Cardiovascular Toxicities in Chimeric Antigen Receptor Therapy in Relapsed and Refractory Multiple Myeloma and Lymphoma Using FAERS Database

Abstract

Introduction: In the past decade, chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of relapsed refractory multiple myeloma (RRMM) and lymphoma, but it is associated with significant cardiovascular adverse effects. We aim to analyze the incidence, patterns, and outcomes of cardiac events in RRMM and lymphoma patients undergoing CAR-T therapy utilizing the FDA Adverse Event Reporting System (FAERS) database, paving the way for future research and being more vigilant in treating high-risk populations. Methods: We conducted a retrospective post-marketing pharmacovigilance inquiry using the FDA Adverse Event Reporting System (FAERS) database and the Medical Dictionary for Regulatory Activities (MEDRA). We examined the adverse effects associated with CAR-T and TCE since their FDA approval in US and non-US populations (accessed 5 January 2024), and we analyzed the incidence of cardiac events related to six CAR-T products: Idecabtagene vicleucel, Ciltacabtagene autoleucel, Axicabtagene ciloleucel, Tisagenlecleucel, Lisocabtagene maraleucel, and Brexucabtagene autoleucel since FDA approval. Cardiotoxicities were assessed, including coronary artery disease (CAD), myocardial infarction (MI), arrhythmia, heart failure, and hypotension. Results: Out of 12,949 adverse events, we identified 675 (5.2%) cardiac events irrespective of severity. Almost 440 (65%) cardiac events were associated with cytokine release syndrome (CRS). The most common cardiotoxic event was atrial fibrillation (122), followed by the development of heart failure (113), ventricular arrhythmia (108), hypotension (87), and bradyarrhythmia (41). The mortality rate was highest among Brexucabtagene autoleucel recipients (n = 26, 2.3%), followed by Tisagenlecleucel (n = 71, 2.1%) and Lisocabtagene maraleucel (n = 10, 2.1%). Conclusions: CAR-T therapy can result in fatal adverse events due to its cardiotoxic properties. Timely monitoring, such as screening echocardiography and electrocardiograms, can help identify the at-risk population and allow for early intervention—particularly in patients with high baseline cardiovascular risk or previous exposure to cardiotoxic agents—thereby improving outcomes by enabling risk stratification and supportive management.

1. Introduction

CAR T-cell therapy shows promising survival rates in treating RRMM and lymphoma. However, it is associated with severe toxicities, including significant toxicities, contributing to considerable morbidity, and it presents a major risk to patients undergoing CAR T-cell therapy [1,2]. As the treatment keeps expanding, understanding the causes and types of cardiovascular toxicities in CAR T-cell therapy is crucial, aiding in developing safer treatment protocols [2].

CAR T-cell therapy involves invoking a patient’s T-cells to target specific antigens, like CD19, on cancer cells, harnessing the immune system’s ability to destroy malignant cells precisely [3]. However, this can trigger inflammatory responses and cytokine release syndrome (CRS), contributing to both direct and indirect cardiovascular toxicities [4,5]. Despite growing research, gaps remain in understanding the cardiovascular side effects associated with CAR T-cell therapy. Most of these studies were performed in small sample sizes, with short follow-up periods, and with a lack of standardization in adverse event reporting [3,4]. While clinical trials demonstrate the potential of disease management, cardiovascular complications remain a persistent concern that needs further investigation [6,7].

Most existing studies are small and single-center, limiting generalizability and failing to capture the full spectrum of cardiovascular adverse events across diverse populations [6]. Although clinical trials provide initial insights, there needs to be real-world cardiovascular risks associated with CAR T-cell therapy, particularly in long-term settings [4,8]. Moreover, standardized criteria for identifying and reporting cardiovascular toxicities are lacking, which can lead to variations in results and potential biases. Current research has not thoroughly utilized large-scale pharmacovigilance databases like FAERS, which provide a broader dataset to capture real-world adverse events that may be underrepresented in clinical trials [8,9].

