Introduction: Immune-related hepatitis is an adverse effect following treatment with immune-checkpoint inhibitors, such as ipilimumab, nivolumab and pembrolizumab. International guidelines advise on the use of corticosteroids as first-line treatment, although guidance on how to treat cases resistant to corticosteroids is limited. We aimed to evaluate the presentation and management of patients with grade 3-4 immune-related hepatitis, following treatment with immune-checkpoint inhibitors for stage 4 or unresectable or stage 3 melanoma, with a particular focus on steroid-refractory cases.
Methods: A retrospective observational review of patients developing immune-related hepatitis whilst undergoing treatment with immune checkpoint inhibitors for advanced melanoma from July 2014 to February 2020 at a tertiary oncology centre.
Results: Forty-one patients developed immune-related hepatitis, of which 83% had been treated with the combination of ipilimumab and nivolumab. The median time to onset of IR-hepatitis was 47 days (range: 4-476), and the median time to peak alanine aminotransferase was 71 days (range: 4-478). Four patients had resolution of grade 3 immune-related hepatitis without the introduction of corticosteroids. A total of 37 patients were treated with corticosteroids. A total of 12 required oral treatment only and 13 were successfully managed as outpatients. Six patients had steroid-refractory immune-related hepatitis; and all received tacrolimus, with one also receiving mycophenolate mofetil and infliximab.
Conclusions: This study describes the largest UK series of immune-related hepatitis patients in the literature. We present two important deviations from current guidelines. Firstly, there is some evidence that withholding steroids is possible in grade 3-4 immune-related hepatitis. Secondly, tacrolimus can be used successfully to manage patients resistant to corticosteroids, with the early introduction most beneficial to reduce time on steroids.
Keywords: Checkpoint inhibitors; immune-related adverse events; immune-related hepatitis; melanoma; tacrolimus.