Acute Coronary Syndrome With Immune Checkpoint Inhibitors: A Proof-of-Concept Case and Pharmacovigilance Analysis of a Life-Threatening Adverse Event

Immune checkpoint inhibitors have become a target for pharmacological research in lung cancer. Immune-related adverse events (irAEs) such as pneumonitis, colitis, hepatitis and endocrinopathies have been well characterized in immune checkpoint inhibitors, but coronary toxicities, like acute coronary syndrome, are poorly described. Herein, we report a possible acute coronary syndrome as immune-related adverse event in a lung cancer patient.

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Drug-Induced Acute Coronary Syndrome: A New Cardiovascular Concern With Immune Checkpoint Inhibitors and the Need for a Prospective Registry

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2020.02.001 ◽

2020 ◽

Vol 36 (4) ◽

pp. 455-456

Author(s):

Waleed Alhumaid ◽

D. Ian Paterson

Keyword(s):

Acute Coronary Syndrome ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Drug Induced ◽

Coronary Syndrome

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Cutaneous Adverse Events of Immune Checkpoint Inhibitors: A Summarized Overview

Current Drug Safety ◽

10.2174/1574886313666180730114309 ◽

2019 ◽

Vol 14 (1) ◽

pp. 14-20 ◽

Cited By ~ 12

Author(s):

Kerasia-Maria Plachouri ◽

Eleftheria Vryzaki ◽

Sophia Georgiou

Keyword(s):

Side Effects ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Skin Toxicity ◽

Maculopapular Rash ◽

Symptomatic Treatment ◽

Stevens Johnson Syndrome ◽

Life Threatening ◽

Skin Side Effects

Background:The introduction of Immune Checkpoint Inhibitors in the recent years has resulted in high response rates and extended survival in patients with metastatic/advanced malignancies. Their mechanism of action is the indirect activation of cytotoxic T-cells through the blockade of inhibitory receptors of immunomodulatory pathways, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and its ligand (PD-L1). Despite their impressive therapeutic results, they can also induce immune-related toxicity, affecting various organs, including the skin.Objective:To provide an updated summarized overview of the most common immune-mediated cutaneous side effects and their management.Method:English articles derived from the databases PubMed and SCOPUS and published between 2009 and 2018, were analyzed for this narrative review.Results:The most common adverse cutaneous reactions include maculopapular rash, lichenoid reactions, vitiligo and pruritus, with severity Grade 1 or 2. Less frequent but eventually life-threatening skin side effects, including Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms and Toxic Epidermal necrolysis, have also been reported.Conclusion:Basic knowledge of the Immune-Checkpoint-Inhibitors-induced skin toxicity is necessary in order to recognize these treatment-related complications. The most frequent skin side effects, such as maculopapular rash, vitiligo and pruritus, tend to subside under symptomatic treatment so that permanent discontinuation of therapy is not commonly necessary. In the case of life-threatening side effects, apart from the necessary symptomatic treatment, the immunotherapy should be permanently stopped. Information concerning the management of ICIs-mediated skin toxicity can be obtained from the literature as well as from the Summary of Product Characteristics of each agent.

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Myocarditis as a rare, yet serious adverse event associated with immune checkpoint inhibitors in patients with non-small cell lung cancer: Case series from a large community-based cancer center.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21047 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21047-e21047

Author(s):

Mohamed Hendawi ◽

Luke Peterson ◽

Eyob ale Tadesse ◽

Frank M. Wolf ◽

Thomas D. Brown ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Event ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Serious Adverse Event

e21047 Background: Patients (pts) with lung cancer and other cancers treated with immune checkpoint inhibitors (ICI) may experience immune related adverse events (irAE). These can present with variable severity and with single- or multi-organ involvement including pneumonitis, colitis, hepatitis, and myocarditis/pericarditis. The incidence of myocarditis has been reported between 0.06% and 2.4% and is associated with a high mortality (25% to 50%). This retrospective review of real-world data (RWD) investigates myocarditis as a high-grade adverse event in pts with lung cancer treated with ICIs. Methods: Pts were identified and characterized using RWD in the Syapse Learning Health Network platform from 2010 to 2020 at Advocate Aurora Health Care. Eligible pts included: ≥18 years old; histologically confirmed NSCLC; and myocarditis diagnosis by ICD codes. Additional chart review was performed to confirm timing of ICI treatment and myocarditis. All pts identification and review were performed after IRB review. Results: 12,686 pts with non-small cell lung cancer were eligible for review. The median age at diagnosis was 70; 54% were female; 86% were White and 12% were Black; 1,975 (15.6%) were treated with an ICI and of those 4 cases (0.2%) of myocarditis were identified. All 4 pts were White females, ages 46, 59, 65, and 74 years. Pathology included lung adenocarcinoma (3) and an undifferentiated lung carcinoma (1). All pts had metastatic disease, and none had a prior history of cardiac disease. ICIs were pembrolizumab (2), durvalumab (1), and nivolumab (1). Median time from initial dose of ICI to diagnosis of myocarditis was 62 days [range: 42-185]. All 4 pts presented with chest pain and elevated troponin T [median 0.07 ng/ml (range: 0.06-0.08)]. All pts had echocardiography at the time of diagnosis, and 2 pts had cardiac MRI that confirmed myocarditis. 3 pts were treated with a prednisone taper. 1 pt died of recurrent congestive heart failure and ventricular tachycardia despite rescue attempt with high dose corticosteroids. 2 pts had additional concomitant irAEs of hypothyroidism/colitis, and thyroiditis/pneumonitis, respectively. Conclusions: Many irAEs are reversible. This RWD analysis confirms that clinically evident myocarditis is a rare but serious adverse event of ICI therapy. Early consideration, diagnosis, and intervention may help prevent poor outcomes. Termination of ICI therapy along with initiation of corticosteroids constitute the current standard of management. Further research is warranted to better identify high risk groups, surveillance measures, and improved management of ICI associated myocarditis.

