Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study
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 per...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-10-01
|
| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923001829 |
| _version_ | 1797688370244091904 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Edmond Atallah |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T01:30:24Z |
| format | Article |
| id | doaj.art-8b947b7a752e42a3a78bb652d68d4f8f |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-03-12T01:30:24Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-8b947b7a752e42a3a78bb652d68d4f8f2023-09-12T04:16:21ZengElsevierJHEP Reports2589-55592023-10-01510100851Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort studyEdmond Atallah0Sarah J. Welsh1Brent O’Carrigan2Ana Oshaughnessy3Igboin Dolapo4Andrew S. Kerr5Joanna Kucharczak6Colin Y.C. Lee7Colin Crooks8Amy Hicks9Chenchu Ramu Chimakurthi10Ankit Rao11Hester Franks12Poulam M. Patel13Guruprasad P. Aithal14Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UKDepartment of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKDepartment of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKDepartment of Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UKDepartment of Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UKDepartment of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKDepartment of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKDepartment of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKNottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UKLeeds Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UKLeeds Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UKDepartment of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKDepartment of Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK; Centre for Cancer Sciences, Translational Medical Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, UKDepartment of Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK; Centre for Cancer Sciences, Translational Medical Sciences, Biodiscovery Institute, University of Nottingham, Nottingham, UKNottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Corresponding author. Address: Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK.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.http://www.sciencedirect.com/science/article/pii/S2589555923001829Checkpoint inhibitorsImmunotherapyImmune-mediated hepatitisHepatotoxicityDrug-induced liver injuryIncidence rate |
| spellingShingle | 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 Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study JHEP Reports Checkpoint inhibitors Immunotherapy Immune-mediated hepatitis Hepatotoxicity Drug-induced liver injury Incidence rate |
| title | Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study |
| title_full | Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study |
| title_fullStr | Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study |
| title_full_unstemmed | Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study |
| title_short | Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study |
| title_sort | incidence risk factors and outcomes of checkpoint inhibitor induced liver injury a 10 year real world retrospective cohort study |
| topic | Checkpoint inhibitors Immunotherapy Immune-mediated hepatitis Hepatotoxicity Drug-induced liver injury Incidence rate |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923001829 |
| work_keys_str_mv | AT edmondatallah incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT sarahjwelsh incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT brentocarrigan incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT anaoshaughnessy incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT igboindolapo incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT andrewskerr incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT joannakucharczak incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT colinyclee incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT colincrooks incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT amyhicks incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT chenchuramuchimakurthi incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT ankitrao incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT hesterfranks incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT poulammpatel incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy AT guruprasadpaithal incidenceriskfactorsandoutcomesofcheckpointinhibitorinducedliverinjurya10yearrealworldretrospectivecohortstudy |