OVERVIEW

CASE REPORT

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Ipilimumab – Yervoy®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

CITED REFERENCES

1.

Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–40. [Case 5.] [PMC free article: PMC3792485] [PubMed: 22434096]

ANNOTATED BIBLIOGRAPHY

References updated: 23 June 2022

Abbreviations used: CPI, checkpoint inhibitor; CTLA-4, cytotoxic T lymphocyte associated antigen 4; HCC, hepatocellular carcinoma; irAE, immune related adverse event; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death receptor ligand-1; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

• Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 517-54.

  (Expert review of hepatotoxicity published in 1999; well before the availability of most monoclonal antibody therapies).
• Reuben A. Biological immunosuppressives. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 580-2.

  (Review of hepatotoxicity of immunosuppressive agents; mentions that "the biological immunosuppressants are largely free from hepatotoxicity, with the exception of the TNF alpha antagonists"; ipilimumab is not specifically discussed).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Danan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2011/125377Orig1s000SumR.pdf.

  (FDA website with current and previous product labels and the initial 2011 multidisciplinary review of the new drug application for ipilimumab).
• Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372–7. [PMC free article: PMC166236] [PubMed: 12826605]

  (Initial study of anti-CTLA-4 therapy in 14 patients with melanoma, 6 of whom developed clinically apparent immune adverse reactions, including one with hepatitis arising after the third infusion [ALT 6820 U/L], resolving over the ensuing 4 months with corticosteroid therapy: Case 1).
• O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, 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. [PubMed: 20147741]

  (In a clinical trial of ipilimumab in 155 patients with metastatic melanoma, 109 patients [70%] suffered an immune related adverse event, including 14 [9%] with a liver related event, 2 of which were severe and 1 fatal).
• Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. [PMC free article: PMC3549297] [PubMed: 20525992]

  (Controlled trial of ipilimumab vs a glycoprotein-100 vaccine vs both in 676 patients with metastatic melanoma from 125 centers in 13 countries found ipilimumab therapy prolonged median survival from 6.4 to 10.0 months, but that adverse events were common and usually immune mediated; ALT elevations [>5 times ULN] occurred in 0.5-0.8% of ipilimumab treated patients, but in none of controls).
• Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin Oncol. 2010;37:499–507. [PubMed: 21074065]

  (Review of immune related adverse events including hepatitis associated with ipilimumab therapy; recommends stopping therapy for grade 3 toxicity [ALT >5 times ULN] and initiating corticosteroids for at least 30 days).
• Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26. [PubMed: 21639810]

  (Trial of ipilimumab and dacarbazine vs dacarbazine alone in 502 patients with metastatic melanoma found ALT elevations in 33% on the combination vs 6% on dacarbazine alone, and ALT values above 5 times ULN in 16% vs 0.7%, but no deaths due to liver failure).
• Ipilimumab (Yervoy) for metastatic melanoma. Med Lett Drugs Ther. 2011;53(1367):51–2. [PubMed: 21701442]

  (Concise review of the pharmacology, efficacy and safety of ipilimumab as therapy of metastatic melanoma shortly after its approval in the US; common side effects are diarrhea, nausea, fatigue, pruritus, rash and colitis; immune related side effects can include hepatitis; cost of a single dose averages $30,000).
• Chmiel KD, Suan D, Liddle C, Nankivell B, Ibrahim R, Bautista C, Thompson J, Fulcher D, Kefford R. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. J Clin Oncol. 2011;29:e237–40. [PubMed: 21220617]

  (61 year old man with melanoma developed fever and rash 10 days after a second dose of ipilimumab [bilirubin 1.2 mg/dL, ALT 2521 U/L, Alk P 275 U/L, ANA negative], rapidly improving on high doses of methylprednisolone, but relapsing when dose was reduced [bilirubin peak 3.8, ALT 6362 U/L], ultimately responding to addition of antithymocyte globulin and mycophenylate).
• Hanaizi Z, van Zwieten-Boot B, Calvo G, Lopez AS, van Dartel M, Camarero J, Abadie E, Pignatti F. The European Medicines Agency review of ipilimumab (Yervoy) for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Eur J Cancer. 2012;48:237–42. [PubMed: 22030452]

  (Summary of safety and efficacy results of ipilimumab forming the basis of approval in Europe; ALT elevations were reported to occur in only 1-2% of patients, with onset of hepatic injury [which can be fatal] after 3-9 weeks).
• Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–40. [PMC free article: PMC3792485] [PubMed: 22434096]

  (Clinical and histological features of 5 patients with liver injury due to ipilimumab; 3 men and 2 women, ages 43 to 76 years, arising after 2-4 courses, 39-71 days after initial dose [peak bilirubin 1.5-5.1 mg/dL, ALT 326-3070 U/L, Alk P 206-427 U/L], only one had autoantibodies, resolving with immunosuppressive therapy within 1-4 months; one had recurrence on rechallenge; liver biopsies showed acute hepatitis usually with prominent inflammation, interface hepatitis and confluent necrosis: Case 1).
• Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7. [PubMed: 22614989]

