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 Kerr, Joanna Kucharczak, Colin Y.C. Lee, Colin Crooks, Amy Hicks, Chenchu Chimakurthi, Ankit Rao, Hester Franks, Poulam Patel, Guruprasad P. Aithal
Abstract
•Risk of checkpoint inhibitor-induced liver injury (ChILI) in real-world is higher than previously reported.•In patients receiving combination therapy regime, the risk of new onset ChILI beyond four and half months of therapy is minimal.•Female sex, lower baseline ALP and higher ALT are independent factors associated with increased risk of ChILI.•Severity of ChILI using DILI criteria is lower than that estimated by the CTCAE criteria used in oncology.•Rechallenge following ChILI is feasible; less than 10% develop recurrent liver injury that meet DILI criteria. Background and AimsCheckpoint inhibitors (CPI) are accounting for increasing number 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).MethodPrescription 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-naïve patients using multivariable logistic regression model. Consecutive patients with suspected ChILI from two other tertiary centres were adjudicated and combined for case characterization and outcomes of ChILI.ResultsOut of 432 patients received CPI over 10 years, ChILI occurred in 38 (8.8%) with an overall incidence rate of 11.5 per 1,000 patient-months (95% CI 8.2-15.8). Probability of ChILI was highest in combination therapy (32%) with 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 (CTCAE) 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.ConclusionThe risk of ChILI in real-world is higher than previously reported. Among patients receiving dual CPI, this risk falls markedly after four and half months. As CTCAE overestimates its clinical severity, case-definition, evaluation and management of ChILI should be revised to harmonise care. Checkpoint inhibitors (CPI) are accounting for increasing number 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). 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-naïve patients using multivariable logistic regression model. Consecutive patients with suspected ChILI from two other tertiary centres were adjudicated and combined for case characterization and outcomes of ChILI. Out of 432 patients received CPI over 10 years, ChILI occurred in 38 (8.8%) with an overall incidence rate of 11.5 per 1,000 patient-months (95% CI 8.2-15.8). Probability of ChILI was highest in combination therapy (32%) with 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 (CTCAE) 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. The risk of ChILI in real-world is higher than previously reported. Among patients receiving dual CPI, this risk falls markedly after four and half months. As CTCAE overestimates its clinical severity, case-definition, evaluation and management of ChILI should be revised to harmonise care.