1138P - A prospective study of patients with immune checkpoint inhibitor-induced hepatitis: Management outcome and association with liver injury subtype, immune infiltration, and clinical parameters

Background

Immune-related hepatitis (ir-hepatitis) ranks among the most frequent adverse events of immune checkpoint inhibitors (ICIs). Characterizing ir-hepatitis subtypes and treatment responses can provide valuable implications for guiding treatment decisions and prognostication.

Methods

This prospective, interventional study includes 34 patients with biopsy-verified grade 3-4 ir-hepatitis. All patients received methylprednisolone 2 mg/kg for at least 72 hours. Ursodeoxycholic acid (UDCA) was added in mixed and cholestatic subtypes, and mycophenolate mofetil (MMF) in patients with insufficient response to steroids. Drug-induced liver injury (DILI) subtypes were determined using Hy's law. Multiplex immunohistochemistry (mIHC) for CD3, CD8, FoxP3, CD20, CD56/NKp46 was performed on all liver biopsies. Single-cell RNA sequencing of peripheral blood samples was used to characterize immunological responses.

Results

Twenty of 34 patients (59%) with ir-hepatitis responded to steroids, while six (18%) were steroid-unresponsive and needed treatment with MMF. Eight (24%) patients had steroid-dependent ir-hepatitis, obtaining an initial response to steroids but relapsed during tapering needing MMF. Patients with insufficient steroid-response received significantly higher accumulated doses of steroids. Alcohol consumption was the only patient characteristic significantly related to treatment outcome (p=0.042). Patients with mixed DILI were most likely to respond to steroids (72%), while only half of patients with hepatocellular and cholestatic DILI responded. Cholestatic DILI had the worst prognosis in relation to recovery from ir-hepatitis and risk of cancer progression and death. mIHC revealed significantly increased T cell infiltration including cytotoxic, helper, and regulatory T cells.

Conclusions

Almost half of the patients who developed ICI-induced ir-hepatitis had an insufficient response to steroids and needed MMF. Patients with mixed DILI were more likely to respond to steroids and UDCA, requiring lower cumulative steroid doses. MIHC revealed high T cell infiltration in the liver among patients with ir-hepatitis.

Clinical trial identification

NCT04810156.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Danish Health Agency, Novo Nordic Foundation, and Sygeforsikring Danmark Foundation.

Disclosure

R.S. Jurlander: Non-Financial Interests, Institutional, Other, Travel expenses: Pierre Fabre. K. Bol: Financial Interests, Institutional, Advisory Board: BMS, Pierre Fabre; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Other, in kind support for clinical trial: Miltenyi Biotec; Non-Financial Interests, Principal Investigator, Local PI: MSD. E. Ellebaek: Financial Interests, Personal, Invited Speaker: Pierre Fabre, BMS, Novartis, MSD, Pfizer; Other, Other, Travel and conference expenses: MSD, Pierre Fabre. I.M. Svane: Financial Interests, Personal, Advisory Board: Novartis, Mendus, Instil Bio; Financial Interests, Personal, Invited Speaker: MSD, BMS, Sanofi, Takeda; Financial Interests, Personal, Writing Engagement: MSD; Financial Interests, Personal, Stocks/Shares, Cofounder and Founder warrents: IO Biotech; Financial Interests, Institutional, Research Grant: Adaptimmune, Enara Bio, Lytix Biopharma, TILT Biotherapeutics, Asgard Therapeutics, IO Biotech; Financial Interests, Institutional, Funding: Evaxion; Financial Interests, Institutional, Other, drug for investigator driven trial: BMS; Non-Financial Interests, Principal Investigator: BMS, Roche, TILT Biotherapeutics, Lytix Biopharma, Novartis, Immunocore, MSD. All other authors have declared no conflicts of interest.