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Class I HLA Alleles Are Associated With an Increased Risk of Osimertinib-Induced Hypersensitivity
Chun-Bing Chen1, Chuang-Wei Wang2, Chun-Wei Lu3
1Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; School of Medicine, National Tsing Hua University, Hsinchu, Taiwan.
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.
Insights
Human leukocyte antigen (HLA)-B∗51:02 is strongly linked to severe hypersensitivity reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis, in patients taking osimertinib. Genetic screening for HLA-B∗51:02 may help prevent these dangerous adverse events.
Area of Science:
- Pharmacogenomics
- Immunology
- Oncology
Background:
- Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is effective for lung cancer.
- Severe hypersensitivity reactions, such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), are common in Asian populations treated with osimertinib, limiting its use.
Purpose of the Study:
- To investigate the genetic human leukocyte antigen (HLA) predisposition and immune pathomechanism underlying osimertinib-induced hypersensitivity.
- To identify specific HLA alleles associated with different severities of osimertinib hypersensitivity.
Main Methods:
- Genotyping of human leukocyte antigen (HLA) alleles in 17 patients with osimertinib-induced hypersensitivity (7 severe SJS/TEN, 10 mild maculopapular exanthema), 98 osimertinib-tolerant subjects, and 2,123 general population controls.
- Performing drug-induced lymphocyte activation tests and surface plasmon resonance assays to assess immune response and drug-protein interactions.
Main Results:
- HLA-B∗51:02 was significantly associated with osimertinib-induced SJS/TEN (83.3% of patients vs. 3.3% of controls; P < 10-6).
- HLA-B∗51:01 and HLA-A∗24:02 were associated with mild maculopapular exanthema.
- Elevated granulysin levels and positive in vitro lymphocyte activation confirmed SJS/TEN immunopathology. HLA-B∗51:02 showed higher binding affinity to osimertinib.
Conclusions:
- HLA-B∗51:02 is a strong genetic marker for severe osimertinib-induced hypersensitivity (SJS/TEN) in Asian populations.
- Preemptive screening for HLA-B∗51:02 may reduce the incidence of severe adverse reactions to osimertinib.
- Patients with hypersensitivity to osimertinib may tolerate other EGFR-TKIs, and HLA-B∗51:02 has a specific binding affinity for osimertinib.
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