Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study

Abstract

Background. Immune-checkpoint-inhibitors (ICIs) have dramatically improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations. However, ICIs can also cause severe or even fatal immune-mediated adverse-events (irAE). Here, we identify and characterize significant cardiovascular irAE (CV-irAEs) associated with ICIs. Methods. We used VigiBase, the WHO’s global Individual-Case-Safety-Report database to identify drug-AE related to ICIs (n:31,321) and related to other drugs (n:16,343,451) through 01/2018. We evaluated the association between ICI and CV events using Reporting-Odds-Ratio (ROR) and Information-Component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find drug-AE associations. IC025 is the lower-end of IC 95% credibility-interval and an IC025>0 is considered statistically significant. Findings. Using this agnostic approach, we identified multiple CV entities over-reported after ICI treatment compared to the entire database. ICI treatment was associated with higher reporting of myocarditis (n:122, ROR: 11.21 [9.36–13.43], IC025:3.2), pericardial diseases (n:95, ROR: 3.8 [3.08–4.62], IC025:1.63), and vasculitis (n:82, ROR: 1.56 [1.25–1.94], IC025:0.03), including temporal-arteritis (n:18, ROR: 12.99 [8.12–20.77], IC025:2.59). These CV-irAE affected mostly men (58–67%), with a wide age range (20–90 years) and occurred early after ICI administration (40–80% within one month of first ICI administration). Pericardial disorders were reported more often in patients with lung cancer (56.3%) whereas myocarditis and vasculitis were more commonly reported in patients with melanoma (40.7% and 60%, respectively; p<0.001). Vision was impaired in 27.8% of temporal-arteritis cases. CV-irAE were serious in the majority of cases (>80%), with fatalities occurring in 50% of myocarditis cases, 21.1% of pericardial disorders and 6.1% of vasculitis (p<0.0001). Among myocarditis cases, fatality was most frequent in ICI combination therapy compared to ICI monotherapy (65.6% vs. 44.4%, p:0.04). Interpretation. ICI may lead to severe and disabling inflammatory CV-irAEs early during therapy. Besides life-threatening myocarditis, these toxicities include pericardial disorders, as well as temporal arteritis with a risk for blindness.

Histopathologic Characterization of Myocarditis Associated With Immune Checkpoint Inhibitor Therapy

“…doi: 10.5858/arpa.2019-0447-OA) C ardiac complications associated with the immunotherapy of advanced malignancies with anti-programmed death receptor-1 (PD-1), anti-programmed death ligand-1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) targeting agents are being encountered, including myocarditis, pericardial disease, and tachyarrhythmias and bradyarrhythmias. 1 The recognition of myocarditis with monotherapy as well as combination therapy as a life-threatening but potentially treatable complication has made diagnosis imperative. We report 6 cases (see supplemental digital content) demonstrating the relatively rapid progression of this complication, with integration of myocardial biopsy in the diagnostic algorithm, while characterizing the distinctive histopathology of this diffuse lymphohistiocytic myocarditis.…”

Expanding Therapeutic Options for Older Adults: Case‐Based Updates in Breast and Lung Cancer

“…Immunosuppressive agents are effective in most cases, especially if treatment is initiated promptly; however, severe and sometimes fatal toxicities have been reported. 74,75 It is not clear, based on current data, if the toxicity profile of ICIs is similar across age groups, with some reports suggesting a higher rate of AEs in older adults and others showing comparable safety across age groups. 76 Although numerical age, based on current limited data, does not seem to have a significant effect on the clinical profile of ICIs, it is still not clear if frailty has any impact on the efficacy or toxicity of these agents.…”

Emerging Challenges of Radiation-Associated Cardiovascular Dysfunction (RACVD) in Modern Radiation Oncology: Clinical Practice, Bench Investigation, and Multidisciplinary Care

“…RACVD is a well-known treatment-related toxicity in the field of cardio-oncology (23-25). Other anti-cancer therapies, such as chemotherapy (26-29), targeted therapy (30- 33), and immunotherapy (34)(35)(36), may also induce cardiovascular dysfunctions (37)(38)(39). As a result, when these therapies are prescribed concurrently or sequentially with RT, the risk of RACVD is increased substantially, especially in vulnerable pediatric (40,41) or elderly cancer patients (42,43).…”