  (Review of the immune related adverse events associated with ipilimumab therapy and their management mentions that hepatotoxicity occurs in 3-9% of patients, usually with asymptomatic increases in ALT and bilirubin, but some with symptoms; authors recommend use of high doses of corticosteroids for 2 days followed by tapering doses to at least 30 days, multiple courses may be necessary and ipilimumab should not be restarted).
• Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, Levy CL, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18:2039–47. [PMC free article: PMC3319861] [PubMed: 22271879]

  (Among 177 patients with metastatic melanoma treated with ipilimumab, 33 had a long term objective response and 15 a complete response).
• Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, Bergmann T, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the Ipilimumab Network. PLoS One. 2013;8:e53745. [PMC free article: PMC3544906] [PubMed: 23341990]

  (Retrospective review of adverse reactions seen in 752 patients with metastatic melanoma treated with ipilimumab in 19 major cancer centers in Europe; 120 events were summarized including 11 involving the liver, which usually presented 3-6 weeks after starting therapy, with marked elevations in serum enzymes; one fatal case described in detail).
• Anderson L, Bhatia V. Ipilimumab immune-related adverse reactions: a case report. S D Med. 2013;66(8):315–7. [PubMed: 24175496]

  (Abstract: a case of autoimmune hypophysitis during ipilimumab therapy).
• Kim KW, Ramaiya NH, Krajewski KM, Jagannathan JP, Tirumani SH, Srivastava A, Ibrahim N. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Invest New Drugs. 2013;31:1071–7. [PubMed: 23408334]

  (Six patients with ipilimumab hepatitis, ages 44 to 82 years, five men and one woman, treated with 2-4 cycles presenting with fatigue, fever and nausea [bilirubin 0.5-19.6 mg/dL, ALT 168-975 U/L], resolving within 34-147 days of stopping, many were treated with corticosteroids).
• Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365–6. [PubMed: 23550685]

  (In a pilot study of the combination of vemurafenib and ipilimumab in 10 patients with metastatic melanoma, serum ALT or AST elevations ≥5 times ULN arose within 13-36 days of starting therapy in 6 patients, all of which were asymptomatic and reversible, which resolved within 4-12 days with corticosteroid therapy, recurring in one patient on restarting ipilimumab).
• Minter S, Willner I, Shirai K. Ipilimumab-induced hepatitis C viral suppression. J Clin Oncol. 2013;31:e307–8. [PubMed: 23690418]

  (42 year old man with melanoma and chronic hepatitis C was treated with four courses of ipilimumab and had improvements in serum ALT [192 U/L to normal] and HCV RNA levels [398,938 to <12 IU/mL] during therapy that was partially sustained thereafter [ALT 39 U/L, HCV RNA 1558 IU/mL]).
• Bernardo SG, Moskalenko M, Pan M, Shah S, Sidhu HK, Sicular S, Harcharik S, et al. Elevated rates of transaminitis during ipilimumab therapy for metastatic melanoma. Melanoma Res. 2013;23:47–54. [PubMed: 23262440]

  (Among 11 patients with malignant melanoma treated with ipilimumab, 6 [54%] developed some degree of ALT elevation after 1-4 courses, but only one had values above 5 times ULN and all resolved with temporary delay in therapy).
• Weber JS, Dummer R, de Pril V, Lebbé C, Hodi FS. MDX010-20 Investigators. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119:1675–82. [PubMed: 23400564]

  (In clinical trials of ipilimumab in 676 patients with melanoma, immune related adverse events occurred in ~60% of patients arising 3-9 weeks after starting and often mild, but severe in 12% and fatal in 1%, including one case of acute liver failure).
• Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 2013;18:733–43. [PMC free article: PMC4063401] [PubMed: 23774827]

  (Thorough review of side effects of ipilimumab therapy of melanoma states that common adverse events include fatigue, nausea, vomiting, diarrhea, fever, headache, dizziness, rash and pruritus occurring in 70-88% of patients, and that hepatotoxicity occurs in 2-9% that can be self-limited, but also can be severe and require corticosteroid therapy).
• McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S. MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013;24:2694–8. [PubMed: 23942774]

  (Among 676 patients with melanoma enrolled in the phase III trial of ipilimumab, 94 [20%] survived for 2 years and 42 [16%] for 3 years; late onset immune related adverse events occurred in 11 patients [14%], but were usually mild and none were hepatic).
• Ascierto PA, Simeone E, Sileni VC, Pigozzo J, Maio M, Altomonte M, Del Vecchio M, et al. Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort. J Transl Med. 2014;12:116. [PMC free article: PMC4030525] [PubMed: 24885479]

  (Among 855 patients with melanoma treated with ipilimumab in an expanded access program, 19 [2%] developed "liver toxicity", which led to stopping therapy in 1 patient and death from hepatitis in another).
• Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17. [PMC free article: PMC5744258] [PubMed: 25891304]

  (Trial of ipilimumab with or without nivolumab in 142 patients with melanoma found higher rates of response but also side effects with the antibody combination, ALT elevations occurring in 22.3% vs 4.3% and values above 5 times ULN in 10.5% vs 0%, but there were no deaths from liver injury).
• Zimmer L, Vaubel J, Mohr P, Hauschild A, Utikal J, Simon J, Garbe C, et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma. PLoS One. 2015;10(3):e0118564. [PMC free article: PMC4356548] [PubMed: 25761109]

