10. https://doi.org/10.1016/j.jaip.2024.10.027

TY - JOUR

T1 - Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity

AU - Chen, Chun Bing

AU - Wang, Chuang Wei

AU - Lu, Chun Wei

AU - Chen, Wei Ti

AU - Zhou, Bing Rong

AU - Chu, Chia Yu

AU - Hsu, Shang Fu

AU - Yang, Cheng Ta

AU - Wen-Cheng Chang, John

AU - Yang, Chan Keng

AU - Wang, Chih Liang

AU - Fang, Yueh Fu

AU - Hsu, Ping Chih

AU - Hua, Chung Ching

AU - Wu, Chiao En

AU - Ko, How Wen

AU - Chen, Kun Chieh

AU - Yang, Yi Chien

AU - Tseng, Han Chi

AU - Cheng, An Yu

AU - Tseng, Li Chuan

AU - Shih, Feng Ya

AU - Hung, Shuen Iu

AU - Huang, Cheng Yang

AU - Chung, Wen Hung

PY - 2024/11/4

Y1 - 2024/11/4

N2 - 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.

AB - 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.

KW - HLA-B∗51:02

KW - Hypersensitivity

KW - Osimertinib

KW - Stevens-Johnson syndrome

KW - Toxic epidermal necrolysis

UR - https://www.scopus.com/pages/publications/85211092267

U2 - 10.1016/j.jaip.2024.10.027

DO - 10.1016/j.jaip.2024.10.027

M3 - 文章

C2 - 39505105

AN - SCOPUS:85211092267

SN - 2213-2198

VL - 13

SP - 143-154.e10

JO - Journal of Allergy and Clinical Immunology: In Practice

JF - Journal of Allergy and Clinical Immunology: In Practice

IS - 1

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

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