Eleonora De Martin1, Jean-Marie Michot2, Barbara Papouin3, Stéphane Champiat2, Christine Mateus4, Olivier Lambotte5, Bruno Roche1, Teresa Maria Antonini1, Audrey Coilly1, Salim Laghouati6, Caroline Robert4, Aurélien Marabelle2, Catherine Guettier3, Didier Samuel7. 1. AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire; Univ Paris-Sud, UMR-S 1193, Université Paris-Saclay; Inserm, Unité 1193, Université Paris-Saclay; Hepatinov, Villejuif, F-94800, France. 2. Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Institut Gustave-Roussy, Université Paris-Saclay, Villejuif, France. 3. AP-HP Hôpital Bicêtre, Laboratoire Anatomie Pathologique, Le Kremlin Bicêtre, France, Université Paris Sud, UMR-S 1193, Université Paris-Saclay, France. 4. Dermatology Unit, Department of Medical Oncology, Gustave-Roussy, Paris Sud University, Villejuif, France. 5. APHP Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Université Paris Sud, CEA, DSV/iMETI, Division of Immunovirology, IDMIT, INSERM, U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre, France. 6. Unité de Pharmacovigilance, Institut Gustave-Roussy, France. 7. AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire; Univ Paris-Sud, UMR-S 1193, Université Paris-Saclay; Inserm, Unité 1193, Université Paris-Saclay; Hepatinov, Villejuif, F-94800, France. Electronic address: didier.samuel@aphp.fr.
Abstract
BACKGROUND & AIMS: Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs). METHODS: Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens. RESULTS: In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1-49) weeks and median number of immunotherapy injections was two (range, 1-36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5-1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction. CONCLUSIONS: Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration. LAY SUMMARY: Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment.
BACKGROUND & AIMS: Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs). METHODS: Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens. RESULTS: In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1-49) weeks and median number of immunotherapy injections was two (range, 1-36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5-1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction. CONCLUSIONS: Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration. LAY SUMMARY: Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment.
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