Objectives The purpose of this study was to estimate heart failure (HF) and cardiomyopathy (CM) rates after adjuvant trastuzumab therapy and chemotherapy in a population of older women with ...early-stage breast cancer. Background Newer biologic therapies for breast cancer such as trastuzumab have been reported to increase HF and CM in clinical trials, especially in combination with anthracycline chemotherapy. Elderly patients, however, typically have a higher prevalence of cardiovascular risk factors and have been underrepresented in trastuzumab clinical trials. Methods Using Surveillance, Epidemiology, and End Results-Medicare data from 2000 through 2007, we identified women 67 to 94 years of age with early-stage breast cancer. We calculated 3-year incidence rates of HF or CM for the following mutually exclusive treatment groups: trastuzumab (with or without nonanthracycline chemotherapy), anthracycline plus trastuzumab, anthracycline (without trastuzumab and with or without nonanthracycline chemotherapy), other nonanthracycline chemotherapy, or no adjuvant chemotherapy or trastuzumab therapy. HF or CM events were ascertained from administrative Medicare claims. Poisson regression was used to quantify risk of HF or CM, adjusting for sociodemographic factors, cancer characteristics, and cardiovascular conditions. Results We identified 45,537 older women (mean age: 76.2 years, standard deviation: 6.2 years) with early-stage breast cancer. Adjusted 3-year HF or CM incidence rates were higher for patients receiving trastuzumab (32.1 per 100 patients) and anthracycline plus trastuzumab (41.9 per 100 patients) compared with no adjuvant therapy (18.1 per 100 patients, p < 0.001). Adding trastuzumab to anthracycline therapy added 12.1, 17.9, and 21.7 HF or CM events per 100 patients over 1, 2, and 3 years of follow-up, respectively. Conclusions HF or CM are common complications after trastuzumab therapy for older women, with higher rates than those reported from clinical trials.
Pivotal trials of chimeric antigen receptor T-cell (CAR-T) have identified common toxicities but may have been underpowered to detect cardiovascular and pulmonary adverse events (CPAEs).
This study ...sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy.
In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. The authors evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 >0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR).
The authors identified CAR-T reports of 2,657 patients, including 546 CPAEs (20.5%). CPAEs overlapped with cytokine release syndrome in 68.3% (373 of 546) of the reports. Compared with the full database, CAR-T was associated with overreporting of tachyarrhythmias (n = 74 2.8%, adj.ROR = 2.78 95% CI: 2.21-3.51), cardiomyopathy (n = 69 2.6%, adj.ROR = 3.51 2.42-5.09), pleural disorders (n = 46 1.7%, adj.ROR = 3.91 2.92-5.23), and pericardial diseases (n = 11 0.4%, adj.ROR = 2.26 1.25-4.09, all IC025 >0). Venous thromboembolic events (VTEs) were associated only with axicabtagene-ciloleucel therapy (n = 28 1.6%, adj.ROR = 1.80 1.24-2.62, IC025 >0). Atrial fibrillation (n = 55) was the leading tachyarrhythmia, followed by ventricular arrhythmias (n = 14). Tachyarrhythmias and VTEs were reported more often following axicabtagene-ciloleucel than tisagenlecleucel in an age- and sex-adjusted model (adj.ROR = 1.82 1.04-3.18 and adj.ROR = 2.86 1.18-6.93, respectively). Finally, the fatality rate of CPAEs was 30.9%.
In this largest post-marketing study to date, the authors identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. These findings should be considered in the multidisciplinary assessment for and monitoring of CAR-T therapy recipients.
Display omitted
Background Interfering with angiogenesis is an effective, widely used approach to cancer therapy, but antiangiogenic therapies have been associated with important systemic cardiovascular toxicities ...such as hypertension, left ventricular dysfunction, heart failure, and myocardial ischemia and infarction. As the use of vascular endothelial growth factor signaling pathway (VSP) inhibitors broadens to include older patients and those with existing cardiovascular disease, the adverse effects are likely to be more frequent, and cardiologists will increasingly be enlisted to help oncologists manage patients who develop adverse cardiovascular effects. Methods The Cardiovascular Toxicities Panel of the National Cancer Institute reviewed the published literature and abstracts from major meetings, shared experience gained during clinical development of VSP inhibitors, and contributed extensive clinical experience in evaluating and treating patients with cancer with cardiovascular disease. This report was edited and approved by the National Cancer Institute Investigational Drug Steering Committee. It presents the panel's expert opinion on the current clinical use and future investigation for safer, more expansive use of these drugs. Results and Conclusions The panel recommends that physicians (1) conduct and document a formal risk assessment for existing cardiovascular disease and potential cardiovascular complications before VSP inhibitor treatment recognizing that preexisting hypertension and cardiovascular disease are common in patients with cancer, (2) actively monitor for blood pressure elevations and cardiac toxicity with more frequent assessments during the first treatment cycle, and (3) aggressively manage blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications of VSP inhibitor therapy.
Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment of patients with relapsed and refractory hematologic malignancies and is increasingly investigated as a ...therapeutic option of other malignancies. The main adverse effect of CAR T-cell therapy is potentially life-threatening cytokine release syndrome (CRS). Clinical cardiovascular (CV) manifestations of CRS include tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction, pulmonary edema, and cardiogenic shock. Although insults related to CRS toxicity might be transient and reversible in most instances in patients with adequate CV reserve, they can be particularly challenging in higher-risk, often elderly patients with pre-existing CV disease. As the use of CAR T-cell therapy expands to include a wider patient population, careful patient selection, pre-treatment cardiac evaluation, and CV risk stratification should be considered within the CAR T-cell treatment protocol. Early diagnosis and management of CV complications in patients with CRS require awareness and multidisciplinary collaboration.
Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to ...trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified (
n
= 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg,
p
< 0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years,
p
= 0.014) with lower LVEF before anthracycline (63 vs. 67 %,
p
< 0.0001) and trastuzumab (62 vs. 67 %,
p
< 0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients.
Purpose
Asymptomatic decline in left ventricular ejection fraction (LVEF) or heart failure (HF) occurs in up to 25% of patients treated with trastuzumab and can result in incomplete breast cancer ...therapy. The cardiac safety of continuing trastuzumab in patients with asymptomatic LVEF decline is unknown. We report the cardiac outcomes of patients treated with trastuzumab after a significant asymptomatic LVEF decline.
Methods
Patients with HER2-positive breast cancer and asymptomatic LVEF decline to < 50% during trastuzumab were identified from an institutional echocardiogram database. Patients who received trastuzumab with a LVEF < 50% were classified as the continued group, whereas patients who had trastuzumab held until LVEF improved to ≥ 50% or who had trastuzumab permanently discontinued were classified as the interrupted group. Cardiac events were defined as HF (New York Heart Association class III–IV) or cardiovascular death.
Results
Sixty patients were included; the median age was 54 years. In 23 patients who continued trastuzumab, 14 (61%) tolerated trastuzumab without a cardiac event, 6 (26%) developed worsening LVEF (range 25–42%) leading to trastuzumab discontinuation, and three (13%) developed a cardiac event (1 HF, 2 possible/probable cardiovascular deaths). In 37 patients with interrupted trastuzumab, 15 (41%) were re-challenged with trastuzumab after LVEF improved to > 50%, 21 (57%) were not re-challenged, and one (3%) developed HF. More patients in the continued trastuzumab group had metastatic disease (39% vs. 5%,
p
= 0.002). The final LVEF after median follow-up of 633 days was similar between patients with trastuzumab continuation versus interruption (54% vs. 56%,
p
= 0.29).
Conclusion
Continuation of trastuzumab after an asymptomatic LVEF decline to < 50% in patients who are expected to benefit from additional anti-HER2 therapy is a promising approach that warrants further investigation.
Abstract
Aims
Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient’s immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related ...cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality.
Methods and results
From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104–647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan–Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6–4.7 after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4–8.8) after adjusting for cancer burden.
Conclusion
Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.
Structured Graphical Abstract
Structured Graphical Abstract
Cancer patients treated with chimeric antigen receptor T-cell therapy (CAR-T) who experience severe cardiovascular events have higher overall mortality and non-relapse mortality and higher peak levels of IL-6, CRP, ferritin, and troponin. The overall survival was graphed as the Simon—Makuch curve. Non-relapse mortality was graphed as cumulative incidence. IL-6, interleukin-6; CRP, C-reactive protein; HR, hazard ratio; CI, confidence interval.
*P-value is from the score test provided by the univariable time-dependent Cox model.
PDF
