scholarly journals Late cardiac adverse events in patients with cancer treated with immune checkpoint inhibitors

2020 ◽  
Vol 8 (1) ◽  
pp. e000261 ◽  
Author(s):  
Charles Dolladille ◽  
Stephane Ederhy ◽  
Stéphane Allouche ◽  
Querntin Dupas ◽  
Radj Gervais ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Left Ventricular Systolic Dysfunction ◽  
Left Ventricular ◽  
Fulminant Myocarditis ◽  
Link Type ◽  
Therapy Initiation ◽  
First 90 Days ◽  
Cardiac Adverse Events

BackgroundImmune checkpoint inhibitor (ICI)-associated early cardiac adverse events (CAEs), mostly acute and fulminant myocarditis, have been well characterized and mainly occur during the first 90 days after ICI therapy initiation. ICI-associated late CAEs (occurring after the first 90 days of treatment) have not yet been described.MethodsFirst, we compared characteristics of a cohort involving early (defined as a CAE time to onset (TTO) of <90 days after ICI therapy initiation) and late (defined as a CAE TTO of ≥90 days after ICI therapy initiation) ICI-associated CAE consecutive cases who were referred to three French cardio-oncology units. Second, ICI-associated CAE cases were searched in VigiBase, the WHO global individual case safety report database, and early and late ICI-associated CAEs were compared.ResultsIn the cohort study, compared with early CAE cases (n=19, median TTO of 14 days), late ICI-associated CAE cases (n=19, median TTO of 304 days) exhibited significantly more left ventricular systolic dysfunction (LVSD) and heart failure (HF) and less frequent supraventricular arrhythmias. In VigiBase, compared with early cases (n=437, 73.3%, median TTO 21 days), the late ICI-associated CAE reports (n=159, 26.7%, median TTO 178 days) had significantly more frequent HF (21.1% vs 31.4%, respectively, p=0.01). Early and late ICI-associated CAE cases had similarly high mortality rates (40.0% vs 44.4% in the cohort and 30.0% vs 27.0% in VigiBase, respectively).ConclusionsLate CAEs could occur with ICI therapy and were mainly revealed to be HF with LVSD.Trial registration numbersNCT03678337,NCT03882580, andNCT03492528.

scholarly journals 540 Baseline mTOR transcriptional signatures in CD8 T cells are associated with immune-related adverse events but not anti-tumor responses in patients receiving immune checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A570-A570
Author(s):  
Chen Zhao ◽  
Matthew Mule ◽  
Andrew Martins ◽  
Iago Pinal Fernandez ◽  
Renee Donahue ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Effector Memory ◽  
Link Type ◽  
Anti Tumor Activity

BackgroundImmune checkpoint inhibitors (ICIs) have changed the cancer treatment landscape, but immune-related adverse events (irAEs) can affect a wide range of tissues in patients receiving ICIs. Severe irAEs can be life-threatening or fatal and prohibit patients from receiving further ICI treatment. While the clinical features of irAEs are well documented, the pathological mechanisms and predictive biomarkers are largely unknown. In addition, there is a critical need to preserve ICI-induced anti-tumor immunity while controlling for irAEs, which requires deciphering molecular and cellular signatures associated specifically with irAEs beyond those more generally linked to anti-tumor immunity.MethodsTo unbiasedly identify immune cells and states associated with irAEs, we applied CITE-seq to measure transcripts and surface proteins (83 protein markers) from PBMCs collected from patients with thymic epithelial tumors before and after treatment with an anti-PD-L1 antibody (avelumab, NCT01772004, NCT03076554).ResultsSamples from 9 patients were analyzed. No patient had a history of pre-existing paraneoplastic autoimmune disease. Anti-tumor activity was observed in all cases, and 5 patients had clinical and/or biochemical evidence of immune-related muscle inflammation (myositis with or without myocarditis). Multilevel models applied within highly resolved cell clusters revealed transcriptional states associated with ICI response and more uniquely with irAEs. A total of 190,000 cells were included in the analysis after quality control. Most notably, CD45RA+ effector memory CD8 T cells with an mTOR transcriptional signature were highly enriched at baseline and post treatment in patients with irAEs.ConclusionsOur findings suggest the potential therapeutic avenues by using mTOR inhibitors to dampen autoimmune responses while potentially sparing anti-tumor activity, to prevent treatment discontinuation and improve clinical outcomes for cancer patients treated with ICIs.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NCI (the Center for Cancer Research), NIAID and NIAMS, and through a Cooperative Research and Development Agreement between the National Cancer Institute and EMD Serono.Trial RegistrationNCT01772004, NCT03076554Ethics ApprovalThis study is approved by NCI institutional review board.

