Immunosuppressant mycophenolate mofetil for patients with steroid-refractory immune-related hepatitis induced by checkpoint inhibitors in oncology

Emily Alouani; Ariane Laparra; Audrey Perret; Madonna Sakkal; Sabine Messayke; Francois-Xavier Danlos; Kaissa Ouali; Antoine Hollebecque; Caroline Even; Samy Ammari; Capucine Baldini; Stéphane Champiat; Benjamin Besse; Caroline Robert; Catherine Guettier; Didier Samuel; Olivier Lambotte; Eleonora De Martin; Jean-Marie Michot

doi:10.1016/j.ejca.2023.113313

Immunosuppressant mycophenolate mofetil for patients with steroid-refractory immune-related hepatitis induced by checkpoint inhibitors in oncology

Eur J Cancer. 2023 Nov:193:113313. doi: 10.1016/j.ejca.2023.113313. Epub 2023 Aug 26.

Authors

Emily Alouani¹, Ariane Laparra², Audrey Perret², Madonna Sakkal³, Sabine Messayke⁴, Francois-Xavier Danlos⁵, Kaissa Ouali³, Antoine Hollebecque³, Caroline Even⁶, Samy Ammari⁷, Capucine Baldini³, Stéphane Champiat³, Benjamin Besse⁶, Caroline Robert⁶, Catherine Guettier⁸, Didier Samuel⁹, Olivier Lambotte¹⁰, Eleonora De Martin⁹, Jean-Marie Michot¹¹

Affiliations

¹ Département d'Innovation Thérapeutique et Essais Précoces, Gustave Roussy - Paris-Saclay University, Villejuif, France; Digestive Medical Oncology Department, IUCT-Rangueil, Toulouse Hospital University, Toulouse, France.
² Département Interdisciplinaire d'Organisation des Parcours Patients, Gustave Roussy - Paris-Saclay University, Villejuif, France.
³ Département d'Innovation Thérapeutique et Essais Précoces, Gustave Roussy - Paris-Saclay University, Villejuif, France.
⁴ Pharmacovigilance Unit, Gustave Roussy - Paris-Saclay University, Villejuif, France.
⁵ Département d'Innovation Thérapeutique et Essais Précoces, Gustave Roussy - Paris-Saclay University, Villejuif, France; INSERM U1015 and CIC1428 BIOTHERIS, Gustave Roussy, Villejuif, France.
⁶ Department of Medical Oncology, Gustave Roussy - Paris-Saclay University, Villejuif, France.
⁷ ELSAN Department of Radiology, Institut de Cancérologie Paris Nord, Sarcelles, France; Department of Radiology, Gustave Roussy Cancer Campus, Biomaps, UMR1281 INSERM, CEA, CNRS, Université Paris-Saclay, Villejuif, France.
⁸ Department of Pathology, Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, Paris-Saclay University, UMR-S 1193, Le Kremlin Bicêtre, France.
⁹ Department of Hepatology, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Centre Hépato-Biliaire, INSERM 1193, Villejuif, France.
¹⁰ Internal Médecine Department, Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, Paris-Saclay University, Le Kremlin-Bicêtre, France; IDMIT Department, IBFJ, Centre Immunology of Viral Infections and Autoimmune Diseases, INSERM, CEA, Université Paris Saclay, Le Kremlin Bicêtre, France.
¹¹ Département d'Innovation Thérapeutique et Essais Précoces, Gustave Roussy - Paris-Saclay University, Villejuif, France; INSERM U1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France. Electronic address: jean-marie.michot@gustaveroussy.fr.

PMID: 37748398
DOI: 10.1016/j.ejca.2023.113313

Abstract

Background: Immune-checkpoint inhibitor (ICI) hepatitis, which does not improve with steroids and requires additional immunosuppressant, is defined as steroid-refractory ICI hepatitis. The outcome of patients with steroid-refractory ICI hepatitis remains poorly determined. Herein, we investigated the incidence, clinical features, and outcome of patients treated with second-line immunosuppressant for steroid-refractory ICI hepatitis.

Methods: This is a retrospective analysis of patients who presented ICI hepatitis from 1st June 2016 to 30th September 2022. Steroid-refractory ICI hepatitis was defined as no clinical and biological improvement after systemic steroid therapy ≥1 mg/kg/d. Main objectives were to assess the frequency and risk factors associated with steroid-refractory ICI hepatitis and to evaluate the efficacy of second-line immunosuppressants.

Results: In total, 130 patients with grade ≥3 ICI hepatitis were screened, of them 60 (46.2%) were treated with systemic steroids. In total, 11/130 (8.5%) had steroid-refractory hepatitis. Statistically significant factors associated with steroid-refractory hepatitis included previous liver comorbidities (54.5% versus 11.6%; p < 0.01), hyperbilirubinemia (p < 0.001), and general symptoms (fever, jaundice, ascites, and/or encephalopathy) associated with hepatitis (72.7% versus 30.8%; p = 0.015). The 11 patients with steroid-refractory hepatitis were treated with mycophenolate mofetil. In total, resolution or return to grade ≤1 for hepatitis was observed in 81.8% (9/11) of patients.

Conclusions: Steroid-refractory ICI hepatitis accounted for 8.5% of patients with grade ≥3 immune-related hepatitis and was statistically associated with previous liver comorbidities, hyperbilirubinemia, and general symptoms. Mycophenolate mofetil was a suitable option of therapy for steroid-refractory ICI hepatitis.

Keywords: Immune-checkpoint inhibitor; Immune-related adverse events; Immune-related hepatitis; Mycophenolate mofetil; Steroids.