Ipilimumab is a human monoclonal antibody to cytotoxic T lymphocyte antigen-4 which acts as an immune checkpoint inhibitor increases immune reactivity and is used to treat metastatic malignant melanoma. Ipilimumab has major side effects, many of which can be serious and life threatening including acute liver injury.
Ipilimumab (ip” i lim’ ue mab) is a human recombinant monoclonal immunoglobulin G1 antibody to the cytotoxic T lymphocyte antigen-4 (CTLA-4) which is used in cancer immunotherapy. The CTLA-4 antigen is an important checkpoint molecule that modulates and down regulates T cell responses. Inhibition of CTLA on the surface of activated T cells prevents its binding to the costimulatory factor B7, which allows for a continued activation and proliferation of T cells. The subsequent enhancement of cytotoxic reactivity may play a beneficial role in cancer immunotherapy and can break immunological tolerance. In several large multicenter studies, ipilimumab therapy resulted in a prolongation of survival in patients with advanced, metastatic or unresectable malignant melanoma, and a proportion of patients had a long term remission. Ipilimumab was approved for use in advanced malignant melanoma in the United States in 2009, the first monoclonal checkpoint inhibitor approved for use in treating neoplastic diseases. Ipilimumab has also been evaluated in several other forms of cancer, including breast, colon, renal cell and pancreatic cancer, alone and in combination with other checkpoint inhibitors such as nivolumab (anti-PD-1). Ipilimumab is available in liquid solution in 50 and 200 mg vials (5 mg/mL) under the brand name Yervoy. The typical regimen is 3 mg/kg as an intravenous infusion every 3 weeks for a total of four doses. Ipililmumab is also approved for adjuvant therapy of melanoma where it is given in higher doses long term. Side effects are common and can be severe, life threatening and even fatal. As many as 70% of treated patients develop immune related side effects as a result of immune enhancement including enterocolitis, dermatitis, endocrinopathy, neuropathy, nephritis and hepatitis. Most of these reactions respond to immunosuppressive therapy. Early recognition and prompt management of these side effects is an integral component of proper use of ipilimumab.
Mild-to-moderate serum aminotransferase elevations are not uncommon (10% to 50%) during ipilimumab therapy, but are usually self-limited and resolve even with continuing cyclic therapy. Serum ALT elevations above 5 times the upper limit of normal (ULN) occur in 1% to 5% of patients, and a proportion of these individuals (~1%) develop clinically apparent liver injury that can be severe. The onset of injury is usually after 2 to 4 cycles, 3 to 9 weeks after initiation of treatment. The pattern of enzyme elevation is most frequently hepatocellular, but can be mixed, particularly at the onset of injury. Liver histology demonstrates an acute hepatitis-like pattern with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, which is compatible with an immune mediated hepatic injury. Fibrin ring granulomas have been described in some cases and considered somewhat pathognomic of ipilimumab hepatic immune injury. Despite features of immune-mediated injury, autoantibodies are usually not present. Restarting ipilimumab can result in recurrence of injury, although corticosteroid treatment may block recurrence.
The effects of anti-CTLA-4 inhibition on hepatitis B have not been reported, as enrollment criteria in the clinical trials of ipilimumab have usually excluded patients with hepatitis B or C or preexisting liver disease. However, it is possible that anti-CTLA-4 treatment would exacerbate chronic hepatitis B and C by enhancing T cell cytotoxicity to viral antigens.
Likelihood score: A (very likely cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of liver injury due to ipilimumab is likely to be immunologically mediated and some cases have appeared to respond to corticosteroid or immunosuppressive therapy, allowing for continuation of ipilimumab therapy.
Outcome and Management
Guidelines for management of patients receiving ipilimumab recommend monitoring of liver test results before starting therapy and at the time of each infusion. Corticosteroid therapy is recommended for patients who develop serum aminotransferase elevations above 5 times the ULN, initiating therapy with high doses of intravenous methylprednisolone, switching to oral prednisone after 1 to 2 days, and continuing tapering doses for at least 30 days. Most cases of hepatitis due to ipilimumab resolve with prompt institution of immunosuppressive therapy. In some more protracted and resistant instances, adding a second agent to corticosteroids, such as antithymocyte globulin, tacrolimus, azathioprine or mycophenolate mofetil, has resulted in resolution of the injury. The few fatal cases that have been reported occurred in patients who had other severe immune related adverse events (Stevens Johnson syndrome, capillary leak syndrome) or who had a delay in starting corticosteroid therapy. Restarting ipilimumab after severe liver injury requiring corticosteroid therapy is usually promptly followed by recurrence of liver injury and is not recommended.
Case 1. Clinically apparent, acute liver injury due to ipilimumab.
[Modified from Case 5 in: Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci 2012; 57: 2233-40. PubMed Citation]
A 43 year old man with metastatic melanoma developed erythema, rash and elevations in serum enzymes 3 days after a third infusion of ipilimumab. He had no history of liver disease, and all liver tests had been normal before starting ipilimumab therapy. Serum ALT was 173 U/L (4 times ULN) and Alk P 131 (1.1 times ULN), while bilirubin levels were normal. The absolute eosinophil count was raised (889/µL) and antinuclear antibody was reactive (2.4 by ELISA), but smooth muscle antibody was not present, and immunoglobulin levels were normal. Over the next few days, liver tests worsened with ALT rising to 2860 U/L, Alk P 410 U/L and total bilirubin 2.2 mg/dL. A liver biopsy showed an acute hepatitis superimposed upon fatty liver disease with steatosis, slight ballooning degeneration, occasional Mallory bodies and slight fibrosis. Initiation of oral prednisone therapy was followed by a slow improvement in enzymes, which fell into the normal range approximately 5 months after onset. Prednisone was later stopped without recurrence of liver injury. He died of progressive metastatic melanoma one year later.
|Pattern:|| Mixed initially (R=3.7), hepatocellular at peak (R=20.2)|
|Severity:||1+ (symptoms and liver enzyme elevations without frank jaundice)|
|Other medications:||None mentioned|
The clinical presentation 10 days after a third infusion of ipilimumab and approximately 90 days after starting therapy was typical of the hepatic injury from this monoclonal antibody. Despite discontinuing further infusions, the liver injury worsened and was eventually treated with low doses of corticosteroids, with a slow but eventually complete response.
Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available for review. Most of these reference cases are from
the Drug-Induced Liver Injury Network, but others are from users of LiverTox who have submitted data from an actual clinical case. All cases have been reviewed and cleared
of personal identifiers and a brief comment added by the LiverTox editors. Click on the following link to view the submitted case reports that have been made publically available.
REPRESENTATIVE TRADE NAMES
Ipilimumab – Yervoy®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO.
References updated: 16 February 2018
Abbreviations: CTLA-4, cytotoxic T lymphocyte-associated antigen-4; PD-1, programmed cell death receptor-1.
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Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci 2012; 57: 2233-40. PubMed Citation (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 to 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).
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Minter S, Willner I, Shirai K. Ipilimumab-induced hepatitis C viral suppression. J Clin Oncol 2013; 31: e307-8. PubMed Citation (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]).
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PubMed Citation (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%).
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MI, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal
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2016; 4: 13. PubMed Citation (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 Citation (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).
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PubMed Citation (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).
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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 Citation (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).
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