Burden of grade 3 or 4 liver injury associated with immune checkpoint inhibitors
Lucia Parlati,
Mehdi Sakka,
Aurelia Retbi,
Samir Bouam,
Lamia Hassani,
Jean-François Meritet,
Pierre Rufat,
Dominique Bonnefont-Rousselot,
Rui Batista,
Benoit Terris,
Agnès Bellanger,
Dominique Thabut,
Aurore Vozy,
Jean-Philippe Spano,
Romain Coriat,
François Goldwasser,
Selim Aractingi,
Philippe Sogni,
Stanislas Pol,
Vincent Mallet,
Jérôme Alexandre,
Jennifer Arrondeau,
Pascaline Boudou-Rouquette,
Sixtine De Percin,
Nora Kramkimel,
Olivier Huillard,
Jeanne Chapron,
Benedicte Deau-Fischer,
Marie-Laure Brandely-Piat,
Diane Damotte,
Audrey Lupo,
Marco Alifano,
Marion Corouge,
Clémence Hollande,
Hélène Fontaine,
Lorianne Lair Mehiri,
Anaïs Vallet Pichard,
Patrick Tilleul
Affiliations
Lucia Parlati
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
Mehdi Sakka
Service de Biochimie Métabolique, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière–Charles Foix, Paris, France
Aurelia Retbi
Département d’Information Médicale, AP-HP.Sorbonne Université, DMU Esprit, Hôpitaux Universitaires Pitié Salpêtrière–Charles Foix, Paris, France
Samir Bouam
Unité d’Information Médicale, AP-HP.Centre, DMU Prime, Groupe Hospitalier Cochin Port Royal, Paris, France
Lamia Hassani
Pharmacie à Usage Intérieur, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière–Charles Foix, Paris, France
Jean-François Meritet
Service de Virologie, AP-HP.Centre, DMU Biophygen, Groupe Hospitalier Cochin Port Royal, Paris, France
Pierre Rufat
Département d’Information Médicale, AP-HP.Sorbonne Université, DMU Esprit, Hôpitaux Universitaires Pitié Salpêtrière–Charles Foix, Paris, France
Dominique Bonnefont-Rousselot
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
Rui Batista
Pharmacie Clinique, AP-HP.Centre, DMU Prime, Groupe Hospitalier Cochin Port Royal, Paris, France
Benoit Terris
Université Paris Cité, Paris, France; Service d’Anatomopathologie, AP-HP.Centre, DMU Prime, Groupe Hospitalier Cochin Port Royal, Paris, France
Agnès Bellanger
Département d’Information Médicale, AP-HP.Sorbonne Université, DMU Esprit, Hôpitaux Universitaires Pitié Salpêtrière–Charles Foix, Paris, France
Dominique Thabut
Université Paris-Sorbonne, Paris, France; Service d’Hépatogastroentérologie, AP-HP.Sorbonne Université, DMU Sapere, Hôpitaux Universitaires Pitié Salpêtrière–Charles Foix, Paris, France
Aurore Vozy
Université Paris-Sorbonne, Paris, France; Service d’Oncologie Médicale, AP-HP.Sorbonne Université, DMU Orphe, Hôpitaux Universitaires Pitié Salpêtrière–Charles Foix, Paris, France
Jean-Philippe Spano
Université Paris-Sorbonne, Paris, France; Service d’Oncologie Médicale, AP-HP.Sorbonne Université, DMU Orphe, Hôpitaux Universitaires Pitié Salpêtrière–Charles Foix, Paris, France
Romain Coriat
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
François Goldwasser
Université Paris Cité, Paris, France; Service de Cancérologie, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France
Selim Aractingi
Université Paris Cité, Paris, France; Département de Dermatologie, AP-HP.Centre, DMU Endromed, Groupe Hospitalier Cochin Port Royal, Paris, France
Philippe Sogni
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
Stanislas Pol
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
Vincent Mallet
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; Corresponding author. Address: 27 rue du Faubourg Saint Jacques 75014, Paris, France. Tel.: +33 1 58 41 30 12 (V. Mallet).
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.