  (Among 53 patients with metastatic uveal melanoma treated with ipilimumab, response rates were poor and side effects were common, ALT elevations occurred in 7% and were above 5 times ULN in 4%).
• Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014;312:1744–53. [PMC free article: PMC4336189] [PubMed: 25369488]

  (Among 245 patients with metastatic melanoma treated with ipilimumab with or without sargramostim [GM-CSF] found improved objective responses with the combination and lower rates of severe adverse events, ALT elevations above 5 times ULN occurring in 5.1% vs 5.8% of patients).
• Ravi S, Spencer K, Ruisi M, Ibrahim N, Luke JJ, Thompson JA, Shirai K, et al. Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: a multicenter, retrospective case series. J Immunother Cancer. 2014;2:33. [PMC free article: PMC4195895] [PubMed: 25317333]

  (Among 9 patients with metastatic melanoma and either chronic hepatitis C [n=4] or B [n=5] treated with ipilimumab, viral levels and serum ALT levels did not change in a consistent manner; most with hepatitis B were on antiviral prophylaxis).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 cases were attributed to antineoplastic agents, one of which was due to ipilimumab).
• Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, et al. KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32. [PubMed: 25891173]

  (Among 834 patients with advance melanoma treated with pembrolizumab [Pem: 10mg/kg every 2 or 3 weeks] or ipilimumab [Ipil: 3 mg/kg every 3 weeks], 6 month progression free survival was higher with Pem [47% and 46%] than Ipil [26.5%] and adverse events were less; thyroiditis was more common with Pem, whereas colitis and hypophysitis were more common with Ipil; ALT elevations occurred in 3% [Pem] vs 3.5% [Ipil] and were above 5 times ULN in 0.2% vs 0.8%).
• Ahmed T, Pandey R, Shah B, Black J. Resolution of ipilimumab induced severe hepatotoxicity with triple immunosuppressants therapy. BMJ Case Rep. 2015;2015:bcr2014208102. [PMC free article: PMC4513455] [PubMed: 26174726]

  (50 year old woman with metastatic melanoma developed fever and liver test abnormalities after a first infusion of ipilimumab [bilirubin 0.9 rising to 1.8 mg/dL, ALT 640 to 4700 U/L, Alk P 366 to 604 U/L], treated with corticosteroids and then ATG and mycophenolate and resolving in 4 weeks, not restarted).
• Johncilla M, Misdraji J, Pratt DS, Agoston AT, Lauwers GY, Srivastava A, Doyle LA. Ipilimumab-associated Hepatitis: Clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol. 2015;39:1075–84. [PubMed: 26034866]

  (Among 11 patients with metastatic melanoma treated with ipilimumab who developed liver injury and had liver biopsy, age range 33 to 71 years, 10 men, arising after 1-4 doses, all with ALT elevations and 3 with jaundice [bilirubin 0.7 to 15.6 mg/dL, ALT 185 to 3075, Alk P 48 to 453 U/L], 9 biopsies showed panlobular or central hepatitis, one showed NASH, one cholangitis; all resolved in 2-12 weeks with corticosteroid therapy).
• Morales RE, Shoushtari AN, Walsh MM, Grewal P, Lipson EJ, Carvajal RD. Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation. J Immunother Cancer. 2015;3:22. [PMC free article: PMC4469313] [PubMed: 26082835]

  (67 year old man with liver transplant for hepatitis C developed metastatic melanoma treated with 4 doses of ipilimumab and 2 weeks later had ALT elevations without jaundice that resolved without corticosteroids or antirejection therapy).
• Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, Schmidgen MI, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:190–209. [PubMed: 27085692]

  (Review of the major immune mediated side effects of anti-PD-1 therapy, with characteristics of 11 cases of hepatitis due to pembrolizumab or nivolumab, arising 1-4 weeks after initial infusions, resolving mostly with corticosteroid therapy and stopping drugs).
• Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist. 2016;21:1230–40. [PMC free article: PMC5061539] [PubMed: 27401894]

  (Review of immune mediated adverse events from anti-PD-1 therapy and their management; ALT elevations are reported in 2-4% of patients with higher rates with combinations; recommend stopping therapy if ALT elevations are above 5 times ULN or bilirubin is raised and use of methylprednisolone, but merely delay in therapy and increased frequency of monitoring if ALT elevations are above 3 times but below 5 times ULN).
• Koelzer VH, Rothschild SI, Zihler D, Wicki A, Willi B, Willi N, Voegeli M, et al. Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors-an autopsy study. J Immunother Cancer. 2016;4:13. [PMC free article: PMC4791920] [PubMed: 26981243]

  (35 year old woman with refractory metastatic melanoma received 4 infusions of ipilimumab and 4 cyclces of nivolumab with partial response only and death, autopsy showing necrotic melanoma metastases and CD8+ T cell infiltrates in many organs, including liver).
• Spänkuch I, Gassenmaier M, Tampouri I, Noor S, Forschner A, Garbe C, Amaral T. Severe hepatitis under combined immunotherapy: resolution under corticosteroids plus anti-thymocyte immunoglobulins. Eur J Cancer. 2017;81:203–5. [PubMed: 28641200]