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Pneumonitis from immune checkpoint inhibitors and COVID-19: current concern in cancer treatment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000952 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000952 ◽

Cited By ~ 5

Author(s):

Ernesto Rossi ◽

Giovanni Schinzari ◽

Giampaolo Tortora

Keyword(s):

Adverse Event ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Clinical Symptoms ◽

Checkpoint Inhibitors ◽

Radiological Findings ◽

Serious Adverse Event ◽

Appropriate Treatment ◽

Current Concern ◽

Coronavirus Infection

Pneumonitis is a rare but serious adverse event caused by cancer immunotherapy. The diagnosis between COVID-19-induced pneumonia and immunotherapy-induced pneumonitis may be challenging in the era of COVID-19 outbreak. Some clinical symptoms and radiological findings of pneumonitis can be attributed to the coronavirus infection as well as to an immune-related adverse event. Identifying the exact cause of a pneumonitis in patients on treatment with immunotherapy is crucial to promptly start the most appropriate treatment. The proper management of immune checkpoint inhibitors for the risk of pneumonia must take into account a series of parameters. Accurate attention should be payed to symptoms like cough, fever and dyspnea during immunotherapy.

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Management of pulmonary toxicity associated with immune checkpoint inhibitors

European Respiratory Review ◽

10.1183/16000617.0012-2019 ◽

2019 ◽

Vol 28 (154) ◽

pp. 190012 ◽

Cited By ~ 14

Author(s):

Myriam Delaunay ◽

Grégoire Prévot ◽

Samia Collot ◽

Laurent Guilleminault ◽

Alain Didier ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Pulmonary Toxicity ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Serious Adverse Events ◽

Programmed Cell Death 1 ◽

Life Threatening

Immunotherapy has become a standard of care in oncology, following the recent approvals of cytotoxic T-lymphocyte-associated protein-4 and programmed cell death-1 inhibitors in lung cancer, melanoma, renal cell carcinoma, Hodgkin's lymphoma, bladder, head and neck cancers. Besides their efficacy, these agents also generate specific immune-related adverse events. Due to the increasing prescription of immune-checkpoint inhibitors, the incidence of immune toxicity will continue to rise. The awareness of immune-related adverse events is key to ensuring both diagnosis and management of the possible serious adverse events. Although severe immune-related adverse events remain rare, they can lead to discontinued treatment or to death if they are not forecasted and managed properly. Even if lung toxicity is not the most frequent adverse event, it remains critical as it can be life-threatening. Herein, the main aspects of pulmonary toxicity are reviewed and guidelines are also proposed in order to manage the possible side-effects.

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Large scale adverse event data mining for targeted therapies development.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2538 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2538-2538

Author(s):

Mayur Sarangdhar ◽

Bruce Aronow ◽

Anil Goud Jegga ◽

Brian Turpin ◽

Erin Haag Breese ◽

...

Keyword(s):

Data Mining ◽

Clinical Trials ◽

Adverse Event ◽

Big Data ◽

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Large Scale ◽

Checkpoint Inhibitors ◽

Anaplastic Lymphoma

2538 Background: Targeted anti-cancer small molecule drugs & immune therapies have had a dramatic impact in improving outcomes & the approach to clinical trials. Increasingly, regulatory approvals are expedited with small studies designed to identify strong efficacy signals. However, this may limit the extent of safety profiling. The use of large scale/big data meta-analyses can identify novel safety & efficacy signals in "real-world" medical settings. Methods: We used AERSMine, an open-source data mining platform to identify drug toxicity signatures in the FDA’s Adverse Event Reporting System of 8.6 million patients. We identified patients (n = 732,198) who received either traditional and targeted cancer therapy & identified therapy-specific toxicity patterns. Patients were classified based on exposures: anthracyclines (n = 83,179), platinum (117,993), antimetabolites (93,062), alkylators (81,507), antimicrotubule agents (97,726), HER2 inhibitors (40,040), VEGFis (79,144), VEGF-TKis (90,734), multi TKis (34,457), anaplastic lymphoma Kis (7,635), PI3K-AKT-mTOR inhibitors (33,864), Bruton TKis (9,247), MEKis (4,018), immunomodulatory agents (174,810), proteasome inhibitors (44,681), immune checkpoint inhibitors (20,287). Pharmacovigilance metrics [Relative Risks & safety signals] were used to establish statistical correlation & toxicity signatures were differentiated using the Kolmogorov–Smirnov test. Results: To validate the use of the AERSMine to detect AEs, we focused on cardiotoxicity. It identified classic drug associated AEs (e.g. ventricular dysfunction with anthracyclines, HER2is & VEGFis; VEGFi hypertension & vascular toxicity; multi TKIs vascular events). AERSMine also identified recently reported uncommon toxicities of myositis/myocarditis with immune checkpoint inhibitors. It indicated a higher frequency of myositis/myocarditis with combination immune checkpoint therapy, paralleling industry corporate safety databases. These toxicities were reported at higher frequencies in patients > 65 yrs. Conclusions: AERSMine “big data” analyses provide a sensitive tool to detect potential new patterns of AEs simultaneously across multiple clinical trials & in the real-world setting.

