Liver dysfunction is associated with poor prognosis in patients after immune checkpoint inhibitor therapy

Abstract

immune-related adverse events (irAes) are induced by immune checkpoint inhibitors (icis). Liver is one of the main target organs which irAEs occur and we investigated the influence of liver dysfunction on prognosis of patients after ICIs. From July 2014 to December 2018, 188 patients with diverse cancers who received icis (nivolumab or pembrolizumab) were enrolled. twenty-nine patients experienced liver dysfunction of any grades after ICIs. Progression-free survival (PFS) was significantly shorter in the liver dysfunction-positive group than in the liver dysfunction-negative group, and a similar result was obtained for overall survival (oS). Multiple logistic regression analysis revealed liver metastasis and alanine aminotransferase before icis were associated with a higher incidence of liver dysfunction after ICIs. Regardless of liver metastasis, PFS and OS were significantly shorter in the liver dysfunction-positive group. in conclusion, this study suggests liver dysfunction is associated with poor prognosis in patients after icis with diverse cancers. Cancer was the second most common cause of death in the last decade, and was responsible for an estimated 9.6 million deaths worldwide in 2018 1. Cancer is treated by surgical resection, radiation and chemotherapy, but the mortality rate in cancer patients is still high. Therefore, new strategies to treat cancer are needed. Recently, immunotherapy has become a mainstay of treatment of cancer. Antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligands (PD-L1/PD-L2) can modulate the immune response to cancer clearance in a various human malignancies. The PD-1 pathway operates in the tumor microenvironment, unlike CTLA-4, which mainly works in the lymph nodes 2. PD-1 interacts with its ligands on the surface of tumor cells and tumor-associated macrophages, dendritic cells, fibroblasts, and activated T cells in the immune milieu 3-6. The binding of PD-1 with its ligands block antitumor activity of T cell 7-9. Nivolumab and pembrolizumab are fully humanized immunoglobulin G4 PD-1 immune checkpoint inhibitor (ICI) antibodies that selectively block the interaction of the PD-1 receptor and its ligands 10,11. These inhibitors have significant clinical activity and have improved prognosis in multiple cancer types, including non-small-cell lung cancer, renal cell carcinoma, urothelial carcinoma, gastric cancer, head and neck squamous cell carcinoma, malignant melanoma, and hepatocellular carcinoma 11-21. Blocking immunosuppressive ligand receptor interactions enhances the anticancer effects of lymphocytes. However, these molecules are also involved in healthy immune tolerance, and therefore adverse reactions to selfantigens can occur. The adverse events caused by autoimmune reactions are currently denoted as immune-related adverse events (irAEs) to differentiate them from idiosyncratic drug-induced organ damage 22. Most patients with irAEs can be managed, but some patients treated with ICIs have died because of ir...

Risk of irAEs in patients with autoimmune diseases treated by immune checkpoint inhibitors for stage III or IV melanoma: results from a matched case–control study

“…In our study, patients with pAID had two times higher risk of developing both all-grade irAEs than controls, independently of known risk factors of irAEs, such as age, sex,27 28 the immunotherapy regimen29 and/or of disease status, such as the melanoma stage, the existence of hepatic or cerebral metastasis, the number of metastasis and the LDH values at baseline 30 31. Additionally, there were no difference between cases and controls for the body mass index values 32.…”

Association between Adverse Events and Prognosis in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab: A Multicenter Retrospective Study

“…In this study, patients who developed liver injury during atezo/beva treatments had a significantly shorter survival time than those who did not. Previous reports have shown that liver injuries are associated with poor prognosis in patients with cancer treated with ICI therapy [ 17 , 18 , 19 ]. Interestingly, the prognosis of patients with HCC with grade 1 or 2 liver injury during ICI treatments was also poor [ 20 ].…”

Negative prognostic implications of splenomegaly in nivolumab-treated advanced or recurrent pancreatic adenocarcinoma

“…A previous study had demonstrated the negative prognostic impact of liver dysfunction after ICI treatment. 21 However, liver dysfunction was rarely observed after nivolumab-based therapy in our patient population. The short duration of nivolumab use (median cycle = 3) and combination of chemotherapy ( n = 38) in the majority patients may preclude or reduce the occurrence of ICI-induced, immune-related, liver-associated adverse events.…”