  (49 year old woman with metastatic melanoma developed abdominal pain after 3 cycles of ipilimumab and nivolumab [bilirubin 5.5 mg/dL, ALT 722 U/L, Alk P 449 U/L], responding slowly to methylprednisolone and ATG, and then tolerating pembrolizumab therapy without recurrence).
• Yildirim S, Deniz K, Doğan E, Başkol M, Gürsoy Ş, Özkan M. Ipilimumab-associated cholestatic hepatitis: a case report and literature review. Melanoma Res. 2017;27:380–2. [PubMed: 28489679]

  (45 year old man with refractory metastatic melanoma developed jaundice 7 days after a 4th dose of ipilimumab [bilirubin 8.5 mg/dL, ALT 96 U/L, Alk P 678 U/L, GGT 1320 U/L], resolving slowly with corticosteroid therapy).
• Tanaka R, Fujisawa Y, Sae I, Maruyama H, Ito S, Hasegawa N, Sekine I, et al. Severe hepatitis arising from ipilimumab administration, following melanoma treatment with nivolumab. Jpn J Clin Oncol. 2017;47:175–8. [PubMed: 28173241]

  (59 year old man with refractory metasatic melanoma treated with 11 doses of nivolumab developed severe hepatitis after one dose of ipilimumab with fever, chills and fatigue [bilirubin 2.1 rising to 12.6 mg/dL, ALT 1623 U/L, Alk P 1306 U/L, INR 1.45], eventually improving with high doses of methylprednisolone and mycophenolate).
• Mirza S, Hill E, Ludlow SP, Nanjappa S. Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome. Melanoma Res. 2017;27:271–3. [PubMed: 28146044]

  (46 year old man with refractory metastatic melanoma developed fever, rash and liver test abnormalities while receiving ipilimumab and nivolumab, but also 1 week after a course of levofloxacin [bilirubin and Alk P not given, ALT 116 U/L, eosinophils 1400/uL], resolving with corticosteroid therapy and stopping monoclonal antibodies).
• Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis. 2017;21:115–34. [PubMed: 27842767]

  (Review of hepatotoxicity of agents newly approved for use in the US including ipilimumab which is associated with ALT elevations in 3-9% of patients [above 5 times ULN in 0.5% to 1.5%], most of which are self-limited in course; however, clinically apparent, largely hepatocellular, injury can also occur, especially when combined with dacarbazine or vemurafenib, usually responding to corticosteroid therapy, but rare deaths from hepatic failure have been reported).
• Everett J, Srivastava A, Misdraji J. Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis. Am J Surg Pathol. 2017;41:134–7. [PubMed: 27792061]

  (Fibrin ring granulomas were found in liver biopsies from 2 patients with metastatic melanoma treated with ipilimumab who developed fever, rash and elevated liver tests after 3 infusions [bilirubin 0.5 and 0.2 mg/dL, ALT 130 and 643 U/L, Alk P 264 and 70 U/L], resolving with corticosteroid therapy).
• Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, et al. CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824–35. [PubMed: 28891423]

  (Among 905 patients with malignant melanoma after surgical resection given adjuvant therapy for at least 18 months, progression free survival was less with ipilimumab than nivolumab [60.8% vs 70.5% at 12 months] and side effects were greater [serious adverse events in 43% vs 18%] including ALT elevations [15% vs 6% which were above 5 times ULN in 5.7% vs 1.1%]).
• Koksal AS, Toka B, Eminler AT, Hacibekiroglu I, Uslan MI, Parlak E. HBV-related acute hepatitis due to immune checkpoint inhibitors in a patient with malignant melanoma. Ann Oncol. 2017;28:3103–3104. [PubMed: 28945827]

  (56 year old man with melanoma and HBsAg in serum developed liver injury 12 weeks after starting ipilimumab [bilirubin 0.7 rising to 1.9 mg/dL, ALT 246 rising to 888 U/L, HBV DNA 244,259 IU/mL], responding to tenofovir and was continued on nivolumab).
• Huffman BM, Kottschade LA, Kamath PS, Markovic SN. Hepatotoxicity after immune checkpoint inhibitor therapy in melanoma: natural progression and management. Am J Clin Oncol. 2018;41(8):760–5. [PubMed: 28749795]

  (Among 218 patients treated with various checkpoint inhibitors at the Mayo Clinic over a 5 year period, 17 developed hepatotoxicity [12 after ipilimumab alone], with onset after median of 52 days [16-151 days] and resolving mostly with corticosteroid therapy after 31 days [6-56 days]).
• Dueland S, Guren TK, Boberg KM, Reims HM, Grzyb K, Aamdal S, Julsrud L, et al. Acute liver graft rejection after ipilimumab therapy. Ann Oncol. 2017;28:2619–20. [PubMed: 28961840]

  (67 year old woman with ocular melanoma underwent liver transplantation and later had metastases to graft, developed liver test abnormalities 3 weeks after stopping immunosuppression [sirolimus and mycophenolate] and receiving one infusion of ipilimumab [ALT 750 U/L], biopsy showing acute rejection).
• 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;31:965–973. [PubMed: 29403081]

