Risk factors and rechallenge outcomes in severe immune-mediated hepatotoxicity: Real-world evidence from two...

Immune checkpoint inhibitors (ICIs) improve cancer outcomes but can lead to immune-mediated hepatotoxicity (IMH). Real-world data on severe IMH remain limited. This study aimed to identify risk factors and evaluate clinical outcomes, including the safety of ICIs rechallenge.

This retrospective dual-center study included patients who developed IMH after ICIs therapy at two high-volume hospitals in China. Univariable and multivariable logistic regression were used to identify independent risk factors. The timing of onset was assessed by treatment cycles, and outcomes of patients who underwent rechallenge were analyzed.

Among 408 patients with IMH, 175 had severe disease. Multivariable analysis identified hepatitis B virus (HBV) infection (OR 1.99, 95% CI 1.16-3.40), liver malignancy (OR 1.89, 95% CI 1.13-3.18), cholelithiasis (OR 2.28, 95% CI 1.41-3.71), and elevated lactate dehydrogenase (LDH) (OR 1.87, 95% CI 1.04-3.39) as independent risk factors. IMH occurred mainly within the first four ICIs cycles, with significantly earlier onset in HBV-positive patients (median 2 vs. 3 cycles, P = 0.038). Among 130 patients with grade 3 IMH, 94.6% recovered. ICIs rechallenge was performed in 65 patients after adequate recovery of liver function; 61/65 (93.8%) were able to continue ICIs, and recurrent hepatotoxicity was generally mild.

Severe IMH was independently associated with HBV infection, liver malignancy, cholelithiasis, and elevated LDH. Grade 3 IMH was largely reversible and, in selected patients with adequate liver function recovery and without severe systemic irAEs, could allow cautious and individualized ICIs rechallenge.