Clinical Features and Outcomes Based on Liver Injury Patterns in Liver Injury Caused by Immune Checkpoint Inhibitors

2021 ◽  
Author(s):  
Takanori Ito ◽  
Masatoshi Ishigami ◽  
Takafumi Yamamoto ◽  
Kazuyuki Mizuno ◽  
Kenta Yamamoto ◽  
...  
Keyword(s):  
Liver Injury ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Clinical Course ◽  
Checkpoint Inhibitors ◽  
Therapeutic Effects ◽  
Injury Patterns ◽  
Injury Grade ◽  
Grade 3 ◽  
Almost All

Abstract BackgroundThe clinical course of liver injury induced by immune checkpoint inhibitors (ICIs) varies among individuals, and there were few reports on the therapeutic effects of corticosteroids based on the patterns of liver injury.MethodsWe evaluated the characteristics and clinical course of immune-related liver injury in 1087 patients treated with ICIs for advanced malignancies between August 2014 and December 2020. ResultsDuring the follow-up period (median, 270 days), 56 patients (5.2%) had immune-related liver injury (≥Grade 3). The liver-injury patterns were hepatocellular (n = 25, 44.6%), mixed (n = 10, 17.9%), or cholestatic (n = 21, 37.5%), and the median time to onset of liver injury was 36, 85, and 53 days, respectively; the hepatocellular pattern occurred earlier than the other types (P = 0.036). Corticosteroids were administered to 29 (51.8%) patients. While liver injury was improved in almost all patients with the hepatocellular pattern (n = 13/14, 92.9%), that failed to show improvement in over half of the patients with the non-hepatocellular patterns (mixed, n = 8; cholestatic, n = 7), and three patients with mixed patterns needed secondary immunosuppression with mycophenolate mofetil. Liver biopsies performed in 13 patients mainly showed lobular injury, endothelialitis, and spotty necrosis with infiltration of T cells positive for CD3 and CD8, but not CD4 or CD20. ConclusionThe incidence pattern and therapeutic response to corticosteroids in immune-related liver injury differs according to the injury type. Although corticosteroids were effective for the hepatocellular pattern, an additional strategy for refractory non-hepatocellular patterns is needed.

Liver injury by immune checkpoint inhibitors in patients with hepatocellular carcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 341-341 ◽  
Author(s):  
Nicola Personeni ◽  
Tiziana Pressiani ◽  
Antonio Capogreco ◽  
Arianna Dal Buono ◽  
Antonio D'Alessio ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Injury ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Subsequent Treatment ◽  
Drug Induced ◽  
Increased Risk ◽  
Grade 3

341 Background: In patients with hepatocellular carcinoma (HCC) and baseline liver dysfunction, hepatic immune-related adverse events (HIRAEs) during immunotherapy have not been adequately characterized and their impact on subsequent treatment outcomes is not known. Methods: 40 patients with advanced/unresectable HCC and Child Pugh score A have been enrolled in first and second-line clinical trials of anti-programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs). HCC etiologies were: hepatitis C (32.5%), hepatitis B (7.5%), alcohol abuse (27.5%), other (32.5%). 7 received anti-PD-1 mAbs alone and 33 received combined regimens that included anti-PD-1 mAbs plus either anti-cytotoxic T lymphocyte antigen 4 (30.4%) or tyrosine kinase inhibitors (TKIs) (54.5%), or both (15.1%). We reviewed their liver function tests and HIRAEs onset was related to time to treatment failure (TTF). Results: Overall, 12 patients (30%) developed grade ≥ 3 hepatitis according to Common Toxicity Criteria for Adverse Events v. 4.03, resulting in 4 cases of grade 2 drug-induced liver injury per DILI Working Group criteria. Time between therapy initiation and hepatitis onset was 1.4 months (0.4-2.8) and median peak aminotransferase (AT) level was 258 IU/L (85-869). Out of 6 permanent treatment discontinuations due to adverse events (AEs), 4 were linked to hepatitis. Higher AT median levels at baseline were significantly linked to grade ≥ 3 hepatitis compared with lower grades (95 IU/L vs. 36 IU/L, respectively; p = 0.008). Etiology, age, treatment did not predict HIRAEs onset. TTF in patients in patients with grade ≥ 3 hepatitis was shorter than in the whole cohort (1.4 vs. 3.8 months, p = 0.041), while overall survival did not differ (p = 0.125). Conclusions: We observed a 30% incidence of clinically significant HIRAEs. HIRAEs represent the most frequent AEs leading to treatment discontinuation in patients with HCC undergoing treatments with immune checkpoint inhibitors. Baseline AT levels may identify patients at increased risk of grade ≥ 3 hepatitis.

