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Acalabrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), associates with dramatic efficacy against B-cell malignancies. Recently, unexplained ventricular arrhythmias (VAs) with next-generation BTKi-therapy have been reported. Yet, whether acalabrutinib associates with VAs in long-term follow-up is unknown. Leveraging a large-cohort of 290 consecutive B-cell malignancy patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence of VAs. The primary-endpoint was incident VA development (ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions). Probability-scores were assessed to determine likelihood of acalabrutinib-association. Incident rates as function of time-on-therapy were calculated. Weighted average observed incidence rates were compared with expected population rates using relative-risks. Absolute excess risk (AER) for acalabrutinib-associated VAs was estimated. Over 1063 person-years of follow-up, there were 8 cases of incident-VAs, including 6 in those without coronary disease (CAD) or heart failure (HF) and 1 sudden-death; median time-to-event 14.9 months. Among those without prior ibrutinib-use, CAD, or HF, the weighted average incidence was 394 per 100 000 person years compared with a reported incidence of 48.1 among similar-aged non–BTKi-treated subjects (relative risk, 8.2; P

OBJECTIVE To assess whether cardiac MRI or various biomarkers can be used to detect myocardial ischemia and fibrosis in dogs with cardiomegaly secondary to myxomatous mitral valve disease (MMVD). ANIMALS 6 dogs with cardiomegaly secondary to naturally occurring stage B2 MMVD being treated only with pimobendan with or without enalapril and 6 control dogs with no cardiac disease. All dogs were ≥ 5 years old with no systemic illness. PROCEDURES Serum cardiac troponin I and concentrations were measured, and dogs were anesthetized for cardiac MRI with ECG-triggered acquisition of native T1- and T2-weighted images. Gadolinium contrast was administered to evaluate myocardial perfusion and late gadolinium enhancement (LGE). Mean T1 and T2 values and regions of LGE were measured with dedicated software. Extracellular volume (ECV) was estimated on the basis of Hct and T1 values of myocardium and surrounding blood. Subjective analysis for myocardial perfusion deficits was performed. RESULTS Dogs with MMVD had significantly (P = .013) higher cardiac troponin I concentrations than control dogs, but galectin-3 concentrations did not differ (P = .08) between groups. Myocardial fibrosis was detected in 4 dogs with MMVD and 3 control dogs; no dogs had obvious myocardial perfusion deficits. Native T1 and T2 values, postcontrast T1 values, and ECV values were not significantly different between groups (all P > .3). CLINICAL RELEVANCE Results suggest that some dogs with cardiomegaly secondary to MMVD may not have clinically relevant myocardial fibrosis.

ImportanceIbrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown.ObjectiveTo assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity.Design, Setting, and ParticipantsThis cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry.ExposuresIbrutinib treatment for cancer control.Main Outcomes and MeasuresThe primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk–matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE.ResultsOverall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P P = .01, and P 2SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE.Conclusions and RelevanceIn this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.

Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.From the Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

This cohort study examines the prevalence and factors associated with postmarketing communications by the US Food and Drug Administration about cardiovascular events associated with anticancer thearpy.

Purpose: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in cancer survivors, particularly after chest radiation therapy (RT). However, the extent to which CVD events are consistently reported in contemporary prospective trials is unknown. Methods and Materials: From 10 high-impact RT, oncology, and medicine journals, we identified all latter phase trials from 2000 to 2019 enrolling patients with breast, lung, lymphoma, mesothelioma, or esophageal cancer wherein chest-RT was delivered. The primary outcome was the report of major adverse cardiac events (MACEs), defined as incident myocardial infarction, heart failure, coronary revascularization, arrhythmia, stroke, or CVD death across treatment arms. The secondary outcome was the report of any CVD event. Multivariable regression was used to identify factors associated with CVD reporting. Pooled annualized incidence rates of MACEs across RT trials were compared with contemporary population rates using relative risks (RRs). Results: The 108 trials that met criteria enrolled 59,070 patients (mean age, 58.0 ± 10.2 years; 46.0% female), with 273,587 person-years of available follow-up. During a median follow-up of 48 months, 468 MACEs were reported (including 96 heart failures, 75 acute coronary syndrome, 1 revascularization, 94 arrhythmias, 28 strokes, and 20 CVD deaths; 307 occurred in the intervention arms vs 144 in the control arms; RR, 1.96; P < .001). Altogether, 50.0% of trials did not report MACEs, and 37.0% did not report any CVD. The overall weighted-trial incidence was 376 events per 100,000 person-years compared with 1408 events per 100,000 person-years in similar nontrial patients (RR, 0.27; P < .001). There were no RT factors associated with CVD reporting. Conclusion: In contemporary chest RT–based clinical trials, reported CVD rates were lower than expected population rates.