scholarly journals Cardiotoxicity Induced by Immune Checkpoint Inhibitors: A Pharmacovigilance Study From 2014 to 2019 Based on FAERS

2021 ◽  
Vol 12 ◽  
Author(s):  
Chenxin Chen ◽  
Ting Chen ◽  
Jizhou Liang ◽  
Xiaojing Guo ◽  
Jinfang Xu ◽  
...  
Keyword(s):  
Adverse Event ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Cardiac Complications ◽  
Cardiac Adverse Events

This study was to scientifically and systematically explore the association between cardiotoxicity and immune checkpoint inhibitors (ICIs) and also to characterize the spectrum of ICI-related cardiac complications. From the first quarter of 2014 to the fourth quarter of 2019, data from the FDA Adverse Event Reporting System database were selected to conduct the disproportionality analysis. Reporting odds ratios and information components were used to evaluate the signal after statistical shrinkage transformation. In total, 7,443,137 cases and 36,326,611 drug-adverse event pairs were collected, among which 9,271 cases were identified to be related to ICI-induced cardiotoxicities. The number of male patients was much higher than that of females (5,579 vs. 3,031) and males presented a slightly higher reporting frequency than females in general, which was statistically significant (ROR = 1.04, 95%CI: 0.99–1.09, p &lt; 0.001). Simultaneously, the proportion of serious or life-threatening outcomes in males was significantly higher than in females (ROR = 1.05, 95%CI: 0.96–1.15, p &lt; 0.001). Importantly, ICIs were associated with over-reporting frequencies of cardiotoxicities in general (ROR025 = 1.06, IC025 = 0.08). PD-1 and PD-L1 were found to be related to cardiac adverse events, corresponding to ROR025 = 1.06, IC025 = 0.08, and ROR025 = 1.06, IC025 = 0.08, respectively, while anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) was significantly associated with some specific adverse events rather than common adverse events. The spectrum of cardiotoxicities induced by ICIs mostly differed among individual agents, but also demonstrated some common features. Dyspnea (N = 2,527, 21.25%), myocarditis (N = 614, 5.16%), atrial fibrillation (N = 576, 4.84%), cardiac failure (N = 476, 4.00%), and pericardial effusion (N = 423, 3.56%) were the top five cardiac adverse events reported in the database. Among them, myocarditis was the only one caused by all ICIs with strong signal value and high risk, warranting further attention. Overall, this investigation mainly showed the profile of cardiotoxicities caused by ICIs, which varied between different ICI therapies, but also shared some similarities in specific symptoms such as myocarditis. Therefore, it is vital and urgent to recognize and manage ICI-related cardiotoxicities, known to frequently occur in clinical practice, at the earliest point.

scholarly journals Cardiac adverse events of immune checkpoint inhibitors in oncology patients: A systematic review and meta-analysis

2020 ◽  
Vol 12 (11) ◽  
pp. 584-598
Author(s):  
Nso Nso ◽  
Daniel Antwi-Amoabeng ◽  
Bryce D Beutler ◽  
Mark B Ulanja ◽  
Jasmine Ghuman ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Oncology Patients ◽  
Cardiac Adverse Events

scholarly journals Acute cardiac manifestations under immune checkpoint inhibitors—beware of the obvious: a case report

