Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study

Edmond Atallah; Sarah J Welsh; Brent O'Carrigan; Ana Oshaughnessy; Igboin Dolapo; Andrew S Kerr; Joanna Kucharczak; Colin Y C Lee; Colin Crooks; Amy Hicks; Chenchu Ramu Chimakurthi; Ankit Rao; Hester Franks; Poulam M Patel; Guruprasad P Aithal

doi:10.1016/j.jhepr.2023.100851

Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study

JHEP Rep. 2023 Jul 18;5(10):100851. doi: 10.1016/j.jhepr.2023.100851. eCollection 2023 Oct.

Authors

Edmond Atallah^{1

2}, Sarah J Welsh³, Brent O'Carrigan³, Ana Oshaughnessy⁴, Igboin Dolapo⁴, Andrew S Kerr³, Joanna Kucharczak³, Colin Y C Lee³, Colin Crooks^{1

2}, Amy Hicks⁵, Chenchu Ramu Chimakurthi⁵, Ankit Rao³, Hester Franks^{4

6}, Poulam M Patel^{4

6}, Guruprasad P Aithal^{1

2}

Affiliations

¹ Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK.
² National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.
³ Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁴ Department of Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁵ Leeds Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁶ Centre for Cancer Sciences, Translational Medical Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, UK.

Abstract

Background & aims: Checkpoint inhibitors (CPI) account for increasing numbers of drug-induced liver injury (DILI) cases. We aimed to determine the incidence rate and risk factors associated with checkpoint inhibitor-induced liver injury (ChILI).

Methods: Prescription event monitoring was performed on all melanoma and renal cancer patients who received CPI at a tertiary centre between 2011 and 2021. ChILI cases were identified using the definitions, grading, and causality assessment methods validated for DILI. We assessed risk factors associated with ChILI in CPI-naive patients using multivariable logistic regression model. Consecutive patients with suspected ChILI from two other tertiary centres were adjudicated and combined for case characterisation and outcomes of ChILI.

Results: Out of 432 patients who received CPI over 10 years, ChILI occurred in 38 (8.8%) with an overall incidence rate of 11.5 per 1,000 person-months (95% CI 8.2-15.8). Probability of ChILI was highest in combination therapy (32%) and no new events occurred beyond 135 days of treatment. Risk factor analysis showed that combination therapy, female sex, higher baseline alanine transferase level and lower baseline alkaline phosphatase level were independently associated with higher risk of ChILI. In total, 99 patients were adjudicated to have ChILI from three centres. Although Common Terminology Criteria for Adverse Events classified 20 patients (20.2%) to have 'life-threatening' grade 4 hepatitis, ChILI severity was graded as mild in 45 (45.5%) and moderate in the remaining 54 (54.5%) cases.

Conclusions: The real-world risk of ChILI is higher than previously reported. Among patients receiving dual CPI, this risk falls markedly after 4.5 months. As Common Terminology Criteria for Adverse Events overestimates its clinical severity, case-definition, evaluation and management of ChILI should be revised to harmonise care.

Impact and implications: Using prescription event monitoring over a 10-year period, the incidence rate of checkpoint inhibitor induced liver injury (ChILI) based on established case definitions for drug-induced liver injury (DILI) is 11.5 per 1,000 person-months. Formal causality assessment identified an alternative cause in 19% of patients with suspected ChILI highlighting the importance of systematic evaluation by clinicians to minimise unnecessary immunosuppression. Intensity of monitoring in patients receiving combination therapy regime after 4.5 months of therapy can be reduced as the risk of new onset ChILI beyond this point is minimal. Current Common Terminology Criteria for Adverse Events (CTCAE) grading overestimates clinical severity of ChILI and hence contributes to avoidable hospitalisation.

Keywords: Checkpoint inhibitors; Drug-induced liver injury; Hepatotoxicity; Immune-mediated hepatitis; Immunotherapy; Incidence rate; Risk factors.