Risk factors and outcomes for steroid-refractory immune-related hepatotoxicity in locally advanced and metastatic cancer

Immune-related hepatotoxicity (IRH) is one of the common immune-related adverse events caused by immune checkpoint inhibitors (ICIs). Some patients with steroid-refractory IRH (Ref-IRH) are potentially life-threatening. This study was designed to determine the risk factors and outcomes for Ref-IRH. Locally advanced or metastatic cancer patients who developed steroid-responsive IRH (Res-IRH) or Ref-IRH were identified between December 1, 2019 and September 1, 2024. Patient characteristics, peripheral blood biomarkers, and cytokine levels were collected. In this cohort of 480 patients treated with immune checkpoint inhibitors, 35 patients (7.3%) developed IRH, including 12 with Res-IRH and 13 with Ref-IRH. Patients with Ref-IRH were more likely to be hepatocellular carcinoma (p = 0.035), receive ICIs plus targeted therapy (p = 0.046), and have higher CTCAE grades (p = 0.044) at diagnosis. Patients with Ref-IRH had lower platelet counts (p = 0.006), higher procalcitonin levels (p = 0.012), and higher IL-6 levels (p = 0.038). Univariate logistic regression analysis indicated that higher IL-6 at diagnosis was a potential risk factor for Ref-IRH (p = 0.019). All Ref-IRH patients were treated with immunosuppressive agents. The survival outcomes of Ref-IRH were comparable to those of Res-IRH. Patients with Ref-IRH were unlikely to quickly recover with a longer time from initial diagnosis of IRH to resolution to grade 1 (p = 0.002), from peak ALT (p = 0.007), AST (p = 0.011), and TBIL (p = 0.048) to resolution to grade 1, from initial diagnosis of IRH to use of prednisone ≤ 20 mg/day (p = 0.025), and prolonged hospital length of stay (p = 0.017). In conclusion, high IL-6 at diagnosis is a potential risk factor for the development of Ref-IRH. There was no significant difference in efficacy and survival between patients with Ref-IRH and Res-IRH, but much more time from the initial diagnosis of IRH to resolution to grade 1 and the use of immunosuppressive agents is needed for Ref-IRH patients.