Immunotherapy-related hepatitis: real-world experience from a tertiary centre

Abstract

ObjectiveImmune checkpoint inhibitors like anti-programmed cell death protein 1 (PD-1) drugs Nivolumab and Pembrolizumab and anti-cytotoxic T-lymphocyte associated (CTLA-4) drug Ipilimumab have become standard of care in many metastatic cancers. Immunotherapy-related hepatitis and cholangitis present a diagnostic and management challenge, being rare and incompletely characterised. We aim to report the incidence, features and treatments used for this in a real-world setting and to identify useful biomarkers, which can be used to predict effective use of steroids.DesignRetrospective review of 453 patients started on immunotherapy over 7 years.SettingTertiary hepatology and oncology centre.Patients21 patients identified with immunotherapy-related hepatotoxicity.ResultsHepatitis was most common in those receiving dual therapy (incidence 20%), with 75% of Grade 4 hepatitis cases occurring with ipilimumab-containing regimens. Corticosteroid monotherapy is first line treatment, but doses above 60 mg OD prednisolone do not demonstrate any additional benefit in time to hepatitis resolution. The alanine transaminase (ALT) reduction in steroid-responsive hepatitis is typically rapid (with a halving of ALT within 11 days). The commencement of additional immunosuppression (typically mycophenolate) appears safe and prompts a more rapid fall in ALT than corticosteroid use alone. Infliximab was safely used twice as hepatitis treatment. We also describe one patient with rare immunotherapy-induced biliary disease.ConclusionsVigilance is required for detection of immunotherapy-associated liver disease as, other than dual immunotherapy, we can identify no predictive factors for its development. Our data suggest that corticosteroid response is not dependent on the higher dosing regimens. Early escalation of immunosuppression may be of benefit in the absence of a rapid response to corticosteroids.

When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report

“…Recently, Cheung et al retrospectively compared two patient cohorts with ir-hepatitis that had been treated either with standard 50-60 mg prednisolone daily or with a higher steroid dose of 1 mg/kg/day. 34 The higher prednisolone dose did not shorten the time of ALT recovery despite the fact that the on November 6, 2020 by guest. Protected by copyright.…”

“…In support of this claim, the large recent retrospective study by Cheung et al identified 21 cases with ir-hepatitis among 453 immunotherapy-treated patients with cancer (incidence: 4%), all of whom were diagnosed and managed empirically without liver biopsy. 34 When to discontinue and when to resume immunotherapy? Given that ICPI-treated patients usually have metastatic cancer without many treatment options, the decision to temporarily withhold or permanently discontinue immunotherapy is a reasonable clinical dilemma.…”

“…5 Switching between ICPIs, from a CTLA-4 inhibitor, with high susceptibility to recurrence, toward a PD-1/PD-L1 inhibitor should also be considered. In the study by Cheung et al, 34 four patients who developed ir-hepatitis after double checkpoint inhibition underwent a rechallenge with immunotherapy when liver function abnormalities had resolved, two patients continued on nivolumab maintenance and another two changed to pembrolizumab with no sign of hepatotoxicity recurrence up to the date of publication.…”

“…http://jitc.bmj.com/ Open access group receiving this dosing regimen had a lower baseline ALT level than the group receiving the standard steroid dose. 34 Looking through the studies on steroid-resistant ir-hepatitis (table 2), high-dose pulse steroids were also tested [39][40][41] as a fast-acting immunosuppressive therapy but do not offer any significant benefit in the resolution of hepatotoxicity. It is interesting that in the case described by Nakano et al, the other immune-mediated toxicities (eg, skin rash and diarrhea) were rapidly improved by highdose pulse steroids but not the patient's hepatotoxicity.…”

“…42 Which is the optimal management of steroids-refractory irhepatitis? In the rare cases of refractoriness on steroids, many agents have been studied and appear to be effective for treating resistant ir-hepatitis, including MMF (500-1000 mg twice daily), 24 32 34 39-41 43-48 azathioprine (AZA) (1-2 mg/kg/ day), 49 50 6-mercaptopurine (6-MP) (1 mg/kg/day), 17 ciclosporin (100 mg twice daily), 50 antithymocyte globulin (ATG) (doses of 1.5 mg/kg), 39 43-45 infliximab (5 mg/ kg/dose), 34 46 tacrolimus (targeting blood levels 8-10 ng/ mL) 34 46 and tocilizumab (4 mg/kg/dose) 51 and plasmapheresis. 47 These therapies, which specifically target T cell subpopulations, are preferred since hepatic infiltration by CD8+ T lymphocytes is the main histopathology finding in ir-hepatitis.…”