scholarly journals Immune-related adverse events caused by combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab for lung cancer

2022 ◽  
Vol 6 (1) ◽  
Author(s):  
Takashi Nomizo ◽  
Haruka Yamamoto ◽  
Tsunetaka Murayama ◽  
Hiroko Fukata ◽  
Yasukiyo Nakamura ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Therapeutic Effects ◽  
Skin Injury ◽  
Checkpoint Inhibitor Therapy ◽  
Grade 3

It has been less than a decade since immune checkpoint inhibitors became the mainstay of lung cancer treatment, and 2020 saw the advent of the era of complex immune checkpoint inhibitors. Although clinical trials have shown that the therapeutic effects of complex immune checkpoint inhibitors are favorable, they are associated with an increase in adverse events. The use of combined immune checkpoint inhibitors in clinical practice has progressed slowly, and the frequency and types of adverse events they cause remain unclear. Here we report the adverse events of six patients with lung cancer treated with regimens containing nivolumab and ipilimumab in 2021. Four of the six patients had grade 3 or higher adverse events, including one patient with lung injury and one patient with skin injury, both of whom died. The timing and nature of the adverse events were difficult to predict.

scholarly journals 522 Transcriptomic changes in cancer patients treated with immune-checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A552-A552
Author(s):  
Dmitrii Shek ◽  
Bo Gao ◽  
Joey Lai ◽  
Won-Hee Yoon ◽  
Tania Moujaber ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Differentially Expressed Genes ◽  
Immune Checkpoint ◽  
Functional Annotation ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Link Type ◽  
Pre Treatment ◽  
Grade 3 ◽  
Transcriptomic Changes

