Editorial: Checkpoint Inhibitor-Induced Liver Injury—Time to Abandon CTCAE?

Immune checkpoint inhibitors (ICIs) are increasingly used in oncologic regimens for a wide variety of cancers with impressive improvement in patient outcomes. Checkpoint inhibitor-induced liver injury (CHILI) is one feared adverse effect of these treatments. CHILI can be heterogeneous in presentation, so it is essential to establish causality and grade the severity of injury to prognosticate and influence management [1]. The U.S. National Cancer Institute created the Common Terminology Criteria for Adverse Events (CTCAE) to grade the severity of injury from oncologic treatments [2]. However, this grading system was developed prior to the advent of widespread immunotherapy and may not adequately capture hepatic dysfunction [3]. Nonetheless, oncologic society guidelines advocate for the use of the CTCAE framework to manage ICI withdrawal and corticosteroid therapy. There is conflicting data on this approach, with some clinical evidence that patients may improve by stopping ICIs alone [4-6]. Among patients with grades 3 and 4 injury, guidelines advise against re-challenging with immunotherapy. There has been increased interest in using alternative grading scales such as the U.S. Drug-Induced Liver Injury Network (DILI-N) and the International DILI Expert Working Group (DILI-IEWG) to more accurately reflect degree of injury and guide treatment recommendations.

Within this emerging context, Hountondji and colleagues examined patients with grades 3 and 4 CHILI as defined by the CTCAE system and compared their clinical characteristics, management and outcomes against the DILI-N and DILI-IEWG framework [7]. The authors demonstrate that the CTCAE scale categorises more patients with severe CHILI compared to the DILI-N or DILI-IEWG classifications. This suggests that the CTCAE framework may prematurely limit a therapeutic opportunity for patients after an episode of an otherwise minor CHILI. The authors demonstrate that the DILI-N and DILI-IEWG models are superior at predicting true liver dysfunction and 90-day mortality compared to CTCAE.

Prior studies evaluating the scoring system for CHILI have found that CTCAE tends to overestimate the clinical severity of liver injury [1, 3]. This paper captures the key component of why DILI-N and DILI-IEWG are more sensitive grading systems compared to CTCAE—they account for true hepatic function by including INR and encephalopathy. The authors also compared these scoring systems to the venerable model for end-stage liver disease (MELD) to provide grounding. This paper advances the field by better defining CHILI outcomes in a key first step to further refine which patients currently classified as grade 3 or 4 via the CTCAE pathway may be safely re-challenged with ICIs. This is especially important given many of these patients have limited therapeutic options left. Most importantly, Hountondji et al. manage to utilise well-researched understanding of DILI within the field of hepatology to validate it in a new oncologic paradigm. We hope this will catalyse a movement towards an encouraging future for patients with advanced malignancy who suffer from CHILI.

Kelly Torosian: writing – review and editing. Shravan Dave: writing – review and editing, conceptualization, supervision.

This article is linked to Hountondji et al papers. To view these articles, visit https://doi.org/10.1111/apt.18276 and https://doi.org/10.1111/apt.18343.