Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients

Biewenga, Maaike; Kooij, Monique K. Van der; Wouters, Michel W.J.M.; Aarts, Maureen J.B.; Berkmortel, Franchette W P J van den; Groot, Jan Willem B. de; Boers‐Sonderen, Marye J.; Hospers, Geke A.P.; Piersma, Djura; Rijn, Rozemarijn S. van; Suijkerbuijk, Karijn P M; Tije, Albert J. ten; Veldt, Astrid A.M. van der; Vreugdenhil, Gerard; Haanen, John B.A.G.; Eertwegh, Alfons J. M. van der; Hoek, Bart van

doi:10.1007/s12072-021-10151-4

Cited by 19 publications

(26 citation statements)

References 35 publications

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“…Conversely, the development of ICI-induced hepatitis did not correlate with OS or PFS and even showed an association with worse therapy response. This is in line with a recent study showing a trend toward favorable OS and PFS only for patients with ICI-induced hepatitis of grade 3-4 (Biewenga et al 2021).…”

Section: Discussionsupporting

confidence: 92%

Presence of autoantibodies in serum does not impact the occurrence of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients

Purde

Niederer

Wagner

et al. 2021

J Cancer Res Clin Oncol

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Purpose Immune checkpoint inhibitor (ICI)-induced hepatitis belongs to the frequently occurring immune-related adverse events (irAEs), particularly with the combination therapy involving ipilimumab and nivolumab. However, predisposing factors predicting the occurrence of ICI-induced hepatitis are barely known. We investigated the association of preexisting autoantibodies in the development of ICI-induced hepatitis in a prospective cohort of cancer patients. Methods Data from a prospective biomarker cohort comprising melanoma and non-small cell lung cancer (NSCLC) patients were used to analyze the incidence of ICI-induced hepatitis, putatively associated factors, and outcome. Results 40 patients with melanoma and 91 patients with NSCLC received ICI between July 2016 and May 2019. 11 patients developed ICI-induced hepatitis (8.4%). Prior to treatment, 45.5% of patients in the hepatitis cohort and 43.8% of the control cohort showed elevated titers of autoantibodies commonly associated with autoimmune liver diseases (p = 0.82). We found two nominally significant associations between the occurrence of ICI-induced hepatitis and HLA alleles associated with autoimmune liver diseases among NSCLC patients. Of note, significantly more patients with ICI-induced hepatitis developed additional irAEs in other organs (p = 0.0001). Neither overall nor progression-free survival was affected in the hepatitis group. Conclusion We found nominally significant associations of ICI-induced hepatitis with two HLA alleles. ICI-induced hepatitis showed no correlation with liver-specific autoantibodies, but frequently co-occurred with irAEs affecting other organs. Unlike other irAEs, ICI-induced hepatitis is not associated with a better prognosis.

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Section: Discussionsupporting

confidence: 92%

Presence of autoantibodies in serum does not impact the occurrence of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients

Purde

Niederer

Wagner

et al. 2021

J Cancer Res Clin Oncol

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“…A higher median number of somatic mutations per megabase of DNA was associated with a greater risk of irAEs (Pearson correlation coefficient R = 0.704; P <.001)). The metastatic liver disease does not predict high-grade liver-irAE (hepatitis), but the risk is significantly higher in the patients who receive combination therapy (compared to monotherapy) ( 67 ).…”

Section: Tumor-specific Risk Factorsmentioning

confidence: 99%

“…The incidence and profile of irAE may differ with the type of agent, PD-1, PDL1, CTLA4, or combination. Studies after studies proved the higher incidence and severity of irAE with CTLA4 inhibitors when used alone or combined with PD-1 or PD-L1 agents such as ipilimumab and nivolumab irrespective of the primary tumor treated ( 22 , 65 – 67 ). No reliable studies proved that one class of non-CTLA4 ICI (PD-1 or PD-L1) is worse than others.…”

Section: Agent-specific Risk Factorsmentioning

confidence: 99%

Risk Factors and Biomarkers for Immune-Related Adverse Events: A Practical Guide to Identifying High-Risk Patients and Rechallenging Immune Checkpoint Inhibitors

et al. 2022

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Immune-related adverse events (irAEs) are a range of complications associated with the use of immune-checkpoint inhibitors (ICIs). Two major classes of ICIs widely used are Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Cell death-1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors. High-grade irAEs are life-threatening and often cause a severe decline in performance status in such that patients do not qualify for any further anticancer treatments. It is difficult to generalize the evidence in the current literature on risk factors or biomarkers for the entire class of ICIs as the studies so far are either disease-specific (e.g., lung cancer or melanoma) or ICI agent-specific (e.g., pembrolizumab, ipilimumab) or irAE-specific (e.g., pneumonitis or gastritis). In this review, risk factors and biomarkers to consider before initiating or monitoring ICI are listed with a practical purpose in day-to-day practice. Risk factors are grouped into demographics and social history, medical history, and medication history, tumor-specific and agent-specific risk factors. A higher risk of irAE is associated with age <60 years, high body mass index, women on CTLA4 and men on PD-1/PD-L1 agents, and chronic smokers. Patients with significant kidney (Stage IV-V), cardiac (heart failure, coronary artery disease, myocardial infarction, hypertension), and lung (asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease) are at a higher risk of respective organ-specific irAEs. Pre-existing autoimmune disease and chronic use of certain drugs (proton pump inhibitors, diuretics, anti-inflammatory drugs) also increase the irAE-risk. Biomarkers are categorized into circulating blood counts, cytokines, autoantibodies, HLA genotypes, microRNA, gene expression profiling, and serum proteins. The blood counts and certain protein markers (albumin and thyroid-stimulating hormone) are readily accessible in current practice. High neutrophil-lymphocyte ratio, eosinophil/monocyte/lymphocyte counts; TSH and troponins at diagnosis and drop in the white count and lymphocyte count can predict irAE. Other biomarkers with limited evidence are cytokines, autoantibodies, HLA genotypes, microRNA, and gene expression profiling. With fast-expanding approvals for ICIs in various cancer types, knowledge on risk factors and biomarkers can help providers assess the irAE-risk of their patients. Prospective disease and agent-specific studies are needed to provide further insight on this essential aspect of ICI therapy.