BackgroundImmune-checkpoint inhibitors (ICIs) are monoclonal antibodies that block inhibitory CTLA-4/PD-1 signalling pathways and thus boost cytotoxic T cell antitumor activity. ICIs have been proven effective in various malignancies, but there is a lack of knowledge regarding factors associated with ICI efficacy and safety. This study aims to examine transcriptomic changes in cancer patients treated with ICIs and their potential association with related clinical outcomes.MethodsThis is a prospective multicentre cohort study (NCT04631731) recruiting cancer patients treated with (1) ICI monotherapy; (2) ICI dual therapy; (3) ICI + kinase inhibitor; (4) ICI + platinum-doublet chemotherapy. Peripheral blood is collected at baseline and 6–8 weeks after first ICI treatment as well as after the development of immune-related adverse events (irAEs, grade 2 and higher). Whole transcriptome sequencing (Novaseq S4 300 cycle lane, Illumina) was performed and followed by functional annotation using the ConsensusPath-DB platform.Results22 patients were recruited to the study and had paired blood taken. Two patients had developed grade 3–4 irAEs. RNA sequencing analysis identified 3,000 genes that were significantly dysregulated at week 6–8 after ICI commencement as compared to pre-treatment in n=20 recruited patients without irAEs (figure 1). Functional annotation established that 132 pathways were associated with the identified set of dysregulated genes. Among them: (1) pre-NOTCH processing in Golgi, (2) Interleukin-15 signalling; (3) STAT5 activation, and (4) RORA activation of gene expression possessed a gene set enrichment of at least 80% and p<0.01. In 2 patients with grade 3 immune-mediated hepatitis, both treated with combination of CTLA-4/PD-1 inhibitors, analysis revealed that 360 and 325 were 2-fold up- and downregulated respectively upon onset of toxicity as compared to both pre-treatment and 1-week post-steroid treatment. Interestingly, this gene set possessed minimal overlap when compared to genes dysregulated in patients without irAEs. Moreover, functional annotation established different pathways that were associated with toxicity. The highest enrichment scores belonged to pathways regulating cell cycle and apoptotic pathways driven by CDC25A, p53 and BCL-2, among others.Abstract 522 Figure 1Volcano plot representing the differentially expressed genesThe figure representing differentially expressed genes elucidated in this pilot study. N=3000 genes were significantly dysregulated between pre- and week 6–8 post-IO commencement.ConclusionsThe preliminary analysis of the first 22 patients recruited to NCT04631731 confirms that ICI treatment interferes with expression of coding and non-coding RNAs. Importantly, patients with and without irAEs show different patterns of transcriptomic changes as well as variability among activated cellular pathways. This data emphasises the need for further exploration and validation of transcriptomic changes in a larger cohort. In the near future, RNA signatures may be utilised as biomarkers to rapidly and accurately diagnose irAEs.AcknowledgementsN/ATrial RegistrationClinicalTrials.Gov identification number: NCT04631731ReferencesN/AEthics ApprovalThis study has been approved by the Western Sydney Local Health District (WSLHD) Human Research Ethics Committee on the November 9th, 2020 to be conducted at Blacktown and Westmead Public Hospitals of the WSLHD, Sydney, NSW, Australia.ConsentEach participant recruited to this translational study has provided written consent approved on the November 6th, 2020 (MASTER version) by the WSLHD HREC.

scholarly journals 237 Infectious complications in patients with non-small cell lung cancer treated with anti-PD(L)1 immune checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A253-A253
Author(s):  
Matthew Guo ◽  
Aanika Balaji ◽  
Joseph Murray ◽  
Joshua Reuss ◽  
Seema Mehta Steinke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Infectious Complications ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

BackgroundImmune checkpoint inhibitors (ICI) are standard treatment for stage III/IV non-small cell lung cancer (NSCLC). ICIs may cause immune-related adverse events (irAEs) often requiring corticosteroids or other immunosuppressive therapy and are associated with increased risk of opportunistic infections.1 2 The burden of infectious complications in NSCLC patients (pts) treated with ICIs is poorly described.MethodsWe retrospectively reviewed NSCLC pts treated with ICIs between 2016–2020 at a large tertiary academic center. An infectious complication related to ICIs was defined as a pathogen-confirmed or clinically diagnosed infection requiring antimicrobials during or within 3 months of ICI discontinuation. High-grade infections were defined as those requiring IV antibiotics (grade 3), life-threatening or requiring ICU stay (grade 4), or resulting in death (grade 5). irAEs were defined by the treating provider and treated according to standard guidelines. Patient demographics, treatment data, cancer outcomes, infectious complications, and irAE details were annotated in an IRB-approved database. An AE treated as both an infection and/or irAE with antibiotics and immunosuppression was coded as a concomitant irAE/infection event. The association between patient features and infectious complications was examined using logistic regression. Treatment and disease characteristics for concomitant irAE with infection were also described.Results302 ICI-treated NSCLC pts were included. 211 pts received PD-1 monotherapy and 91 received PD-1 therapy with CTLA-4 therapy, chemotherapy, or other investigational therapy. The majority (175/302, 57.9%) had a documented infection (bacterial=138, viral=17, fungal=19, mycobacterial=1) during or within 3 months of ICI discontinuation. Grade ≥3 infections occurred in 33.4% of pts (101/302). Pulmonary infections were most common (35.4%), followed by gastrointestinal, urinary, and skin (<10%, each). A subset of pts were treated as having concomitant irAE/infection events (63/302, 20.9%). Among 63 pts who experienced irAEs, pneumonitis occurred most commonly (47/63, 74.6%) followed by colitis (7/63, 11.1%); other irAEs (hepatitis, myocarditis, thyroiditis) occurred in <3 patients each. A concomitant event was associated with a trend toward higher odds of hospitalization (OR 3.91, CI 0.5–30.76) when adjusted for grade ≥3 infection. Similarly, steroid use within one month prior to infection, was also associated with a trend toward higher odds of hospitalization (OR 8.88, CI 0.81–97.15), adjusted for grade ≥3 infection.ConclusionsIn this retrospective study of NSCLC pts treated with ICIs, the majority experienced infections during or within 3 months of ICI discontinuation. The most common infections were bacterial pulmonary in origin. Concomitant irAE/infection was associated with trend toward higher odds of hospitalization.ReferencesHamashima R, Uchino J, Morimoto Y, et al. Association of immune checkpoint inhibitors with respiratory infections: a review. Cancer Treatment Reviews 2020;90:102109. doi:10.1016/j.ctrv.2020.102109Lu M, Zhang L, Li Y, et al. Recommendation for the diagnosis and management of immune checkpoint inhibitor related infections. Thorac Cancer 2020;11(3):805–809. doi:10.1111/1759-7714.13313Ethics ApprovalThis retrospective chart review study has obtained ethics approval from the Institutional Review Board at the Johns Hopkins School of Medicine (number: IRB00129424).