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Case Report: Cardiac Toxicity Associated With Immune Checkpoint Inhibitors

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.727445 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ru Chen ◽

Ling Peng ◽

Zhihua Qiu ◽

Yan Wang ◽

Fen Wei ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Troponin I ◽

Systemic Corticosteroid ◽

Checkpoint Inhibitors ◽

Cardiac Conduction ◽

Fulminant Myocarditis ◽

Cancer Type ◽

Life Threatening ◽

The Subject

Immune checkpoint inhibitors (ICIs) have now emerged as a mainstay of treatment for various cancer. Along with the development of ICIs, immune-related adverse effects (irAEs) have been the subject of wide attention. The cardiac irAE, a rare but potentially fatal and fulminant effect, have been reported recently. This article retrospectively reviewed 10 cases from our hospital with cardiac irAEs, with severity ranging from asymptomatic troponin-I elevations to cardiac conduction abnormalities and even fulminant myocarditis. In our series, all the cases were solid tumors and lung cancer was the most frequent cancer type (4,40%). In total, three (30.0%) patients experienced more than one type of life-threatening complication. A systemic corticosteroid was given to nine patients (90.0%). The majority of cases (7, 70%) were performed at an initial dose of 1–2 mg/kg/day. Two (20.0%) patients were admitted to ICU, three (30.0%) patients were put on mechanical ventilation, two (20.0%) patients received the plasma exchange therapy, and one patient was implanted with a pacemaker. Two (20.0%) of the patients succumbed and died, with a median duration of 7.5 days (IQR5.0–10.0) from diagnosis of cardiac irAE to death. Based on these results, we recommend that clinicians be alert to cardiac irAEs, including performing cardiovascular examinations before ICI treatment to accurately diagnose suspected myocarditis, enabling immediate initiation of immunosuppressive therapy to improve prognosis.

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Pericardial Toxicities Associated With Immune Checkpoint Inhibitors: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Frontiers in Pharmacology ◽

10.3389/fphar.2021.663088 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhuo Ma ◽

Jie Pei ◽

Ximu Sun ◽

Lihong Liu ◽

Wenchao Lu ◽

...

Keyword(s):

Adverse Event ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Reporting System ◽

Checkpoint Inhibitors ◽

Adverse Event Reporting System ◽

Adverse Event Reporting ◽

Interquartile Range ◽

Event Reporting

Introdution: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes for a wide range of cancers but can also lead to serious or fatal immune-related adverse events (irAEs). Although ICI-related pericardial toxicities have been reported, the clinical features are not well characterized in real-world studies.Objective: To characterize the main features of ICI-related pericardial toxicities and identify factors associated with death.Methods: Data from January 1, 2011 to March 31, 2020 in the FDA Adverse Event Reporting System database were retrieved for disproportionality analysis. We used the reporting odds ratio and the information component (IC) to evaluate the association between ICIs and pericardial adverse events. Clinical characteristics of patients with ICI-associated pericardial toxicities were collected and compared between fatal and non-fatal groups. The time to onset following different ICI regimens was further investigated.Results: We identified a total of 705 ICI-associated pericardial toxicities which appeared to influence more men (53.90%) than women (36.03%), with a median age of 63 (interquartile range [IQR] 54–69) years. Patients with lung cancer accounted for the largest proportion (55.6%). ICI therapies were detected with pharmacovigilance signals of pericardial toxicities, corresponding to IC025 = 2.11 and ROR 4.87 [4.51–5.25]. Nevertheless, there was a lack of association between anti-CTLA-4 and pericardial toxicities. There was no difference in onset time among all ICI regimens. However, TTO of fatal cases (25 days (interquartile range [IQR] 6–70)) occurred statistically earlier than non-fatal cases (42 days (IQR 12–114), p = 0.003).Conclusion: ICI monotherapy (PD-1/PD-L1 therapy) and combination therapy can lead to pericardial toxicities that can result in serious outcomes and tend to occur early. Early recognition and management of ICI-related pericardial disorders should attract clinical attention. The findings require further clinical surveillance for the quantification.

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