Hepatotoxicity After Immune Checkpoint Inhibitor Therapy in Melanoma: Natural Progression and Management

Am J Clin Oncol. 2018 Aug;41(8):760-765. doi: 10.1097/COC.0000000000000374.


Objective: To report the clinical features, treatment, and outcomes of patients with immune checkpoint inhibitor-induced hepatotoxicity.

Patients and methods: In this retrospective observational study, we identified patients with metastatic malignant melanoma seen in consultation and/or treated between March 2011 and March 2016. Hepatotoxicity was assessed using the Common Terminology Criteria for Adverse Events, v4.0.

Results: Seventeen patients were identified as having any degree of hepatotoxicity by history (grade 1 to 4). Twelve of 17 were diagnosed after ipilimumab, 3 of 17 were diagnosed after pembrolizumab, and 2 of 17 after ipilimumab combined with nivolumab. Median time from first dose of immune therapy to hepatotoxicity was 52 days. Clinical symptoms were variable: asymptomatic, fatigue, myalgias, headache, abdominal pain, nausea, vomiting, confusion, and/or jaundice. Eight patients had concurrent adverse events including colitis, hypophysitis, pneumonitis, and/or rash. Immune therapy was discontinued in all patients except 3. The patients were most commonly treated with systemic corticosteroids such as prednisone. Immunosuppression was discontinued by taper over a median of 42 days; in 3 patients steroids had to be reinitiated based on clinical or laboratory worsening of liver tests. Normalization of liver tests was seen within a median of 31 days of immunosuppression initiation. One patient with grade 4 hepatotoxicity had normalization with the addition of cyclosporine.

Conclusions: Melanoma patients treated with immune checkpoint inhibitors should be monitored regularly for hepatotoxicity. Treatment with discontinuation of therapy and initiation of corticosteroids is indicated with grade 3 or 4 hepatotoxicity. Cyclosporine may be beneficial in steroid-refractory hepatotoxicity.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology
  • Chemical and Drug Induced Liver Injury / etiology*
  • Disease Management
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Humans
  • Immunotherapy / adverse effects*
  • Ipilimumab / administration & dosage
  • Male
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Melanoma / pathology
  • Middle Aged
  • Nivolumab / administration & dosage
  • Prognosis
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Retrospective Studies
  • Survival Rate
  • Young Adult


  • Antibodies, Monoclonal, Humanized
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ipilimumab
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab
  • pembrolizumab