scholarly journals Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3629
Author(s):  
Hsiao-Ling Chen ◽  
Yu-Kang Tu ◽  
Hsiu-Mei Chang ◽  
Tai-Huang Lee ◽  
Kuan-Li Wu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Small Cell ◽  
Randomized Controlled ◽  
Extensive Stage ◽  
Grade 3

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46–0.98 for nivolumab, HR = 0.70, 95% CI = 0.54–0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59–0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46–0.92 for nivolumab, HR = 0.77, 95% CI = 0.61–0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65–0.94 for durvalumab, HR = 0.75, 95% CI = 0.61–0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3–4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3–4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.

Immune-related adverse events associated with immune checkpoint inhibitors in patients with cancer

2020 ◽  
pp. 030089162095346
Author(s):  
Nilay Sengul Samanci ◽  
Duygu Ilke Cikman ◽  
Kerem Oruc ◽  
Sahin Bedir ◽  
Emir Çelik ◽  
...  
Keyword(s):  
Adverse Events ◽  
Health Care Providers ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Care Providers ◽  
Patients With Cancer ◽  
Combination Treatments ◽  
Grade 3

Introduction: With the widespread use of immune checkpoint inhibitors (ICIs), we are facing challenges in the management of immune-related adverse events (irAEs). We aimed to characterize the spectrum of toxicity, management, and outcomes for irAEs. Methods: Patients who were treated with at least one ICI in clinical trials, expanded access programs, or routine clinical practice were included. Clinical and laboratory parameters were collected retrospectively to determine the incidence of irAEs, methods of management, and treatment outcomes. Results: A total of 255 patients were screened retrospectively. Of these, 71 (27.8%) patients developed irAEs. More than 2 different types of irAEs were detected in 16 (6.2%) out of 255 patients. A total of 3177 doses were given to 255 patients. In 93 (2.9%) of the 3177 doses, 1 episode of irAEs was experienced. A total of 22 out of 93 (23.7%) episodes were reported as grade 1, 49 (52.7%) as grade 2, 19 (20.4%) as grade 3, and 3 (3.2%) as grade 4. The most frequently seen irAEs were pneumonitis, hepatitis, and hypothyroidism. With regard to treatment, 39 out of 93 episodes (42%) of any grade irAEs occurred after anti–programmed cell death-1 therapy, 47 (50.5%) occurred following administration of anti–programmed death-ligand 1, and 7 (7.5%) occurred after combination treatments. Conclusion: With the increased use of immunotherapeutic agents, increased awareness and early recognition are required for effective management of irAEs. Our experience as a single institution might be of use for health care providers in oncology.

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