Since their invention in the early 2000s, tyrosine kinase inhibitors (TKIs) have gained prominence as the most effective pathway-directed anti-cancer agents. TKIs have shown significant utility in the treatment of multiple hematological malignancies and solid tumors, including chronic myelogenous leukemia, non-small cell lung cancers, gastrointestinal stromal tumors, and HER2-positive breast cancers. Given their widespread applications, an increasing frequency of TKI-induced adverse effects has been reported. Although TKIs are known to affect multiple organs in the body including the lungs, liver, gastrointestinal tract, kidneys, thyroid, blood, and skin, cardiac involvement accounts for some of the most serious complications. The most frequently reported cardiovascular side effects range from hypertension, atrial fibrillation, reduced cardiac function, and heart failure to sudden death. The potential mechanisms of these side effects are unclear, leading to critical knowledge gaps in the development of effective therapy and treatment guidelines. There are limited data to infer the best clinical approaches for the early detection and therapeutic modulation of TKI-induced side effects, and universal consensus regarding various management guidelines is yet to be reached. In this state-of-the-art review, we examine multiple pre-clinical and clinical studies and curate evidence on the pathophysiology, mechanisms, and clinical management of these adverse reactions. We expect that this review will provide researchers and allied healthcare providers with the most up-to-date information on the pathophysiology, natural history, risk stratification, and management of emerging TKI-induced side effects in cancer patients.

Background: Chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers, which redirect T-cells to tumor antigens, have immensely benefitted patients with relapsed/refractory B-cell cancers. How these therapies differ in cardiotoxicity is underexplored. We used the World Health Organization pharmacovigilance database, VigiBase, to compare cardiotoxicity profiles between CD19-targeted CAR-T therapy and blinatumomab (a CD19/CD3-targeted bispecific T-cell engager). Methods: Safety reports in VigiBase were filtered for diffuse large B-cell lymphoma (DLBCL, n = 17,479) and acute lymphocytic leukemia (ALL, n = 28,803) for all adverse reactions. Data were further filtered for patients taking CAR-T therapy or blinatumomab. Reporting odds ratios (ROR) and fatality rates were compared between CAR-T cell products (e.g. tisagenlecleucel and axicabtagene ciloleucel), and between CAR-T therapy and blinatumomab. Results: Tisagenlecleucel is associated with cardiac failure (IC₀₂₅ = 0.366) with fatality rates of 85.7% and 80.0% in DLBCL and pediatric ALL patients respectively. For DLBCL patients, axicabtagene ciloleucel has greater reporting for hypotension than tisagenlecleucel (ROR: 2.54; 95% CI: 1.28–5.03; p = 0.012), but tisagenlecleucel has higher fatality rates for hypotension than axicabtagene ciloleucel [50.0% (tisagenlecleucel) vs 5.6% (axicabtagene ciloleucel); p < 0.001]. Blinatumomab and tisagenlecleucel have similar fatality rates for hypotension in pediatric ALL patients [34.7% (tisagenlecleucel) vs 20.0% (blinatumomab); p = 0.66]. Conclusions: Tisagenlecleucel is associated with severe and fatal adverse cardiac events, with higher fatality rates for hypotension compared to axicabtagene ciloleucel in DLBCL patients, but similar hypotension fatality rates compared to blinatumomab in pediatric ALL patients. Effective management necessitates experienced physicians, including cardio-oncologists, skilled in interdisciplinary approaches to manage these toxicities.

Background: Immune checkpoint inhibitor (ICI)-induced cardiac side effects in cancer patients are increasingly being recognized and can be fatal. There is no standardized cardiac imaging test to examine the effects of ICIs in myocardial morphology and function. Objective: To study the utility of echocardiography and cardiac MRI in examining regional and global changes arising from ICI-induced myocarditis and cardiomyopathy in high-risk subjects suspected to have developed ICI cardiomyopathy. Methods: We studied eight consecutive patients referred for cardiac MRI (CMR) from a comprehensive cancer center for suspected ICI-induced myocarditis and compared the data with sixteen age-matched controls. Using newly developed strain analysis algorithms, we measured myocardial strain and strain rates using echocardiography and CMR. Then, we compared the mean longitudinal strain and strain rates derived from echocardiography and CMR in the same ICI-treated cohort of patients (n = 8). They underwent both of these imaging studies with images taken 24–48 h apart and followed up prospectively within the same hospital course. Results: All our cases had preserved ejection fraction (EF) > 50%. Echocardiogram showed reduced mean systolic longitudinal strain (LS, %) (ICI: −12.381 ± 4.161; control: −19.761 ± 1.925; p < 0.001), peak systolic strain rate (SR_S, s⁻¹) (ICI: −0.597 ± 0.218; control: −0.947 ± 0.135; p = 0.002) and early diastolic strain rate (SR_E, s⁻¹) (ICI: 0.562 ± 0.295; control: 1.073 ± 0.228; p = 0.002) in ICI-treated cases. Direct comparison between the echocardiogram vs. CMR obtained within the same hospital course demonstrated strong a correlation of LS scores (r = 0.83, p = 0.012) and SR_S scores (r = 0.71, p = 0.048). The Bland–Altman plots showed that 95% of the data points fitted within the ±1.96 SD of the mean difference, suggesting an agreement among these two imaging modalities. Conclusion: In this feasibility cohort study, both echocardiography- and CMR-based strain indices illustrate changes in myocardial contractility and relaxation suggestive of ICI-induced cardiomyopathy. Our data, after validation in a larger cohort, can form the basis of myocardial imaging in cancer patients treated with ICIs.