  (Liver histology in 7 cases of hepatotoxicity from checkpoint inhibitors [2 ipilimumab, 7 nivolumab] showed lobular hepatitis with prominence of CD8+ lymphocytes in most, with less eosinophilic infiltration and bile plugs than typical drug induced hepatitis and less plasma cell infiltration and portal inflammation than autoimmune hepatitis).
• Huffman BM, Kottschade LA, Kamath PS, Markovic SN. Hepatotoxicity after immune checkpoint inhibitor therapy in melanoma: natural progression and management. Am J Clin Oncol. 2018;41:760–765. [PubMed: 28749795]

  (Among 281 patients with cancer treated with checkpoint inhibitors at the Mayo Clinic over a 5 year period, 17 [6%] developed liver injury within 16 to 151 [median=52] days of starting [ipilimumab alone in 12, with nivolumab in 2 and pembrolizumab alone in 3], all with ALT elevations [59 to 2355 U/L], often with Alk P elevations [up to 1728 U/L], 6 with jaundice [bilirubin 2.5 to 15.7 mg/dL], all but one treated with corticosteroids, responding in 6-56 [median 31] days, 2 requiring a second agent [azathioprine or cycloserine], none fatal).
• Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–168. [PubMed: 29320654]

  (Review of the clinical features, outcomes, pathogenesis and therapy of immune related adverse events of checkpoint inhibitor therapy).
• Wong GL, Wong VW, Hui VW, Yip TC, Tse YK, Liang LY, Lui RN, et al. Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection. Am J Gastroenterol. 2021;116:1274–1283. [PubMed: 33560651]

  (Among 990 patients in Hong Kong with advanced malignancies treated with checkpoint inhibitors between 2014 and 2019 [397 HBsAg positive, 482 with anti-HBc or anti-HBs, 111 negative for both at baseline], 39% of HBsAg-positive vs 30% of HBsAg-negative patients developed ALT elevations during therapy, but only two cases [both HBsAg positive and on prophylaxis] were due to HBV reactivation).
• Mustafayev K, Torres H. Hepatitis B virus and hepatitis C virus reactivation in cancer patients receiving novel anticancer therapies. Clin Microbiol Infect. 2022:S1198-743X(22)00119-7. [PubMed: 35283317]

  (Review of the literature on reactivation of HBV and HCV in patients on “novel” anticancer therapy concludes that reactivation can occur with checkpoint inhibitor therapy, but largely among HBsAg positive patients and only rarely in patients with resolved hepatitis B).
• Yoo S, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Yoo C, et al. Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment. Clin Gastroenterol Hepatol. 2022;20:898–907. [PubMed: 34182151]

  (Among 3,465 patients with advanced malignancies treated with checkpoint inhibitors between 2015 and 2020 at a single referral center in Korean, 511 [15%] were HBsAg positive at baseline, reactivation of HBV occurred in 5 of 511 [1%] HBsAg positive vs none of 2,954 HBsAg negative patients, arising in 2 of 464 [0.4%] patients given prophylaxis [both having stopped antivirals] vs 3 of 47 not given prophylaxis [6.4%]; reactivation arising after 3-141 weeks [median 54 weeks] of nivolumab [n=2], pembrolizumab [n=2] or ipilimumab and nivolumab [n=1] treatment, ALT peak 53 to 1768 IU/mL, HBV DNA 6,100 to 3.9 million IU/mL, resolving with 2 to 6 weeks of starting antiviral therapy).
• De Martin E, Michot JM, Papouin B, Champiat S, Mateus C, Lambotte O, Roche B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181–1190. [PubMed: 29427729]

  (Among 536 patients treated with checkpoint inhibitors, 19 [3.5%] were referred to a liver service for high grade hepatitis and 16 underwent liver biopsy; ages 33 to 84 years, 56% female, injury arising after 1-36 [median=5] weeks and 1-36 [median=2] doses, presenting with fever in 38%, rash in 31%, ALT 266 to 3137 [460] U/L, Alk P 54 to 768 [309] U/L, bilirubin 0.4 to 19 [1.1] mg/dL, enzyme pattern most commonly being mixed, 10 patients treated with corticosteroids and 6 resolving spontaneously and no deaths).
• Pollack MH, Betof A, Dearden H, Rapazzo K, Valentine I, Brohl AS, Ancell KK, et al. Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol. 2018;29:250–255. [PMC free article: PMC5834131] [PubMed: 29045547]

  (Among 80 patients treated with checkpoint inhibitors who developed immune related adverse events requiring discontinuation who were then restarted on therapy, 31 [39%] had recurrence or toxicities requiring discontinuation again, of the 29 who had hepatitis initially, 5 had recurrence on restarting).
• Santini FC, Rizvi H, Plodkowski AJ, Ni A, Lacouture ME, Gambarin-Gelwan M, Wilkins O, et al. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res. 2018;6:1093–1099. [PMC free article: PMC6125223] [PubMed: 29991499]

