학술논문
Burden of grade 3 or 4 liver injury associated with immune checkpoint inhibitors.
Document Type
Academic Journal
Author
Parlati L; Université Paris Cité, Paris, France.; Service de Maladies du foie, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France.; Sakka M; Service de Biochimie Métabolique, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.; Retbi A; Département d'Information Médicale, AP-HP.Sorbonne Université, DMU Esprit, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.; Bouam S; Unité d'Information Médicale, AP-HP.Centre, DMU Prime, Groupe Hospitalier Cochin Port Royal, Paris, France.; Hassani L; Pharmacie à Usage Intérieur, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.; Meritet JF; Service de Virologie, AP-HP.Centre, DMU Biophygen, Groupe Hospitalier Cochin Port Royal, Paris, France.; Rufat P; Département d'Information Médicale, AP-HP.Sorbonne Université, DMU Esprit, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.; Bonnefont-Rousselot D; Université Paris Cité, Paris, France.; Service de Biochimie Métabolique, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.; CNRS, INSERM, UTCBS, Paris, France.; Batista R; Pharmacie Clinique, AP-HP.Centre, DMU Prime, Groupe Hospitalier Cochin Port Royal, Paris, France.; Terris B; Université Paris Cité, Paris, France.; Service d'Anatomopathologie, AP-HP.Centre, DMU Prime, Groupe Hospitalier Cochin Port Royal, Paris, France.; Bellanger A; Département d'Information Médicale, AP-HP.Sorbonne Université, DMU Esprit, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.; Thabut D; Université Paris-Sorbonne, Paris, France.; Service d'Hépatogastroentérologie, AP-HP.Sorbonne Université, DMU Sapere, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.; Vozy A; Université Paris-Sorbonne, Paris, France.; Service d'Oncologie Médicale, AP-HP.Sorbonne Université, DMU Orphe, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.; Spano JP; Université Paris-Sorbonne, Paris, France.; Service d'Oncologie Médicale, AP-HP.Sorbonne Université, DMU Orphe, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.; Coriat R; Université Paris Cité, Paris, France.; Service de Gastroentérologie et Oncologie Digestive, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France.; Goldwasser F; Université Paris Cité, Paris, France.; Service de Cancérologie, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France.; Aractingi S; Université Paris Cité, Paris, France.; Département de Dermatologie, AP-HP.Centre, DMU Endromed, Groupe Hospitalier Cochin Port Royal, Paris, France.; Sogni P; Université Paris Cité, Paris, France.; Service de Maladies du foie, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France.; Pol S; Université Paris Cité, Paris, France.; Service de Maladies du foie, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France.; Mallet V; Université Paris Cité, Paris, France.; Service de Maladies du foie, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France.
Source
Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101761237 Publication Model: eCollection Cited Medium: Internet ISSN: 2589-5559 (Electronic) Linking ISSN: 25895559 NLM ISO Abbreviation: JHEP Rep Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
Background & Aims: There is concern about the burden of liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs).
Methods: In a retrospective cohort study, we evaluated the likelihood of grade 3/4 liver injury, of grade 3/4 cholestatic liver injury, and of liver failure, as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5, following treatment with ICIs. We compared these occurrences with a group of cancer patients who were propensity-matched and treated with conventional chemotherapy. For all ICI patients experiencing grade 3/4 liver injury, we conducted a causality assessment using the RUCAM method and examined patient outcomes.
Results: Among 952 patients (median [IQR] age 66 [57-73] years, 64% males) who were treated with ICI between January 1, 2015, and December 31, 2019, a total of 86 (9%) progressed to grade 3/4 liver injury, and liver failure was not observed. Anti-PD-(L)1/anti-CTLA-4 antibodies combinations (adjusted hazard ratio 3.36 [95% CI: 1.67-6.79]; p < 0.001), and chronic hepatitis B (adjusted hazard ratio 5.48 [95% CI: 1.62-18.5]; p = 0.006], were independent risk factors. Liver injury was attributed to ICI treatment in 19 (2.0%) patients. Patients with ICI toxicity typically presented with granulomatous hepatitis or cholangiocyte inflammation. ICI withdrawal was associated with cancer progression and mortality. Re-introduction of ICI was not associated with recurrent grade 3/4 liver injury. Compared with matched patients treated with conventional, non-ICI-based chemotherapy, anti-PD-(L)1/anti-CTLA-4 combinations ( p < 0.001) and anti-PD-(L)1 monotherapies ( p = 0.053) increased the risk of grade 3/4 liver injury and of grade 3/4 cholestatic liver injury, respectively.