Background: Cancer patients are known to be associated with increased risk of cardiovascular disease. However, no studies have examined the differential impact of hematologic malignancies (HMs) and solid tumors (STs) on cardiac morphology at the tissue level. Objective: We aimed to examine histopathological features alongside cardiovascular biomarkers in patients with HMs and STs who underwent post-mortem evaluation. Methods: We analyzed cardiac changes in 198 patients with HMs and 164 patients with solid tumors STs. We compared demographics, echocardiogram data, exposure to various antineoplastic agents, and post-mortem findings. Additionally, cardiac histological validation was conducted on post-mortem cardiac specimens to examine cardiac tissue morphology, focusing on cardiomyocyte nuclear density, collagen content, and collagen fiber orientation. Results: HM patients displayed significantly disordered collagen fiber alignment (0.71 vs 0.83, P = 0.027), and reduced cardiomyocyte nuclear density (56 vs 72, P = 0.002) compared to ST patients. Similarly, hemoglobin level was decreased (6.71 vs 8.06, P < 0.001) in HM patients compared to ST patients. HM patients also showed elevated B-type natriuretic peptide levels (2,275 vs 867, P < 0.001), without significant differences in creatine-kinase MB and cardiac troponin levels. Multivariate analysis identified increased right ventricular thickness, low diastolic blood pressure, and high cardiac troponin levels as risk factors for cardiac death in HM patients. Conclusions: This study demonstrates that HM patients have fewer cardiomyocyte nuclei and poorly aligned collagen, with serum biomarker evidence of increased cardiac dysfunction. This supports the necessity for specialized cardiac care for these patients.

Background: Cancer survivors with prior chest radiation therapy (CXRT) frequently present with atrial fibrillation, heart failure, and have higher overall long-term mortality. There are no data examining the utility of left atrial (LA) and LA appendage (LAA) volume-indices to predict clinical outcomes in these patients. Objectives: We examined the prognostic value of cardiac phase-dependent 3-D volume-rendered cardiac computerized tomography (CT)-derived LA and LAA volume-indices to predict mortality and major adverse cardiac events (MACE) in cancer survivors treated with thoracic irradiation. Method: We screened 625 consecutive patients with severe aortic stenosis who had undergone transcatheter aortic valve replacement from 2012 to 2017. Based on the gated cardiac CT image quality, we included 184 patients (CXRT:43, non-CXRT:141) for further analysis. We utilized multiplane-3D-reconstructed cardiac CT images to calculate LA and LAA volume-indices, and examined the prognostic role of CCT-derived LA and LAA volume-indices in predicting the all-cause mortality, cardiovascular (CV) mortality, and MACE. We used multivariate cox-proportional hazard analysis to identify the clinical predictors of survival. Results: Overall, the CXRT group had significantly elevated LAA volume-index compared to non-CXRT group (CXRT:11.2 ± 8.9 ml/m²; non-CXRT:8.6 ± 4.5 ml/m², p = 0.03). On multivariate cox-proportional hazard analysis, the elevated LAA volume and LAA volume-index were the strongest predictors of reduced survival in CXRT group compared to non-CXRT group (LAA volume: RR = 1.03,95% CI 1.0–1.01, p = 0.01; and LAA volume index: RR = 1.05, 95% CI 1.0–1.01, p = 0.03). LAA volume > 21.9 ml was associated with increased mortality. In contrast, LA volume was not a significant predictor of mortality. Conclusion: We describe a novel technique to assess LA and LAA volume using 3-D volume-rendered cardiac CT. This study shows enlarged LAA volume rather than LA volume carries a poor prognosis in cancer-survivors treated with prior CXRT. Compared to conventionally reported markers, LAA volume of > 21.9 ml was incremental to that of other risk factors.

Pembrolizumab, a widely used immune checkpoint inhibitor (ICI), has revolutionized the treatment of non-small cell lung cancer (NSCLC). Identifying unique tumor characteristics in patients likely to respond to pembrolizumab could help the clinical adjudication and development of a personalized therapeutic strategy. In this retrospective study, we reviewed the clinical data and pathological features of 84 NSCLC patients treated with pembrolizumab. We examined the correlation between the clinical and demographic characteristics and the tumor histopathologic features obtained before immunotherapy. The response to pembrolizumab therapy was evaluated via the Response Evaluation Criteria in Solid Tumors (RECIST). The clinical data and cancer tissue characteristics were assessed and compared among three groups according to the following RECIST: the responsive group (RG), the stable disease group (SD), and the progressive disease group (PD), where the RG comprised patients with either a complete response (CR) or a partial response (PR). The overall survival rate of the RG group was significantly higher than the SD and PD groups. In addition, the percentage of pre-treatment viable tumor cell content in the RG and SD groups was significantly higher. At the same time, the extracellular stroma proportion was significantly lower than that of the PD group. The number of tumor-infiltrating lymphocytes (TILs) in the RG group was significantly higher than in the PD group. There were no significant differences in tumor necrosis, the stroma composition, PD-L1 expression level (TPS 1–49% vs. ≥50%), and treatment response. In conclusion, our population of NSCLC patients who experienced positive treatment responses to pembrolizumab therapy had a better prognosis compared to patients with either SD or PD. Moreover, the relative proportions of viable tumor cells to tumor-associated lymphocytes were associated with responsiveness to treatment. It is expected that larger prospective clinical studies will further validate these findings.