  (Among 482 patients with metastatic or advanced NSCLC treated with checkpoint inhibitors at a single US referral center between 2011 and 2016, 68 [14%] developed a serious immune related adverse event [irAE] that required discontinuation of whom 38 were retreated, of whom 18 had no recurrence, 10 had recurrence of the same irAE, 10 had a new irAE [2 of which were fatal]; restarting therapy appeared to be beneficial only in those who had no tumor response before onset of the first event).
• Tian Y, Abu-Sbeih H, Wang Y. Immune checkpoint inhibitors-induced hepatitis. Adv Exp Med Biol. 2018;995:159–164. [PubMed: 30539511]

  (Review of the clinical, pathological and immunological features of liver injury associated with immune checkpoint inhibitors such as ipilimumab).
• Karamchandani DM, Chetty R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective. J Clin Pathol. 2018;71:665–671. [PubMed: 29703758]

  (Review of the gastrointestinal and hepatic adverse events of checkpoint inhibitors with focus on histopathologic features, describes three major histologic patterns: ( 1 ) panlobular hepatitis with mixed inflammatory cell infiltrates, sometimes with microgranulomas; (2) hepatitis with prominent centrilobular [zone 3] necrosis; (3) rarely with prominent biliary injury and cholestasis) .
• Johnson DB, Chandra S, Sosman JA. Immune checkpoint inhibitor toxicity in 2018. JAMA. 2018;320(16):1702–1703. [PubMed: 30286224]

  (Brief review of the immune mediated adverse effects of checkpoint inhibitors, mentions that hepatitis arises in ~1% of recipients of anti-PD-1 or anti-PD-L1 monoclonal antibodies but in as many as 10% of recipients of anti-CTLA-4 monoclonals such as ipilimumab).
• Namikawa K, Kiyohara Y, Takenouchi T, Uhara H, Uchi H, Yoshikawa S, Takatsuka S, et al. Efficacy and safety of nivolumab in combination with ipilimumab in Japanese patients with advanced melanoma: An open-label, single-arm, multicentre phase II study. Eur J Cancer. 2018;105:114–126. [PubMed: 30447539]

  (Among 30 Japanese subjects with advanced melanoma treated with nivolumab and ipilimumab, overall survival was 66% at 24 months and adverse events occurred in all patients including ALT elevations in 37% which were above 5 times ULN in 10%).
• Zhang HC, Luo W, Wang Y. Acute liver injury in the context of immune checkpoint inhibitor-related colitis treated with infliximab. J Immunother Cancer. 2019;7:47. [PMC free article: PMC6380028] [PubMed: 30777137]

  (79 year old man with metastatic prostate cancer treated 3 cycles of nivolumab and ipilimumab developed corticosteroid-refractory immune mediated enterocolitis and was treated with a single infusion of infliximab and one month later developed jaundice [bilirubin 7.5 mg/dL, ALT 291 U/L, Alk P 677 U/L, ANA negative], which was attributed to infliximab and eventually resolved without corticosteroid therapy).
• Cheung V, Gupta T, Payne M, Middleton MR, Collier JD, Simmons A, Klenerman P, et al. Immunotherapy-related hepatitis: real-world experience from a tertiary centre. Frontline Gastroenterol. 2019;10(4):364–371. [PMC free article: PMC6788136] [PubMed: 31656561]

  (Among 453 patients treated with checkpoint inhibitors for cancer between 2022 and 2018, 20 [4%] developed immune related hepatitis, with highest rates with the combination of ipilimumab and nivolumab, 18 treated with immunosuppression using corticosteroids, 8 with addition of mycophenolate and 2 with infliximab, none fatal).
• Zen Y, Yeh MM. Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019;36:434–440. [PubMed: 31358424]

  (Liver histology from 7 patients with checkpoint inhibitor [CPI] induced hepatitis [4 nivolumab, 2 ipilimumab, arising after 1-6 doses] and classical autoimmune hepatitis showed similar rates of lobular hepatitis, but less confluent necrosis with CPIs and absence of autoantibodies and IgG elevations).
• Vozy A, De Martin E, Johnson DB, Lebrun-Vignes B, Moslehi JJ, Salem JE. Increased reporting of fatal hepatitis associated with immune checkpoint inhibitors. Eur J Cancer. 2019;123:112–115. [PubMed: 31678768]

  (Review of the VigiBase registry of adverse drug reactions through September 2018 identified 531 cases of immune related hepatitis, 85% due to CPIs alone with an increase in fatality rate over time, being 14% between 2011 to 2016 and 34% in 2017-2018, time to onset median of 42 days, arising after 1-4 courses [median 2] and with concurrent other organ immune related injury in 31%, usually thyroid or skin).
• Zhang D, Hart J, Ding X, Zhang X, Feely M, Yassan L, Alpert L, et al. Histologic patterns of liver injury induced by anti-PD-1 therapy. Gastroenterol Rep (Oxf). 2019;8:50–55. [PMC free article: PMC7244961] [PubMed: 32467761]

  (Liver histology in 8 cases of immune mediated liver injury after monoclonal anti-PD-1 therapy revealed a lobular hepatitis without features of autoimmune hepatitis).
• Imoto K, Kohjima M, Hioki T, Kurashige T, Kurokawa M, Tashiro S, Suzuki H, et al. Clinical features of liver injury induced by immune checkpoint inhibitors in Japanese patients. Can J Gastroenterol Hepatol. 2019;2019:6391712. [PMC free article: PMC6935806] [PubMed: 31929981]