Conclusions: An increased risk of grade 3/4 liver injury under anti-PD-(L)1/anti-CTLA-4 antibodies was observed, whereas no substantial increase in the likelihood of liver failure occurred even after treatment reintroduction.
Impact and Implications: There is concern about liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs). We investigated the burden of grade 3/4 liver injury after treatment with ICIs in a multicentric cohort of patients with cancer. Overall, a 9% incidence of grade 3/4 liver injury was detected after ICIs, and direct ICI hepatotoxicity was demonstrated in 2% of patients. Anti-PD-(L)1/Anti-CTLA-4 antibody combinations, and chronic HBV infection were independent risk factors. ICI withdrawal for grade 3/4 liver injury was associated with cancer progression. Re-introduction of ICI treatment was not associated with recurrent grade 3/4 liver injury.
Competing Interests: LP, MS, AB, JFM, SB, AR, PR, DBR, RB, BT, PT, DT, JPS, PS, SP, and VM declare no conflicts of interest. FG was supported by Fresenius Kabi; Baxter, Nutricia. Please refer to the accompanying ICMJE disclosure forms for further details.
(© 2023 The Authors.)
Methods: In a retrospective cohort study, we evaluated the likelihood of grade 3/4 liver injury, of grade 3/4 cholestatic liver injury, and of liver failure, as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5, following treatment with ICIs. We compared these occurrences with a group of cancer patients who were propensity-matched and treated with conventional chemotherapy. For all ICI patients experiencing grade 3/4 liver injury, we conducted a causality assessment using the RUCAM method and examined patient outcomes.
Results: Among 952 patients (median [IQR] age 66 [57-73] years, 64% males) who were treated with ICI between January 1, 2015, and December 31, 2019, a total of 86 (9%) progressed to grade 3/4 liver injury, and liver failure was not observed. Anti-PD-(L)1/anti-CTLA-4 antibodies combinations (adjusted hazard ratio 3.36 [95% CI: 1.67-6.79]; p < 0.001), and chronic hepatitis B (adjusted hazard ratio 5.48 [95% CI: 1.62-18.5]; p = 0.006], were independent risk factors. Liver injury was attributed to ICI treatment in 19 (2.0%) patients. Patients with ICI toxicity typically presented with granulomatous hepatitis or cholangiocyte inflammation. ICI withdrawal was associated with cancer progression and mortality. Re-introduction of ICI was not associated with recurrent grade 3/4 liver injury. Compared with matched patients treated with conventional, non-ICI-based chemotherapy, anti-PD-(L)1/anti-CTLA-4 combinations ( p < 0.001) and anti-PD-(L)1 monotherapies ( p = 0.053) increased the risk of grade 3/4 liver injury and of grade 3/4 cholestatic liver injury, respectively.
Conclusions: An increased risk of grade 3/4 liver injury under anti-PD-(L)1/anti-CTLA-4 antibodies was observed, whereas no substantial increase in the likelihood of liver failure occurred even after treatment reintroduction.
Impact and Implications: There is concern about liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs). We investigated the burden of grade 3/4 liver injury after treatment with ICIs in a multicentric cohort of patients with cancer. Overall, a 9% incidence of grade 3/4 liver injury was detected after ICIs, and direct ICI hepatotoxicity was demonstrated in 2% of patients. Anti-PD-(L)1/Anti-CTLA-4 antibody combinations, and chronic HBV infection were independent risk factors. ICI withdrawal for grade 3/4 liver injury was associated with cancer progression. Re-introduction of ICI treatment was not associated with recurrent grade 3/4 liver injury.
Competing Interests: LP, MS, AB, JFM, SB, AR, PR, DBR, RB, BT, PT, DT, JPS, PS, SP, and VM declare no conflicts of interest. FG was supported by Fresenius Kabi; Baxter, Nutricia. Please refer to the accompanying ICMJE disclosure forms for further details.
(© 2023 The Authors.)