2021 ◽  
Vol 5 (8) ◽  
Author(s):  
Dimitri Arangalage ◽  
Anna Giulia Pavon ◽  
Berna C Özdemir ◽  
Olivier Michielin ◽  
Jurg Schwitter ◽  
...  
Keyword(s):  
Chest Pain ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Left Ventricular ◽  
Stress Cardiomyopathy ◽  
High Rate ◽  
Cardiac Events ◽  
Cardiac Manifestations

Abstract Background Immune checkpoint inhibitors (ICI) have revolutionized the management of many cancer types by drastically improving the median survival rate of patients. However, this efficiency comes at the cost of a high rate of immune-related adverse events, including lethal cardiac manifestations. Rapidly fatal cases of ICI-induced myocarditis have been reported and drawn considerable attention over the past years. However, it is essential to bear in mind that not all cardiac events occurring under ICI therapy are necessarily myocarditis. Case summary A 61-year-old female treated with pembrolizumab for a stage IV melanoma was admitted for chest pain leading to the diagnosis of ICI-related myocarditis based on the description of a discrete left ventricular subepicardial late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. ICI were suspended and intravenous methylprednisolone initiated. A second line anti-MEK therapy was initiated. After a month of treatment, similar chest pain occurred. CMR revealed a midventricular stress cardiomyopathy and no LGE was detected. A posteriori interrogation revealed emotional stressors preceding both episodes. Review of the first CMR, performed 2 weeks after symptom onset, indicated a pattern compatible with the recovery phase of a stress cardiomyopathy and the presence of LGE was questioned. ICI were reintroduced without recurrence of cardiac events. Discussion Not all cardiac manifestations occurring under ICI therapy are drug-related adverse events, therefore differential diagnoses must systematically be considered as the contraindication of ICI may have a major impact on patient prognosis. Cardiac imaging should be performed early and plays a key role in the management strategy.

scholarly journals Cardiac Adverse Events Related to Immune Checkpoint Inhibitors

2020 ◽  
Vol 2 (2) ◽  
pp. 200-202
Author(s):  
Dorothy M. Gujral ◽  
Elie N. Mouhayar ◽  
Sanjeev Bhattacharyya
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cardiac Adverse Events

scholarly journals The quality of reporting general safety parameters and immune-related adverse events in clinical trials of FDA-approved immune checkpoint inhibitors

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zahra Karimian ◽  
Sandra Mavoungou ◽  
Joe-Elie Salem ◽  
Florence Tubach ◽  
Agnès Dechartres
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Safety Information ◽  
Safety Data ◽  
Phase Iii ◽  
Quality Of Reporting ◽  
Link Type

Abstract Background While immune-checkpoint inhibitors (ICIs) have transformed the field of oncology for advanced-stage cancers, they can lead to serious immune toxicities. Several systematic reviews have evaluated the risk of immune-related adverse events (irAEs); however, most have focused on published articles without evaluating trial registries. The objective of this methodological review was to compare the quality of reporting of safety information and in particular, serious irAEs (irSAEs), in both publications and ClinicalTrials.gov for all current FDA-approved ICIs. Methods PubMed was searched to retrieve all published phase III randomized controlled trials (RCTs) evaluating ICIs. For each eligible trial, we searched for corresponding registration on ClinicalTrials.gov and extracted relevant safety data from both the publication and results posted on registry. We then compared the quality of reporting and the value of safety data between both sources. Results Of 42 eligible published trials, 34 had results posted on ClinicalTrials.gov. Considerable variability was noted in the reporting of safety in both sources. SAEs were reported for all trial results in ClinicalTrials.gov compared to 23.5% of publications. An overall incidence for irAEs and irSAEs was reported in 58.8 and 8.8% of publications respectively, compared to 11.8 and 5.9% in registry results. Comparing the value of specific irSAEs was not possible between the two sources in 32/34 trials either due to different reporting formats (61.8%) or data not being reported in one or both sources (32.4%). From the 2 studies with compatible irSAE format, only 1 had matching data in both sources. Conclusions The reporting of irAEs / irSAEs varies considerably in publications and registries, which outlines the importance of standardizing the terminologies and methodologies for reporting safety information relevant to ICIs.

