Case Report: Cardiac Toxicity Associated With Immune Checkpoint Inhibitors

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.

Download Full-text

Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: Case Series and Review of the Literature

Case Reports in Oncology ◽

10.1159/000498985 ◽

2019 ◽

Vol 12 (1) ◽

pp. 260-276 ◽

Cited By ~ 17

Author(s):

Nikhil Agrawal ◽

Arjun Khunger ◽

Pankit Vachhani ◽

Teresa A. Colvin ◽

Alexander Hattoum ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Troponin I ◽

Cardiac Toxicity ◽

Checkpoint Inhibitors ◽

Case Reports ◽

Case Series ◽

Fulminant Myocarditis ◽

Comprehensive Cancer Center ◽

Cancer Center

The development of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with advanced stage cancers. However, immune-related adverse events are frequently observed. Cardiac toxicity from ICI therapy can range from asymptomatic troponin-I elevations to conduction abnormalities of the heart and even fulminant myocarditis. Although rare, myocarditis is a potentially fatal adverse effect of ICI therapy. We present a series of five cases of ICI-related cardio-toxicity diagnosed and managed at Roswell Park Comprehensive Cancer Center along with a review of published case reports in the literature. Our series highlights the importance of high clinical suspicion, early diagnosis of myocarditis, and prompt initiation of immunosuppressive therapy.

Download Full-text

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.

Download Full-text

Myocarditis Surveillance With High-Sensitivity Troponin I During Cancer Treatment With Immune Checkpoint Inhibitors

JACC: CardioOncology ◽

10.1016/j.jaccao.2021.01.004 ◽

2021 ◽

Vol 3 (1) ◽

pp. 137-139

Author(s):

Sarah Waliany ◽

Joel W. Neal ◽

Sunil Reddy ◽

Heather Wakelee ◽

Sumit A. Shah ◽

...

Keyword(s):

Cancer Treatment ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Troponin I ◽

Checkpoint Inhibitors ◽

High Sensitivity ◽

High Sensitivity Troponin

Download Full-text

Abstract 12563: Retrospective Analysis of Cardiovascular Events With the Use of Immune Checkpoint Inhibitors

Circulation ◽

10.1161/circ.142.suppl_3.12563 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Tushar Tarun ◽

Brian P Bostick ◽

Deepa Baswaraj ◽

Nishchayjit Basra ◽

Meeshal Khan ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Retrospective Analysis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Multiple Organ ◽

Fulminant Myocarditis ◽

Organ Systems ◽

History Of

Introduction: Immune checkpoint inhibitors have emerged as a promising, novel therapy for multiple malignancies. Immune-related adverse reactions pose a serious concern with use of these agents and reportedly involve multiple organ systems, notably cardiotoxicity. Early identification and management of these adverse events is essential in the prevention of morbidity and mortality. Hypothesis: Immune checkpoint inhibitors cause multiple cardiotoxic effects, and patients with prior cardiac history have a higher likelihood of cardiotoxicity. Methods: 1. A retrospective analysis of 150 patients was performed who had received immunotherapy with either the cytotoxic T lymphocyte associated antigen 4 inhibitors (CTLA4) or with the programmed cell death inhibitors (PD1) or programmed death-ligand 1 (PD-L1) inhibitors for a period of two years at a Tertiary health Care from 7/1/2016-6/30/2018. 2. Patients' cardiac diagnoses prior to the initiation of therapy were noted and included, including history of heart failure, coronary artery disease, atrial fibrillation, and sudden cardiac arrest. 3. Patients’ clinic visits and hospitalizations with admitting and discharge diagnosis, electrocardiogram, echocardiogram, troponin T, and NT-proBNP were reviewed. Results: 6% of patients had new onset heart failure (both preserved and reduced), 1.3% had evidence of myocardial infarction, 2% had new atrial fibrillation with rapid ventricular rate, and 0.6% had fulminant myocarditis. Of patients with new cardiac events, 60% had a history of cardiac disease, which was significantly higher than in patients without (p< 0.05). There were no age or sex differences between the groups with and without cardiotoxicity. Conclusion: Immunotherapy with immune checkpoint inhibitors have broadened the horizon for treatment of multiple solid and hematological malignancies. Nonetheless, new adverse effects on multiple organ systems, specifically cardiac involvement, occur with these therapies, which are important and potentially detrimental toxicities. Patients with a history of prior cardiovascular disease have higher likelihood to develop cardiotoxicity.

Download Full-text

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.

Download Full-text

Risk factors for myocarditis associated with immune checkpoint inhibitors using real-world clinical data.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15100 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15100-e15100 ◽

Cited By ~ 1

Author(s):

Prantesh Jain ◽

Jahir Gutierrez Bugarin ◽

Avirup Guha ◽

Chhavi Jain ◽

Tingke Shen ◽

...

Keyword(s):

