Abstract 1981: Immune related liver toxicity and potential risk factors: A case-control study
Authors: Storm Erica M. , Makraki Dimitrios , Lin Genevieve I. , Kennedy Laura C. , Shah Eshana E. , Phipps Amanda I. , Liou Iris W. , Hockenbery David , Grivas Petros , Khaki Ali R. 
Published: June 2022

Abstract
Introduction: Immune-related hepatitis (irH) is a serious but unpredictable immune-related adverse event of checkpoint inhibitor (CPI) therapy. The impact of underlying liver pathology, including liver cirrhosis or metastasis, on the incidence of irH remains poorly understood. We hypothesized that presence of underlying liver pathology would increase the risk of irH in patients with cancer treated with CPI.
Methods: We conducted a retrospective case-control study of irH in patients with cancer receiving CPI at the University of Washington/Seattle Cancer Care Alliance between 2016 and 2020. Cases of irH were first identified through relevant ICD-10 codes, followed by systematic chart review to confirm provider-documented diagnosis and biochemical criteria for ≥ grade II immune related hepatitis. Controls were matched to cases in a 2:1 ratio based on age (± 5 years), sex, time of CPI initiation (± 1 year), and available follow-up time. Cases were excluded if there were no available controls. Conditional logistic regression was used to estimate the relationship between irH, liver metastasis at CPI initiation and history of cirrhosis, and adjusted for covariates, including ECOG performance status at CPI initiation, combination (vs single agent) CPI, history of autoimmune disease, and hepatitis B or C infection.
Results: Of the 97 cases of irH identified, 43% were women and median age was 61; 45% were undergoing treatment for skin, 22% for genitourinary, 16% for lung, 8% for head/neck cancers and 5% for GI cancers including HCC. 94% of cases had metastatic disease at CPI initiation, including 27% of cases with liver metastases. Cirrhosis was present in only 4.9% (n=5) of cases. Among cases, median doses of CPI received prior to onset of irH was 2 (IQR 1-4). Biochemical liver injury presented with transaminase elevation with median peak values of AST 152 (IQR 101-316), ALT 221 (IQR 139-327), alkaline phosphatase 142 (IQR 92-330) and total bilirubin 0.9 (IQR 0.5-1.6). History of cirrhosis was associated with lower odds of irH (adjusted OR 0.15, 95% CI 0.03-0.76). Presence of liver metastasis was associated with an increased odds of irH (OR 2.61, 95% CI 1.42-4.80), although the association between irH and liver metastasis lost significance (OR 2.0, 95% CI 0.94-4.26) when adjusted for covariates, particularly combination CPI therapy.
Conclusion: We demonstrated an independent negative association between liver cirrhosis and irH, while liver metastasis was not significantly associated with increased odds of irH after adjustment for covariates. The former might be related to misattribution, low number of cases with cirrhosis, and/or potentially due to suppressed transaminase elevation due to underlying hepatocyte exhaustion. Limitations include retrospective nature, small sample size of specific case subsets, potential selection and confounding biases; our findings are hypothesis-generating and warrant external validation.
Citation Format: Erica M. Storm, Dimitrios Makraki, Genevieve I. Lin, Laura C. Kennedy, Eshana E. Shah, Amanda I. Phipps, Iris W. Liou, David Hockenbery, Petros Grivas, Ali R. Khaki. Immune related liver toxicity and potential risk factors: A case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1981.