Elsevier

Journal of Hepatology

Volume 68, Issue 6, June 2018, Pages 1181-1190
Journal of Hepatology

Research Article
Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors

https://doi.org/10.1016/j.jhep.2018.01.033Get rights and content

Highlights

  • Acute hepatitis resulting from treatment of metastatic cancer with immune checkpoint inhibitors is rare.

  • Immune-mediated hepatitis diagnosis requires exclusion of all causes of hepatitis.

  • Liver histology is paramount for the diagnosis and severity evaluation of liver damage.

  • Management should be based on biological and histological severity of liver injury.

  • Immune-mediated hepatitis does not require the systematic use of corticosteroids.

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.

Introduction

Immune-modulatory therapies have dramatically improved the survival of patients with metastatic tumours.[1], [2] During the development of cancer, the immune system becomes naturally ‘tolerant’ towards cancer cells, which are seen as part of the ‘self’. This tolerance is maintained by immune checkpoint pathways that downregulate immune functions, permitting cancer cells to evade immune attacks.[3], [4] Monoclonal antibodies (mAbs) directed against regulatory immune checkpoint molecules that inhibit T cell activation enhance antitumour immunity.5 Ipilimumab, a human Ig-G1 mAb, blocks cytotoxic T lymphocyte antigen 4 (CTLA-4).6 Pembrolizumab and nivolumab, humanized IgG4 kappa and human IgG4 mAbs, respectively, block the interaction between programmed cell death protein 1 (PD-1) and the two PD ligands, PD-L1 and PD-L2, by selectively binding the PD-1 receptor.[7], [8] Durvalumab, a human IgG1 kappa mAb, targets PD-L1.9

By unbalancing the immune system, these new immunotherapies could result in immune-related adverse events (IRAEs), which mimic autoimmune conditions.10 The incidence of immune-related acute hepatitis of all grades is estimated to affect between 4% and 9% of patients treated with anti-CTLA-4 mAbs, and 18% of patients treated with the combination of anti-PD-1 and anti-CTLA-4 mAbs.[11], [12] Liver IRAEs occur more rarely with anti-PD-1 mAbs alone, with a reported incidence of 1–4% of patients.[11], [13]

The presentation of anti-CTLA-4-related hepatitis remains highly heterogeneous, with symptoms ranging from a mild rise in aspartate aminotransferase (AST) levels to the patient's death from fulminant liver failure, and pathological reports are scarce because liver biopsies are rarely performed.[12], [14] As with all IRAEs induced by cancer immunotherapy, clinical guidelines are based on the discontinuation of immunotherapy and the administration of corticosteroids (1–2 mg/kg).[15], [16] Few data are available on liver IRAEs induced by anti-PD-1/PD-L1 mAbs,16 and management recommendations are similar to those used for patients treated with anti-CTLA-4 mAbs. Given the implications of permanently discontinuing a potentially life-saving treatment, as well as the adverse effects of the long-term use of high doses of corticosteroids, it appears necessary to clarify the characteristics of these drug-induced liver injuries (DILI). We propose here a comprehensive clinical and pathological description of the hepatic IRAEs associated with immune checkpoint inhibitors, comparing the patterns observed with anti-PD-1/PD-L1 and anti-CTLA-4 treatments.

Section snippets

Patients

A pharmacovigilance register was set up to focus on the adverse effects of anti-PD-1, anti-PD-L1, and anti-CTLA-4 immunotherapy (the REISAMIC register) in 2013 at Institut Gustave-Roussy, Villejuif, France. Since the initiation of the registry, 1,425 patients have been treated with immune checkpoint inhibitors. However, patients were not systematically identified and referred to a hepatologist. To evaluate more accurately the incidence of hepatic IRAEs, the study period was limited to patients

Clinical characteristics

In the 16 patients with histologically proven immune-related hepatitis, the median age was 63 (range, 33–84) years and nine were female (56%). One patient had previous risk factors for liver disease consecutive to metabolic syndrome. Two patients had hepatic tumour metastases at the initiation of immune checkpoint inhibitors. According to the RUCAM scale, the relationship between acute hepatitis and immune checkpoint inhibitors was classified as highly probable in 14 patients (87.5%) because

Discussion

To date, there has been no large-scale review of patients with DILI resulting from the major classes of immune checkpoint inhibitor. This study examined a comprehensive serological, chronological, and histopathological data set of patients with checkpoint inhibitor hepatotoxicity. Despite the heterogeneous presentation of this type of DILI, patients receiving anti-CTLA4 mAbs had a similar presentation and distinct histological patterns compared with patients receiving anti-PD-1/PD-L1 mAbs.

Financial support

No financial support was received for this study.

Conflict of interest

These authors declare the following conflicts of interest associated with this study: J.M.M.: advisory board for BMS; S.C.: lecture and consulting fees from AstraZeneca, Bristol-Myers Squibb (BMS), Merck SHarp and Dohme (MSD), B.R., O.L.: personal fees from BMS, MSD, AstraZeneca, Genzyme, and Janssen. C.R.: consultancy for BMS, Gloxo Smith Klime (GSK), Novartis, Amgen, Merck, and Roche. D.S.: consultancy for Astellas, BMS, Gilead, LFB, MSD, Novartis, Roche, Biotest, Abbvie, and Intercept.

Please

Authors’ contributions

E.D.M., J.M.M., C.G., D.S.: study concept and design. E.D.M., J.M.M., B.P.: acquisition of data. E.D.M., J.M.M., B.P., C.G.: analysis and interpretation of data; drafting of the manuscript. S.C.: references research and critical revision of the manuscript. C.M., T.M.A., B.R., A.C., S.L.: acquisition of data. C.M., O.L., C.R., A.M., C.G., D.S.: critical revision of the manuscript.

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