Risk Factors ◽

Liver Disease ◽

Cancer Patients ◽

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Cancer Type ◽

Real World Data

e15100 Background: Immune checkpoint inhibitors (ICIs) can cause unique, high-grade immune-related adverse events. Although rare, ICI related myocarditis has the highest fatality rate (~50%). Cardiovascular monitoring is not routinely performed in patients on ICI treatment, thus risk factors remain unknown. Characterizing rare but fatal cardiac toxicities requires integration of real-world data. Methods: U.S claims data (IBM MarketScan) of over 30 million commercially insured individuals was leveraged to identify 2,687,301 cancer patients between 2011-2018. Patients ≥18 years of age treated with ICIs (targeting CTLA4 (ipilimumab) and/or the PD1 (nivolumab, pembrolizumab)/PDL1 (atezolizumab, avelumab, durvalumab) alone or in combination with ICI and/or chemotherapy were identified and followed until disenrollment. Myocarditis, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics and Cox proportional hazards regression. Results: 16,541 ICI treated cancer patients were included (median age 60; 58% male). Myocarditis was identified in 252 (1.5%) patients, majority (90%) ≥50 years old (median 63) with 12,040 person-years of follow up. 62% received anti-PD1 monotherapy, 12% anti-CTLA4, and 15% received combination treatment with other ICIs and/or chemotherapy. Most common cancer types were lung (48%), melanoma (25%), and renal cancer (14%). Cumulative incidence of myocarditis at 1 year was 2.06%; 95% CI (1.78-2.37), median onset of 80.5 days, 42% occurring within 60 days of treatment. By univariate analyses, age, cancer type, diabetes (DM), hypertension (HTN), kidney, liver disease, atrial fibrillation (AF) were related to myocarditis. Risk was lower in patients who received anti-CTLA4 monotherapy (HR: 0.490; 95% CI: 0.26-0.92; p = 0.0251). On multivariable regression analyses only age, cancer type (renal, lung cancer), comorbidities DM and liver disease were significantly associated with myocarditis (Table). Conclusions: This is the largest real-world longitudinal study for ICI associated myocarditis showing higher than reported incidence and identifiable risk factors. [Table: see text]

Download Full-text

Association between the type of thyroid dysfunction induced by immune checkpoint inhibitors and prognosis in cancer patients

10.21203/rs.3.rs-841797/v1 ◽

2021 ◽

Author(s):

Han-sang Baek ◽

Chaiho Jeong ◽

Kabsoo Shin ◽

Jaejun Lee ◽

Dong-Jun Lim ◽

...

Keyword(s):

Subclinical Hypothyroidism ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Thyroid Dysfunction ◽

Checkpoint Inhibitors ◽

Hazard Ratio ◽

Cancer Type ◽

Significant Difference ◽

The Difference ◽

Lower Hazard

Abstract Background Immune checkpoint inhibitors (ICIs) cause thyroid immune-related adverse effects (irAEs). However, associations between each type of thyroid immune-related adverse effect (irAE) and the anti-tumor effect of ICI remains unknown. This study aimed to determine the effects of each type of thyroid dysfunction on patient survival. Methods Patients who initiated ICI treatment from January 2015 to December 2019 in Seoul St. Mary’s Hospital were retrospectively analyzed. Thyroid dysfunction was classified into four types: newly developed overt or subclinical hypothyroidism, thyrotoxicosis, worsened hypothyroidism, and subclinical hyperthyroidism. Patients were divided into two groups according to the presence or absence of thyroid dysfunction. Results Among the 196 patients, 66 (33.7%) developed thyroid irAEs. There was no significant difference in age, sex, or cancer type between the two groups. The overall survival in patients with thyroid irAEs was significantly higher than that in patients without thyroid irAEs (38 months vs. 13 months, respectively, p = 0.005). After adjusting for confounding factors, the hazard ratio for mortality in the thyroid irAE group compared to the no thyroid irAE group was 0.520 (p = 0.007). Newly developed overt or subclinical hypothyroidism patients showed a significantly lower hazard ratio for morbidity of 0.309 (p = 0.001). Patients with thyrotoxicosis showed a worse hazard ratio for morbidity than those without thyroid irAE, although the difference was not statistically significant. Conclusions It was verified that ICI treatment-induced thyroid dysfunction was associated with better survival, even in the real-world practice. Thus, endocrinologists should cooperate with oncologists to monitor patients treated with ICIs.

Download Full-text

Chromosomal Instability May Not Be a Predictor for Immune Checkpoint Inhibitors from a Comprehensive Bioinformatics Analysis

Life ◽

10.3390/life10110276 ◽

2020 ◽

Vol 10 (11) ◽

pp. 276

Author(s):

Chiao-En Wu ◽

Da-Wei Yeh ◽

Yi-Ru Pan ◽

Wen-Kuan Huang ◽

Ming-Huang Chen ◽

...

Keyword(s):

Immune Checkpoint ◽

Predictive Value ◽

Chromosomal Instability ◽

Immune Checkpoint Inhibitors ◽

Bioinformatics Analysis ◽

Checkpoint Inhibitors ◽

P Value ◽

Cancer Type ◽

Significant Difference ◽

The Impact

Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although their predictive tools have not yet completely developed. Here, we aimed to exam the role of 70-gene chromosomal instability signature (CIN70) in cancers, and its association with previous predictors, tumor mutation burden (TMB), and microsatellite instability (MSI), for patients undergoing ICIs, as well as the possible predictive value for ICIs. We examined the association of CIN70 with TMB and MSI, as well as the impact of these biomarkers on the survival of 33 cancer cohorts from The Cancer Genome Atlas (TCGA) databank. The predictive value of the ICIs of CIN70 in previously published reports was also validated. Using the TCGA dataset, CIN70 scores were frequently (either positively or negatively) associated with TMB, but were only significantly associated with MSI status in three types of cancer. In addition, our current study showed that all TMB, MSI, and CIN70 had their own prognostic values for survival in patients with various cancers, and that they could be cancer type-specific. In two validation cohorts (melanoma by Hugo et al. and urothelial cancer by Snyder et al.), no significant difference of CIN70 scores was found between responders and non-responders (p-value = 0.226 and 0.108, respectively). In addition, no overall survival difference was noted between patients with a high CIN70 and those with a low CIN70 (p-value = 0.106 and 0.222, respectively). In conclusion, the current study, through a comprehensive bioinformatics analysis, demonstrated a correlation between CIN70 and TMB, but CIN70 is not the predictor for cancer patients undergoing ICIs. Future prospective studies are warranted to validate these findings.

Download Full-text