Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), an immune checkpoint molecule that negatively regulates T-cell activation [1]. It is hypothesized that CTLA-4 blockade can break peripheral tolerance to tumor antigens, promoting an antitumor immune response [2]. Ipilimumab has shown durable objective responses and encouraging long-term survival in phase II trials involving patients with metastatic melanoma [3–6]. In a phase III, randomized controlled trial, ipilimumab monotherapy demonstrated a statistically significant improvement in overall survival in previously treated patients with metastatic melanoma [7]. Recently, the results of another phase III trial with ipilimumab were reported for previously untreated patients with metastatic melanoma, which showed a statistically significant improvement in overall survival for ipilimumab plus dacarbazine compared with dacarbazine alone [8]. The treatment-related adverse events (AEs) with ipilimumab therapy can be severe and life-threatening, but most are reversible with appropriate treatment [7, 8]. Treatment guidelines, which involve vigilant follow-up and early corticosteroid use, were used to manage AEs in ipilimumab clinical trials [9, 10].

The most common treatment-related AEs with ipilimumab in clinical studies were inflammatory in nature [3–8]. The inflammatory AEs that occurred with ipilimumab monotherapy primarily affected the skin and gastrointestinal tract, but to a lesser extent affected the liver and endocrine system as well [3–7]. When ipilimumab was used in combination with dacarbazine in a phase III trial [8], much higher rates of elevated aminotransferases were observed compared with prior studies. Severe liver AEs (grade C 3) were uncommon with ipilimumab monotherapy in clinical studies [3–7], but occurred at higher rates when ipilimumab was combined with dacarbazine in the phase III trial [8]. There are limited clinical descriptions of ipilimumab-related liver inflammation and only one report with biopsy findings to date [11]. We report four new cases of hepatitis in patients who received ipilimumab in clinical studies, along with a more complete histologic description of the previously reported case from the US National Cancer Institute [11].