Severe immune-related hepatitis induced by immune checkpoint inhibitors: Clinical features and management proposal - 20/04/21

Doi : 10.1016/j.clinre.2020.06.016

Marie-Léa Gauci ^a,^b,^c, Barouyr Baroudjian ^a,^b,^c, Ulysse Bédérède ^c,^d, Charlotte Zeboulon ^a,^b,^c, Julie Delyon ^a,^b,^c, Clara Allayous ^a,^b,^c, Isabelle Madelaine ^c,^e, Pirayeh Eftekhari ^c,^f, Matthieu Resche-Rigon ^c,^d, Nicolas Poté ^c,^g,^h, Valerie Paradis ^c,^g,^h, François Durand ^c,^h,ⁱ, Céleste Lebbé ^a,^b,^c, Olivier Roux ^c,^i,^{^{1
Co-last authors.}}, Mohamed Bouattour ^j,⁎, ^{^{1
Co-last authors.}}
PATIO group^a,^b,^c,^d,^f,^g,^h,^i,^j
^a AP–HP, Département de Dermatologie, Hôpital Saint-Louis, Paris, France
^b INSERM U976, Paris, France
^c Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France
^d AP–HP, Service de Biostatistiques, Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Hôpital Saint-Louis, Paris, France
^e AP–HP, Service de Pharmacologie,Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Hôpital Saint-Louis, Paris, France
^f AP–HP, Centre Régional de Pharmacovigilance, Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Fernand Widal Hospital Paris, Paris, France
^g AP–HP, Département d’Anatomopathologie, Hôpital Beaujon Clichy, Clichy, France
^h INSERM UMR 1149, Paris, France
ⁱ AP–HP, Service d’Hépatologie et Réanimation Hépatique, Pôle des maladies de l’appareil digestif, Hôpital Beaujon, Clichy, France
^j AP–HP, Département d’Oncologie Digestive, Pôle des maladies de l’appareil digestif, Hôpital Beaujon, Clichy, France

^⁎Corresponding author.

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Highlights

•	Extension of the indication of immune checkpoint inhibitors yielded to the emergence of specific liver toxicities.
•	Liver biopsy is strongly recommended in case of grade≥3 immune-related hepatitis.
•	The place of systemic steroids and immunosuppressive agents in severe immune-related hepatitis is controversial.
•	Favorable outcomes may be achieved spontaneously and with no steroids in patients with severe immune-related hepatitis.
•	Treatment with steroids should be discussed case by case with a multidisciplinary team, taken into account the bilirubin and prothrombin levels.
•	A management algorithm for severe immune-related hepatitis is proposed.

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Summary

Background

Immune-related hepatitis (IRH) occurs in 1 to 18% of immune checkpoint inhibitor (ICI)-treated patients. Steroids are usually recommended for grade≥3 IRH, but their impact on IRH resolution and patient survival remains unclear.

Methods

We retrospectively analyzed a prospective cohort of 339 patients treated at Saint-Louis Hospital (Paris, France) with ICIs for advanced melanoma. Cases of grade≥3 IRH were collected and analyzed. Two groups were compared for their biological features and time for IRH resolution and survival: patients who received steroids (steroids group: SG) and patients who did not (nonsteroids group: NSG).

Findings

Grade≥3 IRH was observed in 21 patients. Thirteen were treated with steroids (SG), and 8 were not (NSG). The median time for toxicity resolution was 49 days in SG and 24 days in NSG (P=0.62). All but one patient showed a favorable outcome. Two-year survival was 56% in SG and 54% in NSG (P=0.83). Higher transaminase (P=0.002) and bilirubin (P=0.008) and lower prothrombin (P=0.035) levels were observed in SG than in NSG. For 8 (4 SG/4 NSG) patients, ICI was resumed without any hepatitis relapse.

Interpretation

Favorable outcomes may be achieved spontaneously and with no steroids in patients with severe IRH. Steroid initiation should be discussed in cases of high bilirubin levels and decreased prothrombin levels. ICI could be resumed without hepatitis relapse. We propose a management algorithm for grade≥3 IRH that should be validated in larger and prospective cohorts.

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Keywords : Melanoma, Cancer, Immune-related adverse events, Immune-related hepatitis, Immunotherapy, Ipilimumab

Abbreviations : AE, CD, CTCAE, CTLA-4, ESMO, ICI, IRAE, IRH, NSG, PD-1, PD-L1, SG

Plan

Grade≥3 immune-related hepatitis clinical and biological features

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Vol 45 - N° 2

Article 101491- mars 2021 Retour au numéro

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Severe immune-related hepatitis induced by immune checkpoint inhibitors: Clinical features and management proposal - 20/04/21

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