Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

Ito, Takanori; Ishigami, Masatoshi; Yamamoto, Takafumi; Mizuno, Kazuyuki; Yamamoto, Keizô; Imai, Norihiro; Ishizu, Yoji; Honda, Takashi; Kawashima, Hiroki; Yasuda, Satoshi; Toyoda, Hidenori; Yokota, Kenji; Hase, Takashi; Nishio, Naoki; Maeda, Osamu; Kato, Masashi; Hashimoto, Naozumi; Hibi, Hideharu; Kodera, Yasuhiro; Ando, Yuichi; Akiyama, Masashi; Shimoyama, Yoshie; Fujishiro, Mitsuhiro

doi:10.1007/s12072-021-10238-y

Cited by 24 publications

(29 citation statements)

References 35 publications

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“…In a study from Oxford, 19/21 patients (90.5%) with hepatotoxicity due to Check Point Inhibitors were treated with corticosteroids (Cheung et al, 2019) (Table 1), but only 50% had a treatment response, which was similar to a study from Japan (Kitagataya et al, 2020). The study by Ito et al from Japan was somewhat of an outlier showing a response to steroid treatment in only 33% of cases (Ito t al. 2021) as shown in Table 1.…”

Section: Steroid Use In Check Point Inhibitor Induced Liver Injurysupporting

confidence: 56%

Role of Corticosteroids in Drug-Induced Liver Injury. A Systematic Review

et al. 2022

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Introduction: Apart from cessation of the implicated agent leading to drug-induced liver injury (DILI), there is no standard therapy for DILI. Corticosteroids have been used in DILI, although their efficacy is unclear. Published data showed either beneficial effects or no improvement associated with steroid therapy. The aim of the current study was to perform a systematic review of the role of corticosteroids in the treatment of DILI.Methods: A search was performed in PubMed, searching for the terms: “corticosteroids” and “drug-induced liver injury”. Observation studies were included, but case reports excluded.Results: A total of 24 papers were retrieved. Most of these were observational studies on the effects of corticosteroids in moderate/severe DILI (n = 8), reports on the corticosteroid treatment in patients with drug-induced autoimmune hepatitis (DI-AIH) (n = 5), and effects of corticosteroids in drug-induced fulminant acute liver failure (ALF, n = 2). Furthermore, treatment of corticosteroids in patients with liver injury due to check point inhibitors (CPIs) was addressed in nine studies. In moderate/severe DILI, six out of eight studies suggested steroid treatment to be beneficial, whereas two studies showed negative results. All five observational studies on the effects of corticosteroids in DI-AIH showed good therapeutic response with rapid and long lasting effects after discontinuation of corticosteroids and without evidence of relapse. Steroid therapy was not associated with improved overall survival in patients with drug-induced fulminant ALF. CPIs-induced liver injury was found to improve spontaneously in 33–50% without corticosteroids, and the rate of patients who were treated responded to steroids in 33–100% (mean 72%).Conclusions: The majority of studies analyzing the effects of corticosteroids in moderate/severe DILI have demonstrated beneficial effects. However, this was not the case in drug-induced fulminant ALF. Patients with DI-AIH had an excellent response to corticosteroids. The majority of those with CPIs-induced liver injury responded to corticosteroids; however, patients without treatment usually recovered spontaneously. The observational design and comparison with historical controls in these studies makes it very difficult to draw conclusions on the efficacy of corticosteroids in DILI. Therefore, there is a strong need for a randomized controlled trial to properly assess the role of corticosteroids in DILI.

