PMID- 36512357 OWN - NLM STAT- MEDLINE DCOM- 20221221 LR - 20240112 IS - 2574-3805 (Electronic) IS - 2574-3805 (Linking) VI - 5 IP - 12 DP - 2022 Dec 1 TI - Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma. PG - e2246400 LID - 10.1001/jamanetworkopen.2022.46400 [doi] LID - e2246400 AB - IMPORTANCE: Treatment with immune checkpoint inhibitors (ICIs) has increased survival in patients with advanced malignant melanoma but can be associated with a wide range of immune-related adverse events (irAEs). The role of human leukocyte antigen (HLA)-DR alleles in conferring irAE risk has not been well studied. OBJECTIVE: To evaluate the association between irAEs and treatment response, survival, and the presence of HLA-DR alleles after ICI therapy in advanced melanoma. DESIGN, SETTING, AND PARTICIPANTS: This case-control study used the patient registry and biobanked samples from the tertiary referral University of Colorado Cancer Center. Specimens and clinical data were collected between January 1, 2010, and December 31, 2021. Patients with advanced (stage III unresectable and stage IV) melanoma who received ICI therapy (n = 132) were included in the analysis. EXPOSURES: Immune checkpoint inhibitors (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed cell death protein 1 or its ligand, or the combination) for the treatment of advanced melanoma. MAIN OUTCOMES AND MEASURES: The association between irAEs and response to therapy, survival, and HLA-DR alleles. RESULTS: Among the cohort of 132 patients with advanced melanoma (mean [SD] age, 63.4 [7.2] years; 85 men [64%] and 47 women [36%]) treated with ICIs, 73 patients had at least 1 irAE and 59 did not have an irAE. Compared with patients without an irAE, patients with an irAE had higher treatment response rates (50 of 72 [69%] vs 28 of 57 [49%]; P = .02) and increased survival (median, 4.8 [IQR, 0.2-9.6] vs 3.2 [IQR, 0.1-9.2] years; P = .02). Specific HLA-DR alleles were associated with the type of irAE that developed: 7 of 10 patients (70%) who developed type 1 diabetes had DR4; 6 of 12 (50%) who developed hypothyroidism had DR8; 5 of 8 (63%) who developed hypophysitis had DR15; 3 of 5 (60%) who developed pneumonitis had DR1; and 8 of 15 (53%) who developed hepatitis had DR4. CONCLUSIONS AND RELEVANCE: These findings suggest that IrAEs are associated with treatment response rates and increased survival after ICI therapy for advanced melanoma. Because distinct HLA-DR alleles are associated with given adverse events, HLA genotyping before ICI therapy may aid in identifying risk for specific irAEs that could develop with such treatment. FAU - Akturk, Halis Kaan AU - Akturk HK AD - Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora. AD - Department of Pediatrics, University of Colorado School of Medicine, Aurora. AD - Department of Medicine, University of Colorado School of Medicine, Aurora. FAU - Couts, Kasey L AU - Couts KL AD - Department of Medicine, University of Colorado School of Medicine, Aurora. AD - University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora. FAU - Baschal, Erin E AU - Baschal EE AD - Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora. FAU - Karakus, Kagan E AU - Karakus KE AD - Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora. FAU - Van Gulick, Robert J AU - Van Gulick RJ AD - Department of Medicine, University of Colorado School of Medicine, Aurora. FAU - Turner, Jacqueline A AU - Turner JA AD - Department of Medicine, University of Colorado School of Medicine, Aurora. FAU - Pyle, Laura AU - Pyle L AD - Department of Pediatrics, University of Colorado School of Medicine, Aurora. AD - Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora. FAU - Robinson, William A AU - Robinson WA AD - Department of Medicine, University of Colorado School of Medicine, Aurora. AD - University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora. FAU - Michels, Aaron W AU - Michels AW AD - Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora. AD - Department of Pediatrics, University of Colorado School of Medicine, Aurora. AD - Department of Medicine, University of Colorado School of Medicine, Aurora. AD - Department of Immunology, University of Colorado School of Medicine, Aurora. LA - eng GR - P30 DK116073/DK/NIDDK NIH HHS/United States GR - R01 DK032083/DK/NIDDK NIH HHS/United States GR - R01 DK108868/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20221201 PL - United States TA - JAMA Netw Open JT - JAMA network open JID - 101729235 RN - 0 (Antineoplastic Agents, Immunological) RN - 0 (HLA-DR Antigens) RN - 0 (Immune Checkpoint Inhibitors) SB - IM MH - Female MH - Humans MH - Male MH - Middle Aged MH - Alleles MH - *Antineoplastic Agents, Immunological/adverse effects MH - Case-Control Studies MH - *HLA-DR Antigens/genetics MH - *Immune Checkpoint Inhibitors/adverse effects MH - *Melanoma/drug therapy/genetics MH - Melanoma, Cutaneous Malignant PMC - PMC9856415 COIS- Conflict of Interest Disclosures: None reported. EDAT- 2022/12/14 06:00 MHDA- 2022/12/16 06:00 PMCR- 2022/12/13 CRDT- 2022/12/13 11:33 PHST- 2022/12/13 11:33 [entrez] PHST- 2022/12/14 06:00 [pubmed] PHST- 2022/12/16 06:00 [medline] PHST- 2022/12/13 00:00 [pmc-release] AID - 2799441 [pii] AID - zoi221310 [pii] AID - 10.1001/jamanetworkopen.2022.46400 [doi] PST - epublish SO - JAMA Netw Open. 2022 Dec 1;5(12):e2246400. doi: 10.1001/jamanetworkopen.2022.46400.