Clinical pattern of checkpoint inhibitor-induced liver injury in a multicentre cohort
Lina Hountondji,
Christophe Ferreira De Matos,
Fanny Lebossé,
Xavier Quantin,
Candice Lesage,
Pascale Palassin,
Valérian Rivet,
Stéphanie Faure,
Georges-Philippe Pageaux,
Éric Assenat,
Laurent Alric,
Amel Zahhaf,
Dominique Larrey,
Philine Witkowski Durand Viel,
Benjamin Riviere,
Selves Janick,
Stéphane Dalle,
Alexandre Thibault Jacques Maria,
Thibaut Comont,
Lucy Meunier
Affiliations
Lina Hountondji
Department of Liver Transplantation, Saint Eloi Hospital, Montpellier University Hospital, Montpellier, France
Christophe Ferreira De Matos
Department of Internal Medicine, IUCT-Oncopole, Toulouse University Hospital, Toulouse, France
Fanny Lebossé
Department of Hepatology, Croix Rousse Hospital, Lyon Liver Institute, Hospices Civils of Lyon, Lyon, France
Xavier Quantin
Department of Medical Oncology, Montpellier Cancer Institute, Montpellier University Hospital, Montpellier, France
Candice Lesage
Department of Dermatology, Saint Eloi Hospital, Montpellier University Hospital, Montpellier, France
Pascale Palassin
Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France
Valérian Rivet
Department of Internal Medicine, IUCT-Oncopole, Toulouse University Hospital, Toulouse, France
Stéphanie Faure
Department of Liver Transplantation, Saint Eloi Hospital, Montpellier University Hospital, Montpellier, France
Georges-Philippe Pageaux
Department of Liver Transplantation, Saint Eloi Hospital, Montpellier University Hospital, Montpellier, France
Éric Assenat
Department of Oncology, Saint Eloi Hospital, Montpellier University Hospital, Montpellier, France
Laurent Alric
Department of Internal Medicine and Digestive Diseases, Purpan Hospital, Toulouse University Hospital, Toulouse, France
Amel Zahhaf
Department of Liver Transplantation, Saint Eloi Hospital, Montpellier University Hospital, REFHEPS, Montpellier, France
Dominique Larrey
Department of Liver Transplantation, Saint Eloi Hospital, Montpellier University Hospital, REFHEPS, Montpellier, France
Philine Witkowski Durand Viel
Internal Medicine, Beziers Hospital, France
Benjamin Riviere
Department of Pathology, Montpellier University Hospital, University of Montpellier, Montpellier, France
Selves Janick
Department of Pathology, Oncopole, Toulouse, France
Stéphane Dalle
Department of Dermatology, Lyon Sud Hospital, Lyon Cancer Institute, Hospices Civils of Lyon, Lyon, France
Alexandre Thibault Jacques Maria
Internal Medicine & Immuno-Oncology (MedI2O), Institute for Regenerative Medicine and Biotherapy (IRMB), Saint Eloi Hospital, Montpellier University Hospital, Montpellier, France
Thibaut Comont
Department of Internal Medicine, IUCT-Oncopole, Toulouse University Hospital, Toulouse, France
Lucy Meunier
Department of Liver Transplantation, Saint Eloi Hospital, Montpellier University Hospital, REFHEPS, Montpellier, France; Corresponding author. Address: Department of Liver Transplantation, Saint Eloi Hospital, Montpellier University Hospital, REFHEPS, 80 avenue Augustin Fliche, 34090 Montpellier, France. Tel: +33 4 67 33 02 24, Fax: +33 4 67 33 69 42.
Background & Aims: Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer therapy. Liver toxicity occurs in up to 25% of patients treated with ICIs. The aim of our study was to describe the different clinical patterns of ICI-induced hepatitis and to assess their outcome. Methods: We conducted a retrospective observational study of patients with checkpoint inhibitor-induced liver injury (CHILI) discussed in multidisciplinary meetings between December 2018 and March 2022 in three French centres specialised in ICI toxicity management (Montpellier, Toulouse, Lyon). The hepatitis clinical pattern was analysed by the ratio of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) (R value = (ALT/ULN)/(ALP/ULN)) for characterisation as cholestatic (R ≤2), hepatocellular (R ≥5), or mixed (2 <R <5). Results: We included 117 patients with CHILI. The clinical pattern was hepatocellular in 38.5%, cholestatic in 36.8%, and mixed in 24.8% of patients. High-grade hepatitis severity (grade ≥3 according to the Common Terminology Criteria for Adverse Events system) was significantly associated with the hepatocellular hepatitis (p <0.05). No cases of severe acute hepatitis were reported. Liver biopsy was performed in 41.9% of patients: granulomatous lesions, endothelitis, or lymphocytic cholangitis were described. Biliary stenosis occurred in eight patients (6.8%) and was significantly more frequent in the cholestatic clinical pattern (p < 0.001). Steroids alone were mainly administered to patients with a hepatocellular clinical pattern (26.5%), and ursodeoxycholic acid was more frequently used in the cholestatic pattern (19.7%) than in the hepatocellular or mixed clinical pattern (p <0.001). Seventeen patients improved without any treatment. Among the 51 patients (43.6%) rechallenged with ICIs, 12 (23.5%) developed CHILI recurrence. Conclusions: This large cohort indicates the different clinical patterns of ICI-induced liver injury and highlights that the cholestatic and hepatocellular patterns are the most frequent with different outcomes. Impact and Implications: ICIs can induce hepatitis. In this retrospective series, we report 117 cases of ICI-induced hepatitis, mostly grades 3 and 4. We find a similar distribution of the different patterns of hepatitis. ICI could be resumed without systematic recurrence of hepatitis.