  (Among 343 Japanese patients with cancer treated with checkpoint inhibitors, 56 [16%] developed evidence of liver injury, arising after 21 to 94 [median=46] days, with initial ALT 39 to 136 [mean 60] U/L, Alk P 263 to 857 [471] U/L, bilirubin 0.4 to 1.0 [0.7] mg/dL, and thus a cholestatic pattern was found in most patients, and there was a low rate of high grade liver injury [3.2%] and no fatalities).
• Jennings JJ, Mandaliya R, Nakshabandi A, Lewis JH. Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies. Expert Opin Drug Metab Toxicol. 2019;15:231–244. [PubMed: 30677306]

  (Review of the incidence, clinical features, histopathology, diagnosis, grading, and management of the liver injury associated with checkpoint inhibitor therapy which occurs in up to half of patients, but ALT values above 5 times ULN in 1-20% being highest with ipilimumab and particularly when given in combination with nivolumab or other PD-1 or PD-L1 inhibitors).
• Abu-Sbeih H, Tran CN, Ge PS, Bhutani MS, Alasadi M, Naing A, Jazaeri AA, et al. Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment. J Immunother Cancer. 2019;7:118. [PMC free article: PMC6499962] [PubMed: 31053161]

  (Among 4253 patients treated with checkpoint inhibitors at the MD Anderson Cancer Center between 2010 and 2018, 25 [0.6%] developed acalculous cholecystitis attributed to the immunotherapy most frequently with anti-CTLA-4 agents alone [1.6%], than anti-PD-1/PD-L1 [0.4%] and combination [0.9%], mean age of patients was 60 years, 60% male, 64% white, median peak ALT 55 U/L, bilirubin 1.4 mg/dL, 20% underwent cholecystectomy, all recovered, 10 [40%] restarted therapy, all without recurrence).
• Mizuno K, Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Kawashima H, et al. Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies. J Gastroenterol. 2020;55:653–661. [PubMed: 32124082]

  (Among 546 patients with advanced malignancies treated with checkpoint inhibitors at two Japanese referral centers between 2014 and 2019, high grade, immune mediated liver injury occurred in 29 [5%], mean age 69 years, 73% male, mean onset 52 [range 1-273] days, after 3 [1-15] doses of ipilimumab [6%], nivolumab [54%], pembrolizumab [30%], atezolizumab [6%], durvalumab [2.4%], combination [1.3%], presenting with hepatocellular [21%], cholestatic [59%] or mixed [21%] enzyme elevations, 4 with cholangitis and biliary dilatation without obstruction, only 1 case fatal; predictive factors for injury included ipilimumab [hazard ratio 4.2]).
• Zen Y, Chen YY, Jeng YM, Tsai HW, Yeh MM. Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes. Histopathology. 2020;76:470–480. [PubMed: 31550390]

  (Description of 10 cases of second generation checkpoint inhibitor induced immune liver injury mentions 3 patterns, hepatocellular, cholestatic and granulomatous injury, the cholestatic form often with a delayed latency and poor response to corticosteroids).
• Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR. Hepatotoxicity from immune checkpoint inhibitors: a systematic review and management recommendation. Hepatology. 2020;72:315–329. [PubMed: 32167613]

  (Review of the clinical features, biochemical findings, histology, pathogenesis, diagnosis and management of immune related liver injury due to the checkpoint inhibitors).
• Li M, Sack JS, Rahma OE, Hodi FS, Zucker SD, Grover S. Outcomes after resumption of immune checkpoint inhibitor therapy after high-grade immune-mediated hepatitis. Cancer. 2020;126:5088–5097. [PMC free article: PMC7655516] [PubMed: 32888341]

  (Among 102 patients with advanced melanoma treated with checkpoint inhibitors at 3 Boston medical centers between 2010 and 2019 who developed high grade liver injury, 31 were rechallenged with a checkpoint inhibitor of whom 15 [48%] developed an immune related adverse event, but only 6 [20%] required drug discontinuation, 4 with recurrence of liver injury most commonly with ipilimumab).
• Miller ED, Abu-Sbeih H, Styskel B, Nogueras Gonzalez GM, Blechacz B, Naing A, et al. Clinical characteristics and adverse impact of hepatotoxicity due to immune checkpoint inhibitors. Am J Gastroenterol. 2020;115:251–261. [PubMed: 31789632]

  (Among 5762 recipients of checkpoint inhibitor therapy of cancer at the MD Anderson Cancer Center between 2010 and 2018, 433 [8%] developed ALT levels and 100 had levels above 5 times ULN [2%), the rate being 8% with combination therapy, 1.7% with anti-CTLA agents and 1.1% with PD1 and PDL1 blockers, the abnormalities arising after a median of 59 days; all had the checkpoint inhibitor therapy held, 67 received corticosteroids [for a median of 43 days], 3 with mycophenolate, and 31 were rechallenged after resolution of the hepatitis, of whom 8 [26%] had a recurrence).
• Kitagataya T, Suda G, Nagashima K, Katsurada T, Yamamoto K, Kimura M, Maehara O, et al. Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan. J Gastroenterol Hepatol. 2020;35:1782–1788. [PubMed: 32187734]