scholarly journals FRI0494 RHEUMATIC IMMUNE RELATED ADVERSE EVENTS OF CHECKPOINT INHIBITORS: A RETROSPECTIVE REVIEW OF 70 PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 845.2-846
Author(s):  
T. Lenfant ◽  
L. Calabrese ◽  
C. Calabrese
Keyword(s):  
Adverse Events ◽  
Prospective Studies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Aspects ◽  
Link Type ◽  
Conventional Dmards

Background:Immune Checkpoint inhibitors (ICI) have revolutionized cancer therapy by achieving remarkable survival benefits however, at the cost of a myriad of immune-related adverse events (irAEs)[1]. Rheumatic irAE can develop in 5-10% of patients although the true incidence is unknown given the lack of prospective studies [2]. Symptoms are heterogenous and probably underreported with few data available about their management and outcome [3].Objectives:To describe the clinical, biological, and radiological features of the largest cohort of rheumatic irAEs from ICI along with their therapeutic management, outcome and follow-up in real-world practice.Methods:A referral process for emergent rheumatic irAEs was initiated in February 2016 between the oncology and rheumatology departments at the Cleveland Clinic Foundation. All patients were evaluated by authors CC and/or LHC. Patients’ characteristics were retrospectively collected from medical charts after IRB approval.Results:70 patients referred for one or more rheumatic irAEs between February 2016 and January 2020 were included. 66% were male, median age was 60.8 years. Among them, 24 (34%) had pre-existing rheumatic complaints. Melanoma was the most frequent malignancy (56%). ICI therapy included anti-CTLA4 (40%), anti-PD1/L1 (79%), and dual therapy ipilimumab/nivolumab (41%). Rheumatic irAE occurred in a median 4 months after ICI initiation, with phenotypes including inflammatory arthritis (32 patients), sicca-like symptoms (12), polymyalgia rheumatica-like (7), and myositis (2). Oral, intravenous or intraarticular glucocorticoids (GC) were administered to 54 patients (77%). Of these 54 patients, 22 (41%) required long term GC, 19 had bone density scan and 15 received pneumocystis (PJP) prophylaxis. One PJP case, 1 osteoporotic fracture and 2 avascular necrosis cases were reported. 16 patients received conventional DMARDS (23%) and 9 received biologics (13%). ICI therapy was held for rheumatic irAE in 31% of cases and for another systemic irAE in 29%. Median follow-up was 13.6 months, at end of follow-up 51 patients were still on treatment for rheumatic irAE and 41% of them were still symptomatic despite ongoing treatment.Conclusion:Rheumatic irAEs are heterogeneous and often chronic requiring prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term oncologic outcomes.References:[1]Suarez-Almazor ME, Kim ST, Abdel-Wahab N, Diab A. Review: Immune-Related Adverse Events With Use of Checkpoint Inhibitors for Immunotherapy of Cancer. Arthritis Rheumatol 2017;69:687–99.https://doi.org/10.1002/art.40043.[2]Abdel-Wahab N, Suarez-Almazor ME. Frequency and distribution of various rheumatic disorders associated with checkpoint inhibitor therapy. Rheumatol (United Kingdom) 2019;58:vii40–8.https://doi.org/10.1093/rheumatology/kez297.[3]Kostine M, Rouxel L, Barnetche T, Veillon R, Martin F, Dutriaux C, et al. Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Ann Rheum Dis 2018;77:393–8.https://doi.org/10.1136/annrheumdis-2017-212257.Disclosure of Interests:Tiphaine Lenfant: None declared, Leonard Calabrese Consultant of: AbbVie, GSK, Bristol-Myers Squibb, Genentech, Janssen, Novartis, Sanofi, Horizon, Crescendo, and Gilead, Speakers bureau: Sanofi, Horizon, Crescendo, Novartis, Genentech, Janssen, and AbbVie, cassandra calabrese Consultant of: AbbvieGSK, Speakers bureau: Sanofi-Genzyme

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