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Immune Checkpoint Inhibitors-Induced Hepatitis

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Immunotherapy

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 995))

Abstract

Immune checkpoint inhibitors (ICIs) have been increasingly used for multiple cancer types in the past decade. ICIs include CTLA-4 inhibitors (e.g., ipilimumab) and the PD-1 and PD-L1 inhibitors (e.g., nivolumab and pembrolizumab). Hepatotoxicity is not uncommon secondary to ICI treatment. It can occur 8–12 weeks after the initiation of ICI and presents with elevation of aspartate transaminase and alanine transaminase. ICI-induced hepatitis is usually asymptomatic but may present with fever, malaise, and even death in rare cases. It is a diagnosis of exclusion after other etiologies are excluded based on medical history, laboratory evaluation, and imaging and histological findings. ICI-induced hepatitis might require discontinuation of ICI and/or treatment with immunosuppressants.

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References

  1. Foller S, Oppel-Heuchel H, Fetter I, Winkler Y, Grimm MO. [Adverse events of immune checkpoint inhibitors]. Der Urologe Ausg A. 2017;56:486–91.

    Google Scholar 

  2. Ali AK, Watson DE. Pharmacovigilance assessment of immune-mediated reactions reported for checkpoint inhibitor cancer immunotherapies. Pharmacotherapy. 2017;37:1383–90.

    Article  CAS  Google Scholar 

  3. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020–30.

    Article  CAS  Google Scholar 

  4. Bernardo SG, Moskalenko M, Pan M, et al. Elevated rates of transaminitis during ipilimumab therapy for metastatic melanoma. Melanoma Res. 2013;23:47–54.

    Article  CAS  Google Scholar 

  5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.

    Article  Google Scholar 

  6. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712–7.

    Article  Google Scholar 

  7. Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390:1853–62.

    Article  CAS  Google Scholar 

  8. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.

    Article  CAS  Google Scholar 

  9. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–84.

    Article  CAS  Google Scholar 

  10. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.

    Article  Google Scholar 

  11. Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:190–209.

    Article  CAS  Google Scholar 

  12. van den Eertwegh AJ, Versluis J, van den Berg HP, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:509–17.

    Article  Google Scholar 

  13. Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.

    Article  CAS  Google Scholar 

  14. Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13:473–86.

    Article  CAS  Google Scholar 

  15. Sznol M, Ferrucci PF, Hogg D, et al. Pooled analysis safety profile of nivolumab and ipilimumab combination therapy in patients with advanced melanoma. J Clin Oncol. 2017;35:3815–22.

    Article  CAS  Google Scholar 

  16. De Martin E, Michot JM, Papouin B, et al. Liver injury from cancer immunotherapy using monoclonal immune checkpoint inhibitors. J Hepatol. 2018 Oct 5. pii: S0168-8278(18)32379-1. doi: 10.1016/j.jhep.2018.09.006. PMID: 30297274.

    Google Scholar 

  17. Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Investig New Drugs. 2013;31:1071–7.

    Article  CAS  Google Scholar 

  18. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7.

    Article  CAS  Google Scholar 

  19. Kwak JJ, Tirumani SH, Van den Abbeele AD, Koo PJ, Jacene HA. Cancer immunotherapy: imaging assessment of novel treatment response patterns and immune-related adverse events. Radiographics. 2015;35:424–37.

    Article  Google Scholar 

  20. Johncilla M, Misdraji J, Pratt DS, et al. Ipilimumab-associated hepatitis: clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol. 2015;39:1075–84.

    Article  Google Scholar 

  21. Chmiel KD, Suan D, Liddle C, et al. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. J Clin Oncol. 2011;29:e237–40.

    Article  CAS  Google Scholar 

  22. Cramer P, Bresalier RS. Gastrointestinal and hepatic complications of immune checkpoint inhibitors. Curr Gastroenterol Rep. 2017;19:3.

    Article  Google Scholar 

  23. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48.

    Article  CAS  Google Scholar 

  24. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2016;2:1346–53.

    Article  Google Scholar 

  25. Tirumani SH, Ramaiya NH, Keraliya A, et al. Radiographic profiling of immune-related adverse events in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res. 2015;3:1185–92.

    Article  CAS  Google Scholar 

  26. Imafuku K, Yoshino K, Yamaguchi K, Tsuboi S, Ohara K, Hata H. Successful treatment of sudden hepatitis induced by long-term nivolumab administration. Case Rep Oncol. 2017;10:368–71.

    Article  Google Scholar 

  27. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. US Department of Health and Human Services. 2009

    Google Scholar 

  28. Suzuki A, Brunt EM, Kleiner DE, et al. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology. 2011;54:931–9.

    Article  Google Scholar 

  29. Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–40.

    Article  Google Scholar 

  30. Mortele KJ, Segatto E, Ros PR. The infected liver: radiologic-pathologic correlation. Radiographics. 2004;24:937–55.

    Article  Google Scholar 

  31. Widmann G, Nguyen VA, Plaickner J, Jaschke W. Imaging features of toxicities by immune checkpoint inhibitors in cancer therapy. Curr Radiol Rep. 2016;5:59.

    Article  Google Scholar 

  32. Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol. 2017;8:49.

    Article  CAS  Google Scholar 

  33. Alessandrino F, Tirumani SH, Krajewski KM, et al. Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors. Clin Radiol. 2017;72:521–33.

    Article  CAS  Google Scholar 

  34. Everett J, Srivastava A, Misdraji J. Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis. Am J Surg Pathol. 2017;41:134–7.

    Article  Google Scholar 

  35. Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol. 2018;31:965–73.

    Article  Google Scholar 

  36. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95.

    Article  CAS  Google Scholar 

  37. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17.

    Article  Google Scholar 

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Disclosure

The authors declared no financial conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oncology, Shanghai Dermatology Hospital, Tongji University, Shanghai, China

    Yun Tian

  2. Tongji University Cancer Center, The Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China

    Yun Tian

  3. Department of Gastroenterology, Hepatology and Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Hamzah Abu-Sbeih & Yinghong Wang

Authors
  1. Yun Tian
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  2. Hamzah Abu-Sbeih
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  3. Yinghong Wang
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Corresponding author

Correspondence to Yinghong Wang .

Editor information

Editors and Affiliations

  1. MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    Aung Naing

  2. Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

    Joud Hajjar

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Tian, Y., Abu-Sbeih, H., Wang, Y. (2018). Immune Checkpoint Inhibitors-Induced Hepatitis. In: Naing, A., Hajjar, J. (eds) Immunotherapy. Advances in Experimental Medicine and Biology, vol 995. Springer, Cham. https://doi.org/10.1007/978-3-030-02505-2_8

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