The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
권호 표지
DOI QR코드

DOI QR Code

Patterns of hormonal changes in hypophysitis by immune checkpoint inhibitor

  • Hyunji Sang (Department of Endocrinology and Metabolism, Kyung Hee University Hospital) ;
  • Yun Kyung Cho (Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Sang-hyeok Go (Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Hwa Jung Kim (Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Eun Hee Koh (Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2023.11.28
  • Accepted : 2024.05.02
  • Published : 2024.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background/Aims: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events, including endocrine dysfunctions, which can have serious consequences on patient health and quality of life. The clinical course and characteristics of immune-related hypophysitis (irH) are not well established. This study aimed to analyze the clinical course and characteristics of irH. Methods: This single-center, retrospective study analyzed data from electronic medical records of Asan Medical Center, spanning January 2017 through June 2021. It included adult patients with solid tumors who underwent thyroid and adrenal function tests, along with gonadotropin and/or growth hormone evaluations, following the initiation of ICI treatment within the same period. The study explored the clinical characteristics of ICI-treated patients with and without irH, the incidence of irH, the time to irH onset, and the associated hormonal changes. Results: Twenty-one patients were included in this analysis. Clinical characteristics did not differ significantly between the irH (n = 13) and non-irH (n = 8) groups. Deficiency rates in the irH group were 23.1% for thyroid-stimulating hormone (n = 3), 76.9% for adrenocorticotropic hormone (n = 10), 61.5% for gonadotropin (n = 8), and 15.4% for growth hormone (n = 2). The overall incidence was 0.9 per person-year, with 6-month and 1-year cumulative incidences of 38.8% and 57.1%, respectively. The median time from ICI initiation to irH diagnosis was 7.7 months. Time to levothyroxine replacement was shorter in the irH group. Conclusions: The findings provide evidence that could facilitate the prediction of ICI-induced irH based on clinical course and characteristics.

Keywords

Acknowledgement

We would like to thank the Scientific Publications Team of Asan Medical Center for providing language editing and proofreading support.

References

  1. Dine J, Gordon R, Shames Y, Kasler MK, Barton-Burke M. Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs 2017;4:127-135.
  2. Haslam A, Gill J, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs. JAMA Netw Open 2020;3:e200423.
  3. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021;39:4073-4126.
  4. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol 2017;13:195-207.
  5. Iwama S, De Remigis A, Callahan MK, Slovin SF, Wolchok JD, Caturegli P. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med 2014;6:230ra45.
  6. Paschou SA, Stefanaki K, Psaltopoulou T, et al. How we treat endocrine complications of immune checkpoint inhibitors. ESMO Open 2021;6:100011.
  7. Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer 2014;21:371-381.
  8. Kwon H, Roh E, Ahn CH, et al. Immune checkpoint inhibitors and endocrine disorders: a position statement from the Korean Endocrine Society. Endocrinol Metab (Seoul) 2022;37:839-850.
  9. Mizukoshi T, Fukuoka H, Takahashi Y. Immune checkpoint inhibitor-related hypophysitis. Best Pract Res Clin Endocrinol Metab 2022;36:101668.
  10. Faje AT, Sullivan R, Lawrence D, et al. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 2014;99:4078-4085.
  11. Lam T, Chan MM, Sweeting AN, et al. Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. Intern Med J 2015;45:1066-1073.
  12. Snyders T, Chakos D, Swami U, et al. Ipilimumab-induced hypophysitis, a single academic center experience. Pituitary 2019;22:488-496.
  13. Albarel F, Gaudy C, Castinetti F, et al. Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur J Endocrinol 2015;172:195-204.
  14. Gonzalez-Rodriguez E, Rodriguez-Abreu D; Spanish Group for Cancer Immuno-Biotherapy (GETICA). Immune checkpoint inhibitors: review and management of endocrine adverse events. Oncologist 2016;21:804-816.
  15. Barroso-Sousa R, Barry WT, Garrido-Castro AC, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 2018;4:173-182.
  16. Cho YK, Kang YM, Hwang JY, et al. Association between serum gamma-glutamyltransferase and the progression of coronary artery calcification. Atherosclerosis 2015;243:300-306.
  17. Rhee EJ, Kim HC, Kim JH, et al. 2018 Guidelines for the management of dyslipidemia. Korean J Intern Med 2019;34:723-771.
  18. Fleseriu M, Hashim IA, Karavitaki N, et al. Hormonal replacement in hypopituitarism in adults: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab 2016;101:3888-3921.
  19. Jessel S, Weiss SA, Austin M, et al. Immune checkpoint inhibitor-induced hypophysitis and patterns of loss of pituitary function. Front Oncol 2022;12:836859.
  20. Briet C, Albarel F, Kuhn E, Merlen E, Chanson P, Cortet C. Expert opinion on pituitary complications in immunotherapy. Ann Endocrinol (Paris) 2018;79:562-568.
  21. Chen P, Li J, Tan H. Progress and challenges of immune checkpoint inhibitor-induced hypophysitis. J Clin Med 2023;12:3468.
  22. Labadzhyan A, Wentzel K, Hamid O, et al. Endocrine autoantibodies determine immune checkpoint inhibitor-induced endocrinopathy: a prospective study. J Clin Endocrinol Metab 2022;107:1976-1982.
  23. Persani L, Brabant G, Dattani M, et al. 2018 European Thyroid Association (ETA) guidelines on the diagnosis and management of central hypothyroidism. Eur Thyroid J 2018;7:225-237.
  24. Hartman ML, Crowe BJ, Biller BM, et al. Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinol Metab 2002;87:477-485.
  25. Biller BM, Samuels MH, Zagar A, et al. Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab 2002;87:2067-2079.
  26. Caturegli P, Newschaffer C, Olivi A, Pomper MG, Burger PC, Rose NR. Autoimmune hypophysitis. Endocr Rev 2005;26:599-614.
  27. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454.
  28. Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 2013;98:1361-1375.
  29. Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary 2016;19:82-92.
  30. Inaba H, Ariyasu H, Okuhira H, et al. Endocrine dysfunctions during treatment of immune-checkpoint inhibitors. Trend Immunother 2020;4:18-26.
  31. Caturegli P, Di Dalmazi G, Lombardi M, et al. Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am J Pathol 2016;186:3225-3235.
  32. Kassi E, Angelousi A, Asonitis N, et al. Endocrine-related adverse events associated with immune-checkpoint inhibitors in patients with melanoma. Cancer Med 2019;8:6585-6594.
  33. Kanie K, Iguchi G, Bando H, et al. Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome. Cancer Immunol Immunother 2021;70:3669-3677.
  34. Tan MH, Iyengar R, Mizokami-Stout K, et al. Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clin Diabetes Endocrinol 2019;5:1.
  35. Stelmachowska-Banas M, Czajka-Oraniec I. Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review. Endocr Connect 2020;9:R207-R228.
  36. Lupi I, Brancatella A, Cosottini M, et al. Clinical heterogeneity of hypophysitis secondary to PD-1/PD-L1 blockade: insights from four cases. Endocrinol Diabetes Metab Case Rep 2019;2019:19-0102.