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.

Background: Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized. Methods: We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC 025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. Results: Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14. 5-18.9]; IC 025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC 025 3.15), peripheral neuropathy (1. 16% vs. 0.67%, IC 025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC 025 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6-12%), later onset (median 61-80 days), and were non-overlapping. Conclusions: ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.

Background: Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in front-line setting showed increased mortality during treatment compared to conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directed assessed in the study. Objective: We aimed to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib. Methods: We utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds-ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and ADR using disproportionate Bayesianreporting; IC025 (lower end of the IC 95% credibility interval)> 0 is significant. Results: We identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with

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Targeted oncology therapies have revolutionized cancer treatment over the last decade and have resulted in improved prognosis for many patients. This advance has emanated from elucidation of pathways responsible for tumorigenesis followed by targeting of these pathways by specific molecules. Cardiovascular care has become an increasingly critical aspect of patient care in part because patients live longer, but also due to potential associated toxicities from these therapies. Because of the targeted nature of cancer therapies, cardiac and vascular side effects may additionally provide insights into the basic biology of vascular disease. We herein provide the example of tyrosine kinase inhibitors utilized in chronic myelogenous leukemia to illustrate this medical transformation. We describe the vascular considerations for the clinical care of chronic myelogenous leukemia patients as well as the emerging literature on mechanisms of toxicities of the individual tyrosine kinase inhibitors. We additionally postulate that basic insights into toxicities of novel cancer therapies may serve as a new platform for investigation in vascular biology and a new translational research opportunity in vascular medicine.