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; CERTIM Research Group; DEMOSTHENES Research Group

doi:10.1016/j.jhepr.2023.100880

Burden of grade 3 or 4 liver injury associated with immune checkpoint inhibitors

JHEP Rep. 2023 Aug 12;5(12):100880. doi: 10.1016/j.jhepr.2023.100880. eCollection 2023 Dec.

Authors

Lucia Parlati^{1

2}, Mehdi Sakka³, Aurelia Retbi⁴, Samir Bouam⁵, Lamia Hassani⁶, Jean-François Meritet⁷, Pierre Rufat⁴, Dominique Bonnefont-Rousselot^{1

3

8}, Rui Batista⁹, Benoit Terris^{1

10}, Agnès Bellanger⁴, Dominique Thabut^{11

12}, Aurore Vozy^{11

13}, Jean-Philippe Spano^{11

13}, Romain Coriat^{1

14}, François Goldwasser^{1

15}, Selim Aractingi^{1

16}, Philippe Sogni^{1

2}, Stanislas Pol^{1

2}, Vincent Mallet^{1

2}; CERTIM Research Group; DEMOSTHENES Research Group

Collaborators

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

¹ Université Paris Cité, Paris, France.
² Service de Maladies du foie, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France.
³ Service de Biochimie Métabolique, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.
⁴ Département d'Information Médicale, AP-HP.Sorbonne Université, DMU Esprit, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.
⁵ Unité d'Information Médicale, AP-HP.Centre, DMU Prime, Groupe Hospitalier Cochin Port Royal, Paris, France.
⁶ Pharmacie à Usage Intérieur, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.
⁷ Service de Virologie, AP-HP.Centre, DMU Biophygen, Groupe Hospitalier Cochin Port Royal, Paris, France.
⁸ CNRS, INSERM, UTCBS, Paris, France.
⁹ Pharmacie Clinique, AP-HP.Centre, DMU Prime, Groupe Hospitalier Cochin Port Royal, Paris, France.
¹⁰ Service d'Anatomopathologie, AP-HP.Centre, DMU Prime, Groupe Hospitalier Cochin Port Royal, Paris, France.
¹¹ Université Paris-Sorbonne, Paris, France.
¹² Service d'Hépatogastroentérologie, AP-HP.Sorbonne Université, DMU Sapere, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.
¹³ Service d'Oncologie Médicale, AP-HP.Sorbonne Université, DMU Orphe, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.
¹⁴ Service de Gastroentérologie et Oncologie Digestive, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France.
¹⁵ Service de Cancérologie, AP-HP.Centre, DMU Cancérologie et Spécialités Médico-Chirurgicales, Groupe Hospitalier Cochin Port Royal, Paris, France.
¹⁶ Département de Dermatologie, AP-HP.Centre, DMU Endromed, Groupe Hospitalier Cochin Port Royal, Paris, France.

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.

Keywords: Cancer treatment protocols; Drug-induced Liver Injury; Hepatitis; Immune checkpoint inhibitors.