Volume 12 Issue 5
Sep.  2021
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HUA Yuwei, ZHAO Lin. Diagnosis and Management of Immunotherapy-related Liver Toxicity[J]. Medical Journal of Peking Union Medical College Hospital, 2021, 12(5): 798-806. doi: 10.12290/xhyxzz.2021-0138
Citation: HUA Yuwei, ZHAO Lin. Diagnosis and Management of Immunotherapy-related Liver Toxicity[J]. Medical Journal of Peking Union Medical College Hospital, 2021, 12(5): 798-806. doi: 10.12290/xhyxzz.2021-0138

Diagnosis and Management of Immunotherapy-related Liver Toxicity

doi: 10.12290/xhyxzz.2021-0138
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  • Corresponding author: ZHAO Lin  Tel: 86-10-88068315, E-mail: wz20010727@aliyun.com
  • Received Date: 2021-01-31
  • Accepted Date: 2021-03-12
  • Available Online: 2021-08-03
  • Publish Date: 2021-09-30
  • Immune checkpoint inhibitors have revolutionized the treatment of cancer. With the increasing use of immunotherapy, clinicians have observed that immunotherapy is often related to a spectrum of adverse events. Liver toxicity is one of the most common and severe immune-related adverse events. It is very important to increase awareness and outline a clear and detailed strategy of managing immune-related liver toxicity. Some guidelines have published systematic advice on the management of immune-related liver toxicity. However, there are controversial problems remaining, including the levels of liver toxicity, the minimal effective dosage of hormone, treatments for hormone-refractory patients, and immunotherapy re-challenge. Additional, finding predictors with high specificity and sensitivity is a pressing concern.
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  • [1] Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy[J]. Cancer Discov, 2018, 8: 1069-1086. doi:  10.1158/2159-8290.CD-18-0367
    [2] Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Block-ade[J]. N Engl J Med, 2018, 378: 158-168. doi:  10.1056/NEJMra1703481
    [3] Wang DY, Salem JE, Cohen JV, et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis[J]. JAMA Oncol, 2018, 4: 1721-1728. doi:  10.1001/jamaoncol.2018.3923
    [4] Brahmer JR, Lacchetti C, Schneider BJ, et al. Manage-ment of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline[J]. J Clin Oncol, 2018, 36: 1714-1768. doi:  10.1200/JCO.2017.77.6385
    [5] Everett J, Srivastava A, Misdraji J. Fibrin Ring Granulo-mas in Checkpoint Inhibitor-induced Hepatitis[J]. Am J Surg Pathol, 2017, 41: 134-137. doi:  10.1097/PAS.0000000000000759
    [6] De Martin E, Michot JM, Rosmorduc O, et al. Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors[J]. JHEP Rep, 2020, 2: 100170. doi:  10.1016/j.jhepr.2020.100170
    [7] Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage Ⅲ or Ⅳ Melanoma[J]. N Engl J Med, 2017, 377: 1824-1835. doi:  10.1056/NEJMoa1709030
    [8] Thompson JA, Schneider BJ, Brahmer J, et al. Manage-ment of Immunotherapy-Related Toxicities, Version 1.2019[J]. J Natl Compr Canc Netw, 2019, 17: 255-289. doi:  10.6004/jnccn.2019.0013
    [9] Yau T, Kang YK, Kim TY, et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial[J]. JAMA Oncol, 2020, 6: e204564. doi:  10.1001/jamaoncol.2020.4564
    [10] Chan SL, Yip TC, Wong VW, et al. Pattern and impact of hepatic adverse events encountered during immune checkpoint inhibitors- A territory-wide cohort study[J]. Cancer Med, 2020, 9: 7052-7061. doi:  10.1002/cam4.3378
    [11] Spigel DR, Reynolds C, Waterhouse D, et al. Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation-Positive Advanced Non-Small Cell Lung Cancer (CheckMate 370)[J]. J Thorac Oncol, 2018, 13: 682-688. doi:  10.1016/j.jtho.2018.02.022
