Clinical Characteristics and Adverse Impact of Hepatotoxicity due to Immune Checkpoint Inhibitors

Abstract

INTRODUCTION: We conducted this study to characterize the incidence, clinical features, treatment, and outcomes of immune checkpoint inhibitor (ICI) hepatotoxicity. METHODS: Patients who received ICIs (with either single-agent or combination regimens) from January 1, 2010, to March 31, 2018, were identified. Hepatotoxicity was defined as alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN), in the absence of an alternate cause, and categorized as grade 3 (ALT 5–20× ULN) or grade 4 (ALT >20× ULN), according to Common Terminology Criteria for Adverse Events 4.03. RESULTS: Among 5,762 patients, 100 (2%) developed hepatotoxicity, occurring in a higher proportion of recipients of combination therapy (9.2%) compared with monotherapy (up to 1.7%, P < 0.001). ICIs were discontinued permanently in 69 and temporarily in 31 patients. Sixty-seven patients received steroids, 10 of whom (14%) had recurrent hepatotoxicity after the steroid taper. Thirty-one patients resumed ICIs after ALT improvement, 8 of whom (26%) developed recurrent hepatotoxicity. Characteristics of liver injury, response to steroids, and outcomes were similar between 38 individuals with and 62 without possible pre-existing liver disease. The severity and outcome of hepatotoxicity due to combination therapy were not significantly different from monotherapy. There were 36 deaths. Two had liver failure at the time of death, both with progression of liver metastases and grade 3 hepatotoxicity. DISCUSSION: Clinically significant ICI-related hepatotoxicity was uncommon but led to permanent ICI discontinuation in the majority. ICIs were restarted in a sizable proportion of patients, most of whom did not experience recurrent hepatotoxicity.

Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance

“…A retrospective study conducted at MD Anderson Cancer Center on 5762 patients receiving ICIs found that 2% developed hepatotoxicity (especially in combination treatment), of whom 69% permanently discontinued relevant ICIs; 10 of 67 patients receiving corticosteroids had recurrent hepatotoxicity after the corticosteroid taper, and 31 patients resumed ICIs after transaminases improvement, 8 of whom (26%) developed recurrent hepatotoxicity. Notably, no differences emerged in terms of characteristics of liver injury, response to corticosteroids, and outcomes between individuals with and without possible pre-existing liver diseases [88].…”

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy

“…BILIARY TRACT CPI therapy-induced liver injury is reported in about 2% to 10% patients with CPI therapy. 45,47 The injury occurs between approximately 1 to 3 months with anti-PD-1/PD-L1 agents, and between about 3 to 9 weeks with anti-CTLA-4 agents after initiation of therapy. 45,48,49 The injury may vary with the type of CPI therapy agents used.…”

Immune Checkpoint Inhibitor Associated Hepatotoxicity in Primary Liver Cancer Versus Other Cancers: A Systematic Review and Meta‐Analysis

“…Overall incidence of all grade elevated ALT from anti-PD-1 or anti-PD-L1 in patients with primary liver cancer was 14 3A and Supplemental Figure S3). Interestingly, the incidence of allgrade elevated ALT, AST and bilirubin, and hepatobiliary disorders was statistically higher in primary liver cancer versus other cancer types (p<0.001, Table 3), but not the elevation of ALP/GGT and ir-hepatitis.…”

“…Clinically, hepatotoxicity can present with a range findings, from mild elevation of liver enzymes to hepatobiliary disorders like autoimmune hepatitis, cholangitis, jaundice and liver failure (10,11). Currently, there are several meta-analyses that have evaluated hepatotoxicity from ICIs and found a general incidence of 2-30% (7,8,(11)(12)(13)(14).…”