Background Gilteritinib is a novel FMS-like tyrosine kinase 3 inhibitor recently approved by the United States Food and Drug Administration in 2018 for relapsed or refractory acute myeloid leukemia. However, gilteritinib may be associated with underrecognized cardiotoxicities. Case presentation This case describes a patient with a history significant for hyperlipidemia who was diagnosed with relapsed acute myeloid leukemia. After four doses of gilteritinib monotherapy, she abruptly developed acute systolic heart failure with global hypokinesis and septal wall motion abnormalities. Two days after discontinuation, cardiac magnetic resonance imaging showed partial recovery of her left ventricular ejection fraction as well as myocardial edema and non-ischemic fibrosis suggestive of inflammatory cardiomyopathy. She underwent intravenous diuresis and eventually started guideline-directed heart failure therapy. Follow-up cardiac magnetic resonance imaging five months later showed improved ejection fraction with mild non-ischemic fibrosis and resolution of myocardial edema and inflammation. She later received an allogeneic stem cell transplant from a matched unrelated donor. Conclusions Gilteritinib may be associated with early cardiotoxicities, including non-ischemic cardiomyopathy and myocarditis. Cardiac magnetic resonance imaging can be an important modality to help differentiate or diagnose early cardiotoxicities associated with novel targeted therapies.

6521 Background: Contemporary anticancer drugs frequently have different efficacy and side effects in men and women. Yet, whether women are well-represented in pivotal trials supporting contemporary anticancer drugs is unknown. The objective of this study was to characterize the representation of women in trials supporting the use of contemporary anticancer drugs. Methods: We retrospectively evaluated all pivotal (phase II and III) trials supporting FDA-approval of anticancer drugs from 1998 to 2018, derived from Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available FDA-drug reviews. Expected population rates were derived from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, and US Census databases. The primary outcome was the report of any gender-specific analysis of efficacy and/or safety, irrespective of treatment-arm. The secondary outcome was the proportional representation of women across trials, evaluated by a participation-to-prevalence ratio (PPR) of 0.85, according to cancer-type. Female representation was also assessed as change across time. Differences in pooled binary endpoint hazard ratios, by the presence or absence of adequate female representation, were also assessed. Results: In total, there were 97,566 participants, enrolled in 189 clinical trials, evaluating 123 anticancer therapies. Gender was reported in 182 (96.3%) clinical trials, of which 43.4% (42,299) were women, compared to 55.6% (55,267) men ( P < 0.01). Overall, women were under-represented in clinical trials of anticancer therapies by a mean of 16.5% compared to the proportional incidence of all cancers in women. Women were the most under-represented in gastric (PPR = 0.821) and liver (PPR = 0.619) cancer trials. Sex-based drug efficacy analysis was only published in 36.8% of trials. Over time, the trend of percentage women recruited into clinical trials increased, but not at a rate comparable to prevalence (-5.0 to -5.5% of prevalence), and the gap in under-representation of women in anticancer therapy clinical trials is widening. Conclusions: Among pivotal clinical trials supporting contemporary FDA-approved cancer drugs, women were frequently under-represented. Additional studies are needed to understand the impact of under-representation on contemporary anticancer therapy outcomes.

Radiation-induced cardiovascular disease, including coronary artery disease, is a well-known sequela of radiation therapy and represents a significant source of morbidity and mortality for cancer survivors. This review examines current literature and guidelines to care for this growing population of cancer survivors. The development of radiation-induced ischemic heart disease following radiation can lead even to early cardiotoxicities, inclusive of coronary artery disease, which limit cancer treatment outcomes. These coronary lesions tend to be diffuse, complex, and proximal. Early detection with multimodality imaging and targeted intervention is required to minimize these risks. Early awareness, detection, and management of radiation-induced cardiovascular disease are paramount as cancer survivorship continues to grow.

e18629 Background: Proliferation of novel anticancer therapies has dramatically improved survival. However, in practice, cardiovascular disease (CVD) events have become an increasing concern. Post-market safety communications by the US Food and Drug Administration (FDA) are a primary source of new safety information for patients and providers. Yet, the prevalence and factors associated with the issuance of CVD warnings among cancer therapies are unknown. Methods: Leveraging the Drugs@FDA database and publicly available FDA drug reviews, we identified all anticancer drugs given new-drug applications from 1998-2018. Characteristics related to approval, including drug class, therapeutic area, priority review status, accelerated approval status, orphan product status, regulatory review times, near-regulatory deadline approval status, and post-market safety events were evaluated. Post-market safety communications were defined as the composite of safety-related drug withdrawals and the issuance of black box label warnings or precautions. CVD was defined as heart failure, hypertension (HTN), coronary disease, myocardial infarction, stroke, thromboembolic disease, arrhythmia/electrocardiographic change, or sudden cardiac death. Multivariable logistic regression was used to assess for characteristics associated with the need for CVD safety communications. Results: Overall, there were 125 novel anticancer therapies, including 24 biologics, 10 immunotherapies, and 48 targeted drugs. There were 177 safety communications (41 black box warnings, 7 withdrawals, 4 dose adjustments, and 84 general warnings). Cardiac safety warnings were issued for 63 (51.2%) of therapies, including 23 (36.5% of all) black box warnings. CVD was the most common reason for a black box warning; Table. Among all CVD warnings, arrhythmias (21.6%) followed by heart failure (13.9%), thromboembolic disease (13.9%), uncontrolled HTN (11.8%), sudden CVD death (9.0%), ischemic disease (6.9%), stroke (4.9%), and other CVD events (12.5%) were found. In a multivariable model, only therapeutic class and prior in-class cardiotoxicity were associated with the issuance of CVD safety communications. Conclusions: Among novel cancer therapies, cardiac safety communications are prevalent.[Table: see text]