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Section: Steroid Use In Check Point Inhibitor Induced Liver Injurysupporting

confidence: 56%

Role of Corticosteroids in Drug-Induced Liver Injury. A Systematic Review

et al. 2022

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“…Regarding liver-irAE, cholestasis and mixed liver injury are less responsive to PSL than hepatocellular injury. 20 The present case was classified as a mixed type. 21,22 Another characteristic of the clinical course of this case was that cholangitis, but not pancreatitis, relapsed despite maintenance therapy with steroids.…”

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confidence: 79%

A case of antiprogrammed death‐ligand 1 antibody‐induced multisystem immune‐related adverse events with pancreatitis and steroid‐resistant sclerosing cholangitis

Yamamoto

Ito

Mizuno

et al. 2022

J of Digest Diseases

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Immune checkpoint inhibitors (ICIs) have been indicated for several cancers; however, these treatments may cause immune-related adverse events (irAE). 1 According to our previous study, immunerelated liver injury (liver-irAE) is a relatively rare adverse event, with incidence rates of 2.7% and 5.3% for grades 2 and ≥3 liver injury, respectively. Additionally, over 50% of the patients with liver-irAE showed a cholestatic or mixed, but not hepatocellular, pattern. 2 Recently, a few studies have suggested that immune-related sclerosing cholangitis (irSC) is caused by ICIs. 3,4 The irSC is more widely recognized by clinicians, and is diagnosed in approximately 7% of all liver-irAEs of ≥grade 3. 2 The irSC shows predominant elevation of γ-glutamyl transpeptidase (γ-GT) and alkaline phosphatase (ALP) than liver transaminases with extrahepatic biliary duct dilatation in the absence of obstruction on imaging. Moreover, the effects of steroid therapy, which is the main treatment for irAEs, 5,6 are known to be limited in irSC. 7 However, there are only a few studies on irSC that fol-

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“…skin, endocrine, and digestive tract irAEs), severe liver‐irAEs (grade ≥ 3) do not correlate favorably with the treatment response to ICI 33 . Furthermore, liver‐irAE is also known to be heterogeneous in terms of pathogenesis 34 . Therefore, the interpretation of the predictive biomarkers may differ for each irAE.…”

Section: Discussionmentioning

confidence: 99%

“…33 Furthermore, liver-irAE is also known to be heterogeneous in terms of pathogenesis. 34 Therefore, the interpretation of the predictive biomarkers may differ for each irAE. The associations between inflammatory markers and liver-irAE occurrence require further validation in additional patient cohorts.…”

Section: Discussionmentioning

confidence: 99%

Clustering using unsupervised machine learning to stratify the risk of immune‐related liver injury

Yamamoto

Morooka

Ito

et al. 2022

J of Gastro and Hepatol

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Background and Aim: Immune-related liver injury (liver-irAE) is a clinical problem with a potentially poor prognosis. Methods: We retrospectively collected clinical data from patients treated with immune checkpoint inhibitors between September 2014 and December 2021 at the Nagoya University Hospital. Using an unsupervised machine learning method, the Gaussian mixture model, to divide the cohort into clusters based on inflammatory markers, we investigated the cumulative incidence of liver-irAEs in these clusters.Results: This study included a total of 702 patients. Among them, 492 (70.1%) patients were male, and the mean age was 66.6 years. During the mean follow-up period of 423 days, severe liver-irAEs (Common Terminology Criteria for Adverse Events grade ≥ 3) occurred in 43 patients. Patients were divided into five clusters (a, b, c, d, and e). The cumulative incidence of liver-irAE was higher in cluster c than in cluster a (hazard ratio [HR]: 13.59, 95% confidence interval [CI]: 1.70-108.76, P = 0.014), and overall survival was worse in clusters c and d than in cluster a (HR: 2.83, 95% CI: 1.77-4.50, P < 0.001; HR: 2.87, 95% CI: 1.47-5.60, P = 0.002, respectively). Clusters c and d were characterized by high temperature, C-reactive protein, platelets, and low albumin. However, there were differences in the prevalence of neutrophil count, neutrophil-tolymphocyte ratio, and liver metastases between both clusters. Conclusions: The combined assessment of multiple markers and body temperature may help stratify high-risk groups for developing liver-irAE.

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Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

Cited by 24 publications

References 35 publications

Role of Corticosteroids in Drug-Induced Liver Injury. A Systematic Review

Role of Corticosteroids in Drug-Induced Liver Injury. A Systematic Review

A case of antiprogrammed death‐ligand 1 antibody‐induced multisystem immune‐related adverse events with pancreatitis and steroid‐resistant sclerosing cholangitis

Clustering using unsupervised machine learning to stratify the risk of immune‐related liver injury

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