    [12] Yang JC, Gadgeel SM, Sequist LV, et al. Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation[J]. J Thorac Oncol, 2019, 14: 553-559. doi:  10.1016/j.jtho.2018.11.028
    [13] Dougan M, Blidner AG, Choi J, et al. Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors[J]. Support Care Cancer, 2020, 28: 6129-6143. doi:  10.1007/s00520-020-05707-3
    [14] Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-rando-mised, open-label phase 2 trial[J]. Lancet Oncol, 2018, 19: 940-952. doi:  10.1016/S1470-2045(18)30351-6
    [15] Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial[J]. Lancet, 2019, 393: 1819-1830. doi:  10.1016/S0140-6736(18)32409-7
    [16] Reynolds K, Thomas M, Dougan M. Diagnosis and Management of Hepatitis in Patients on Checkpoint Blockade[J]. Oncologist, 2018, 23: 991-997. doi:  10.1634/theoncologist.2018-0174
    [17] Tsung I, Dolan R, Lao CD, et al. Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy[J]. Aliment Pharmacol Ther, 2019, 50: 800-808. doi:  10.1111/apt.15413
    [18] Tison A, Quéré G, Misery L, et al. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Preexisting Autoimmune Disease: A Nationwide Multicenter Cohort Study[J]. Arthritis Rheumatol, 2019, 71: 2100-2111. doi:  10.1002/art.41068
    [19] Argentiero A, Solimando AG, Ungaro V, et al. Case Report: Lymphocytosis Associated With Fatal Hepatitis in a Thymoma Patient Treated With Anti-PD1: New Insight Into the Immune-Related Storm[J]. Front Oncol, 2020, 10: 583781. doi:  10.3389/fonc.2020.583781
    [20] 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]. J Immunother Cancer, 2017, 5: 95. doi:  10.1186/s40425-017-0300-z
    [21] Anderson MA, Kurra V, Bradley W, et al. Abdominal immune-related adverse events: detection on ultrasonography, CT, MRI and 18F-Fluorodeoxyglucose positron emission tomography[J]. Br J Radiol, 2021, 94: 20200663. doi:  10.1259/bjr.20200663
    [22] Haanen JBAG, Carbonnel F, Robert C, et al. Manage-ment of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2018, 29: iv264-iv266. doi:  10.1093/annonc/mdy162
    [23] Hasegawa S, Ikesue H, Nakao S, et al. Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database[J]. Pharmacoepidemiol Drug Saf, 2020, 29: 1279-1294. doi:  10.1002/pds.5108
    [24] Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020[J]. J Natl Compr Canc Netw, 2020, 18: 230-241. doi:  10.6004/jnccn.2020.0012
    [25] 中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)免疫检查点抑制剂相关的毒性管理指南2019[M]. 北京: 人民卫生出版社, 2019: 1-116.
    [26] Kurokawa K, Hara M, Iwakami SI, et al. Cholestatic Liver Injury Induced by Pembrolizumab in a Patient with Lung Adenocarcinoma[J]. Intern Med, 2019, 58: 3283-3287. doi:  10.2169/internalmedicine.2591-18
    [27] Ziogas DC, Gkoufa A, Cholongitas E, et al. When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report[J]. J Immunother Cancer, 2020, 8: e001322. doi:  10.1136/jitc-2020-001322
    [28] Riveiro-Barciela M, Muñoz-Couselo E, Fernandez-Sojo J, et al. Acute liver failure due to immune-mediated hepatitis successfully managed with plasma exchange: New settings call for new treatment strategies?[J]. J Hepatol, 2019, 70: 564-566. doi:  10.1016/j.jhep.2018.10.020
    [29] Dougan M. Gastrointestinal and Hepatic Complications of Immunotherapy: Current Management and Future Perspec-tives[J]. Curr Gastroenterol Rep, 2020, 22: 15. doi:  10.1007/s11894-020-0752-z
    [30] Zhang D, Hart J, Ding X, et al. Histologic patterns of liver injury induced by anti-PD-1 therapy[J]. Gastroenterol Rep (Oxf), 2019, 8: 50-55. http://www.researchgate.net/publication/341764431_Histologic_patterns_of_liver_injury_induced_by_anti-PD-1_therapy