  (Among 202 patients with cancer treated with checkpoint inhibitors at a single referral center in Japan, 17 [8.5%] developed immune related hepatitis which was severe in 8 [4.5%] often requiring corticosteroids, 2 receiving mycophenolate as well, but none died).
• Ruggiero R, Fraenza F, Scavone C, di Mauro G, Piscitelli R, Mascolo A, Ferrajolo C, et al. Immune checkpoint inhibitors and immune-related adverse drug reactions: data from Italian Pharmacovigilance Database. Front Pharmacol. 2020;11:830. [PMC free article: PMC7295943] [PubMed: 32581796]

  (Among 2088 safety reports of check point inhibitors enrolled in an Italian pharmacovigilance registry, 801 were immune related including gastrointestinal [33%], skin [17%] and liver [2.7%] due to nivolumab [70%], pembrolizumab [11%], ipilimumab [15%], atezolizumab [4%] and avelumab [<1%]).
• Riveiro-Barciela M, Barreira-Díaz A, Vidal-González J, Muñoz-Couselo E, Martínez-Valle F, Viladomiu L, Mínguez B, et al. Immune-related hepatitis related to checkpoint inhibitors: clinical and prognostic factors. Liver Int. 2020;40:1906–1916. [PubMed: 32329119]

  (Among 414 patients treated with checkpoint inhibitors, 28 [6.8%] developed high grade liver injury but 19 were considered mild, 7 moderate, 1 severe and only 1 fatal).
• Gauci ML, Baroudjian B, Bédérède U, Zeboulon C, Delyon J, Allayous C, Madelaine I, et al. PATIO group. Severe immune-related hepatitis induced by immune checkpoint inhibitors: Clinical features and management proposal. Clin Res Hepatol Gastroenterol. 2021;45:101491. [PubMed: 32773362]

  (Among 339 patients treated at a single French referral center with checkpoint inhibitors, 21 [6.2%] developed high grade liver toxicity, including 8% [7/86] receiving ipilimumab, 3% [3/105] nivolumab, 1% [1/122] pembrolizumab and 38% [10/26] combination therapy; 13 patients received corticosteroids, all except one with severe biliary lesions recovered and 8 restarted therapy none of whom relapsed).
• Cho YA, Han JM, Kang SY, Kim DC, Youn YJ, Choi KH, Gwak HS. Analysis of risk factors for hepatotoxicity induced by immune checkpoint Inhibitors. J Immunother. 2021;44:16–21. [PubMed: 33290362]

  (Among 194 patients with cancer treated with checkpoint inhibitors at two Korean referral centers, 125 [64%] developed liver test abnormalities, more frequently in younger patients vs older [30-50 years - 80% vs 50-70 years - 72%, and >70 years - 50%] and in men than women [68% vs 58%]).
• Au M, Body A, Mant A, Nicoll A. Checkpoint inhibitor induced steroid refractory drug-induced liver injury. Intern Med J. 2021;51:810–811. [PubMed: 34047030]

  (75 year old man with metastatic melanoma developed ALT elevations [peak 451 U/L] starting 4 weeks after starting ipilimumab and nivolumab treated with corticosteroids, with a prompt improvement but relapse once predniosone was tapered [ALT 647 U/L], which responded with addition of mycophenolate).
• Ortland I, Mirjalili M, Kullak-Ublick GA, Peymani P. Drug-induced liver injury in Switzerland: an analysis of drug-related hepatic disorders in the WHO pharmacovigilance database VigiBase^TM from 2010 to 2020. Swiss Med Wkly. 2021;151:w20503. [PubMed: 34000058]

  (Among 2042 cases of drug induced liver injury reported from Switzerland to VigiBase between 2010 and 2020, average age 57 years, males and females similar proportions, 10% were fatal and the most common causes included acetaminophen [5.8%], amoxicillin/clavulanate 3.1%, esomeprazole [2.0%], atorvastatin [1.9%], and nivolumab [1.3%]).
• Yamamoto A, Yano Y, Ueda Y, Yasutomi E, Hatazawa Y, Hayashi H, Yoshida R, et al. Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers. J Cancer Res Clin Oncol. 2021;147:1747–1756. [PubMed: 33222015]

  (Among 250 patients with cancer treated with checkpoint inhibitors, 21 [9.5%] developed immune mediated liver injury, most frequently with ipilimumab [60%], ipilimumab and nivolumab [57%] compared to nivolumab alone [7%] or pembrolizumab [3%], and rates were higher in patients with melanoma [35%] compared to renal cell cancer [10%] and others).
• Purde MT, Niederer R, Wagner NB, Diem S, Berner F, Hasan Ali O, Hillmann D, et al. Presence of autoantibodies in serum does not impact the occurrence of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients. J Cancer Res Clin Oncol. 2022;148:647–656. [PMC free article: PMC8881258] [PubMed: 34874490]

  (Among 131 patients with melanoma or NSCLC treated with checkpoint inhibitors between 2016 and 2019, 11 developed high grade hepatitis [8.4%] which did not correlate with existence or titer of autoantibodies in pretreatment serum samples).