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“…Of the included studies, 46 were retrospective ( 13 – 17 , 32 , 34 , 35 , 39 , 41 , 43 – 52 , 54 , 55 , 57 , 59 – 72 , 74 – 78 , 82 – 85 ), 13 were prospective ( 18 , 33 , 36 – 38 , 40 , 53 , 56 , 58 , 73 , 79 – 81 ) (including four studies that extracted data from clinical trials ( 18 , 33 , 73 , 79 )), and one included both retrospective and prospective data ( 42 ). All included studies assessed the relationship between the presence of irAEs and prognosis (12 of them examined the effect of irAE grades ( 14 , 37 , 45 , 57 , 58 , 68 , 71 , 73 , 76 , 82 , 84 , 85 )), 18 studies assessed endocrine irAEs (any, thyroiditis, or hypophysitis) ( 32 , 34 , 44 , 46 – 48 , 51 , 55 , 56 , 60 , 68 – 70 , 73 , 76 , 78 , 81 , 85 ), five assessed pulmonary irAEs ( 32 , 34 , 46 ...…”

Section: Resultsmentioning

confidence: 99%

“…Five articles assessed the association between the occurrence of hepatic irAEs and OS and PFS in patients with melanoma (32, 34,36,76,85). The study by Bai et al (34) included data from two cohorts, and the study by Wu et al (76) contained data of two different irAE grades.…”

Section: Correlation Of Hepatic Iraes With Os and Pfsmentioning

confidence: 99%

Patients with melanoma treated with immune checkpoint inhibitors who had non-thyroid endocrine and skin immune-related adverse events have better prognosis: A systematic review and meta-analysis

Sun

et al. 2022

Front. Oncol.

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BackgroundSeveral studies have reported an association between the occurrence of immune-related adverse events (irAEs) and prognosis in patients with melanoma treated with immune checkpoint inhibitors (ICIs), but the results remain controversial. We conducted a systematic review and meta-analysis to investigate the association between irAEs and survival in patients with melanoma treated with ICIs.MethodsWe searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases through May 5, 2022 for clinical studies evaluating the association between irAEs and in melanoma patients treated with ICIs. Combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were calculated using fixed- or random-effects models based on heterogeneity. ResultsA total of 60 articles were included, with 16,520 patients. In patients with melanoma treated with ICIs, the occurrence of irAEs was significantly associated with better OS (HR, 0.58; 95% confidence interval [CI], 0.51–0.66; P<0.00001) and PFS (HR, 0.61; 95%CI, 0.51–0.72; P<0.00001). Endocrine irAEs (OS, HR, 0.81; 95%CI, 0.72–0.92; P=0.001; PFS: HR, 0.84; 95%CI, 0.73–0.96, P=0.009), skin irAEs (OS, HR, 0.59; 95%CI, 0.41–0.85; P=0.004; PFS: HR, 0.43; 95%CI, 0.36–0.52; P<0.00001), vitiligo (OS, HR, 0.22; 95%CI, 0.15–0.31; P<0.00001; PFS, HR, 0.33; 95%CI, 0.25–0.44; P<0.00001), and grade 1–2 irAEs (OS, HR, 0.67; 95%CI, 0.58–0.78; P<0.00001; PFS, HR, 0.62; 95%CI, 0.51–0.76; P<0.00001) showed similar results. However, thyroid, lung, gastrointestinal, liver, and grade 3–4 irAEs were not significantly associated with OS and PFS. The occurrence of non-thyroid endocrine irAEs was significantly associated with better OS (HR, 0.22; 95%CI, 0.15–0.31; P<0.00001). In patients with melanoma treated with anti-programmed cell death protein 1 (OS, HR, 0.61; 95%CI, 0.51–0.72; P<0.00001; PFS, HR, 0.59; 95%CI, 0.47–0.74; P<0.00001), the association between irAEs and clinical benefit was clearer than in patients treated with anti-cytotoxic T-lymphocyte-associated protein 4 (OS, HR, 0.68; 95%CI, 0.52–0.89; P=0.005; PFS, HR, 0.93; 95%CI, 0.49–1.78; P=0.83).ConclusionAmong patients with melanoma treated with ICIs, those who developed non-thyroid endocrine irAEs and cutaneous irAEs have better prognosis. This suggests that non-thyroid endocrine irAEs and cutaneous irAEs may be a prognostic biomarker for patients with melanoma treated with ICIs.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022338308.

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Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients

Cited by 19 publications

References 35 publications

Presence of autoantibodies in serum does not impact the occurrence of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients

Presence of autoantibodies in serum does not impact the occurrence of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients

Risk Factors and Biomarkers for Immune-Related Adverse Events: A Practical Guide to Identifying High-Risk Patients and Rechallenging Immune Checkpoint Inhibitors

Patients with melanoma treated with immune checkpoint inhibitors who had non-thyroid endocrine and skin immune-related adverse events have better prognosis: A systematic review and meta-analysis

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