Management of Severe, Steroid-Resistant and Steroid-Refractory Hepatotoxicity in Patients Treated with Checkpoint Inhibitor Immunotherapy - European Medical Journal

Management of Severe, Steroid-Resistant and Steroid-Refractory Hepatotoxicity in Patients Treated with Checkpoint Inhibitor Immunotherapy

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EMJ Hepatology 10.1 Feature Image
Nashla Hamdan,1 Marco Iafolla,2 Yada Kanjanapan,2 Keyur Patel,1 Marcus Butler,2 Philippe Bedard,2 Lillian Siu,2 Anna Spreafico,2 Jordan Feld,1 *Morven Cunningham1

Cunningham has received honoraria from Janssen and AbbVie. Iafolla has consulted for Novartis; received research (clinical trials) support from Astellas Pharma Global Development Inc., AstraZeneca, Bristol-Myers Squibb, and Seagen; and received honoraria from Bayer, Canadian Urologic Association, CompassMD, Ipsen, MD Analytics, Merck, Sanofi, Save Your Skin, and Sermo Team. Kanjanapan has consulted for Novartis. Butler has consulted for Bristol-Myers Squibb, EMD Serono, GlaxoSmithKline, Immunocore, Immunovaccine, Merck, and Novartis; and has received grant/research support from Merck and Takara Bio. Siu has consulted for Arvinas, AstraZeneca/MedImmune, Celgene, GeneSeeq, GlaxoSmithKline, Loxo, Merck, Morphosys, Navire, Oncorus, Pfizer, Roche, Seattle Genetics, Symphogen, Tessa, Treadwell Therapeutics, and Voronoi; has received grant/research support from AbbVie, Amgen, Astellas, AstraZeneca/Medimmune, Avid, Bayer, Boerhinger-Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Intensity Therapeutics, Karyopharm, Merck, Mirati, Novartis, Pfizer, Roche/Genentech, Shattucks, and Symphogen; and has spousal shareholder interests in Agios and Treadwell Therapeutics. Bedard has consulted for BMS, Pfizer, and Sanofi; and has received grant/research support from AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Immunomedics, Lilly, Merck, Mersana, Nektar, Novartis, PTC Therapeutics, Sanofi, Seattle Genetics, Servier, and SignalChem. Spreafico has consulted for Bristol-Myers Squibb, Janssen, Merck, Novartis, and Oncorus; and has received grant/research support from Alkermes, Array Biopharma, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, Janssen Oncology/Johnson & Johnson, Merck, Novartis, Northern Biologics, Regeneron, Roche, Surface Oncology, and Symphogen. Feld has consulted for Abbott, AbbVie, Entanta, Gilead, and Roche; and has received grant/research support from AbbVie, Eiger, Gilead, Janssen, and Wako/Fujifilm. Hamdan and Patel have declared no conflicts of interest.

EMJ Hepatol. ;10[1]:34-36. DOI/10.33590/emjhepatol/10082046.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.


Checkpoint inhibitor immunotherapy (ICI) has revolutionised cancer care but is associated with immune-related toxicities, which may require ICI discontinuation and immunosuppressive therapies (IST). Severe ICI hepatotoxicity is treated with high-dose corticosteroids; however, 30% of patients may be steroid-refractory (no response after 48–72 hours) or steroid-resistant (rebound alanine aminotransferase [ALT] upon steroid taper).1,2 Further management for these patients is not well defined. The authors sought to better understand management of severe ICI hepatotoxicity and responses to IST.


Patients receiving ICI in early phase clinical trials at Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, or treated at the Toronto Centre for Liver Disease, Ontario, Canada, for ICI hepatotoxicity were included. Patients with Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 ICI hepatotoxicity (ALT >5 times the upper limit of normal) were identified and clinical records reviewed for management and outcomes. Patients with an alternate cause for ALT elevation, who did not receive corticosteroids, or with HCC or viral hepatitis were excluded.


Between August 2012 and December 2021, 36 patients with Grade 3 ICI hepatotoxicity were identified. Most (23; 64%) had metastatic melanoma. Thirteen received anti-CTLA-4/PD-1, 18 received anti-PD-1 or anti-PD-L1, and five received anti-CTLA-4 monotherapy. All patients initially received corticosteroids (1–2 mg/kg/day prednisone equivalent). Figure 1 shows response to corticosteroids and sequence of additional IST. Eighteen patients (50%) were poor corticosteroid responders, either steroid-refractory (four; 11%) or steroid-resistant (14; 39%). Age, sex, liver metastases, prior ICI exposure, or peak ALT did not predict steroid response, although poor responders were more likely to have been treated with combination anti-CTLA-4/PD-1 (10 [55%] of poor responders versus three [17%] of responders; p=0.04). Thirteen received steroid dose escalation (up to 2 mg/kg/day), with response in eight. Overall, 12 patients (66%) required treatment with mycophenolate (MMF) as second-line IST. Five were transitioned directly to MMF, and seven after failure of steroid escalation. Four (33%; 11% of total cohort) did not respond to MMF and required third-line IST (tacrolimus). Age, sex, liver metastases, prior ICI exposure, or peak ALT did not predict need for second- or third-line IST. ALT normalised in all, after median 14 days (range: 3–142 days). Total time on IST was shorter in steroid responders than poor responders (medians of 45 days [range: 9–177 days] and 104 days [range: 30–371 days], respectively; p<0.01). Amongst patients with poor response to initial corticosteroids, there was no difference in peak ALT or time to normalisation of ALT between patients treated with steroid escalation relative to MMF. The MMF group showed numerical trends towards shorter duration of corticosteroids (medians of 61 days [range: 32–86 days] and 97 days [range: 21–275 days], respectively) and reduced need for additional lines of IST (one patient [20%] versus seven [54%]), although not reaching statistical significance in this small cohort. Steroid-related adverse events occurred in two patients (vertebral fracture; hyperglycaemia); both were poor steroid responders treated with steroid escalation. Over median follow-up of 14.1 months (range: 2.3–81.5 months), 14 patients died. Ten patients were rechallenged with ICI, and none developed recurrent hepatotoxicity. No patients died of complications of hepatotoxicity.

Figure 1- Sequence of treatment with immunosuppressive therapies in patients with severe immune checkpoint inhibitor-related hepatotoxicit

Figure 1: Sequence of treatment with immunosuppressive therapies in patients with severe immune checkpoint inhibitor-related hepatotoxicity.
ALT: alanine aminotransferase; ICI: immune checkpoint inhibitor; ULN: upper limit of normal.


Poor steroid response is common in patients with severe ICI hepatotoxicity. Earlier introduction of second-line IST (MMF) may be associated with equivalent outcomes to steroid escalation and reduce total time on IST. Tacrolimus is effective as third-line therapy, if required. These results will assist development of treatment algorithms for severe ICI hepatotoxicity, for further prospective evaluation.

Miller ED et al. Clinical characteristics and adverse impacts of hepatotoxicity due to immune checkpoint inhibitors. Am J Gastroenterol. 2020;115(2):251-61. Li M et al. Effect of corticosteroid dosing on outcomes in high-grade immune checkpoint inhibitor hepatitis. Hepatology. 2022;75(3):531-40.

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