    [31] Zen Y, Yeh MM. Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy[J]. Semin Diagn Pathol, 2019, 36: 434-440. doi:  10.1053/j.semdp.2019.07.009
    [32] 梁庆升, 孙颖, 邹正升. 药物性肝损伤与自身免疫性肝炎[J]. 肝脏, 2019, 24: 577-580. https://www.cnki.com.cn/Article/CJFDTOTAL-ZUAN201905033.htm
    [33] De Martin E, Michot JM, Papouin B, et al. Characteriza-tion of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors[J]. J Hepatol, 2018, 68: 1181-1190. doi:  10.1016/j.jhep.2018.01.033
    [34] Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center[J]. J Clin Oncol, 2015, 33: 3193-3198. doi:  10.1200/JCO.2015.60.8448
    [35] Faje AT, Lawrence D, Flaherty K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma[J]. Cancer, 2018, 124: 3706-3714. doi:  10.1002/cncr.31629
    [36] Scott SC, Pennell NA. Early Use of Systemic Corticoste-roids in Patients with Advanced NSCLC Treated with Nivolumab[J]. J Thorac Oncol, 2018, 13: 1771-1775. doi:  10.1016/j.jtho.2018.06.004
    [37] Cheung V, Gupta T, Payne M, et al. Immunotherapy-related hepatitis: real-world experience from a tertiary centre[J]. Frontline Gastroenterol, 2019, 10: 364-371. doi:  10.1136/flgastro-2018-101146
    [38] Miller ED, Abu-Sbeih H, Styskel B, et al. Clinical characteristics and adverse impact of hepatotoxicity due to immune checkpoint inhibitors[J]. Am J Gastroenterol, 2020, 115: 251-261. doi:  10.14309/ajg.0000000000000398
    [39] Chmiel KD, Suan D, Liddle C, et al. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy[J]. J Clin Oncol, 2011, 29: e237-e240. doi:  10.1200/JCO.2010.32.2206
    [40] Onishi S, Tajika M, Bando H, et al. Ursodeoxycholic acid and bezafibrate were useful for steroid-refractory, immune-related hepatitis: a case report[J]. J Med Case Rep, 2020, 14: 230. doi:  10.1186/s13256-020-02541-3
    [41] Perez-Ruiz E, Minute L, Otano I, et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy[J]. Nature, 2019, 569: 428-432. doi:  10.1038/s41586-019-1162-y
    [42] Yamada Y, Kirillova I, Peschon JJ, et al. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor[J]. Proc Natl Acad Sci U S A, 1997, 94: 1441-1446. doi:  10.1073/pnas.94.4.1441
    [43] Stroud CR, Hegde A, Cherry C, et al. Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade[J]. J Oncol Pharm Pract, 2019, 25: 551-557. doi:  10.1177/1078155217745144
    [44] Biehl A, Harinstein L, Brinker A, et al. A case series analysis of serious exacerbations of viral hepatitis and non-viral hepatic injuries in tocilizumab-treated patients[J]. Liver Int, 2021, 41: 515-528. doi:  10.1111/liv.14766
    [45] Santini FC, Rizvi H, Plodkowski AJ, et al. Safety and Efficacy of Re-treating with Immunotherapy after Immune-Related Adverse Events in Patients with NSCLC[J]. Cancer Immunol Res, 2018, 6: 1093-1099. doi:  10.1158/2326-6066.CIR-17-0755
    [46] Li M, Sack JS, Rahma OE, et al. Outcomes after resumption of immune checkpoint inhibitor therapy after high-grade immune-mediated hepatitis[J]. Cancer, 2020, 126: 5088-5097. doi:  10.1002/cncr.33165
    [47] De Martin E, Michot JM, Papouin B, et al. Reply to: "Acute liver failure due to immune-mediated hepatitis successfully managed with plasma exchange: New settings call for new treatment strategies?"[J]. J Hepatol, 2019, 70: 566-567. doi:  10.1016/j.jhep.2018.11.016
    [48] von Itzstein MS, Khan S, Gerber DE. Investigational Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Event Prediction and Diagnosis[J]. Clin Chem, 2020, 66: 779-793. doi:  10.1093/clinchem/hvaa081
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