We used the extensive pharmacovigilance real-world FAERS database to investigate the incidence, prevalence, severity, and outcomes of cardiovascular toxicities associated with CAR T-cell therapy in patients with RRMM and lymphoma [10]. Our findings will provide valuable insights for enhancing cardiovascular risk management in CAR T-cell therapy and informing clinic guidelines [8].

2. Results

A total of 12,949 CAR-T-related adverse events of varying intensity were reported in the FAERS database (

Table 1. Cardiotoxic events with various CAR-T therapies.

Adverse Events	Axicabtagene Ciloleucel	Brexucabtagene Autoleucel	Tisagenlecleucel	Lisocabtagene Maraleucel	Idecabtagene Vicleucel	Ciltacabtagene Autoleucel
Total Adverse Events	6222	1127	3290	463	722	1125
Cardiac Events	278	85	208	17	50	37
Cardiac Events with Associated CRS	174	62	137	13	39	15
Hospitalized	152	26	62	7	14	15
Death	92	26	71	10	5	13
Mortality Rate	1.4%	2.3%	2.1%	2.1%	0.6%	1.1%
CAD/ACS	19	9	18	1	1	10
Atrial Fibrillation	59	12	36	5	5	5
Ventricular Arrhythmia	10	40	10	6	34	8
Bradyarrhythmia	17	8	13	2	1	0
Heart Failure	58	5	41	1	1	7
Hypotension	57	21	-	3	4	2

). Of those, the highest reported adverse events were seen with Axicabtagene ciloleucel (n = 6222), followed by Tisagenlecleucel (n = 3290), Brexucabtagene autoleucel (n = 1127), Ciltacabtagene autoleucel (n = 1125), Idecabtagene vicleucel (n = 722), and Lisocabtagene maraleucel (n = 463).

We identified 675 cardiac events irrespective of severity. The highest incidence of cardiotoxicity was noted with Brexucabtagene autoleucel (n = 85), followed by Idecabtagene vicleucel (n = 50), Tisagenlecleucel (n = 208), Axicabtagene ciloleucel (n = 278) Lisocabtagene maraleucel (n = 17), and Ciltacabtagene autoleucel (n = 37).

Almost 440 (65%) cardiac events were associated with cytokine release syndrome (CRS), with Axicabtagene ciloleucel reporting the highest number of such cases (n = 174), followed by Tisagenlecleucel (n = 137) and Brexucabtagene autoleucel (n = 62). Lisocabtagene maraleucel reported the fewest cases of cardiac events with CRS (n = 13).

Axicabtagene ciloleucel had the highest number of hospitalizations related to cardiac events (n = 152), followed by Tisagenlecleucel (n = 62). In contrast, Lisocabtagene maraleucel had the lowest number of hospitalizations (n = 7).

Across therapies, atrial fibrillation (n = 122) was reported as the most frequent cardiotoxic effect, with Axicabtagene ciloleucel reporting the highest number of cases (n = 59), followed by Tisagenlecleucel (n = 36).

The second most common cardiotoxic event was the development of heart failure (n = 113), with the highest incidence noted in Axicabtagene ciloleucel (n = 58), followed by Tisagenlecleucel (n = 41) and Ciltacabtagene autoleucel (n = 7).

Out of 108 ventricular arrhythmias reported, Brexucabtagene autoleucel had the highest number of ventricular arrhythmia (n = 40), standing out compared to the other therapies.

Axicabtagene ciloleucel had the most bradyarrhythmia cases (n = 17), followed by Tisagenlecleucel (n = 13), Brexucabtagene autoleucel (n = 8), Lisocabtagene maraleucel (n = 2), Idecabtagene vicleucel (n = 1), and Ciltacabtagene autoleucel (n = 1).

Mortality rate was highest among Brexucabtagene autoleucel recipients (n = 26), followed by Tisagenlecleucel (n = 71), Lisocabtagene maraleucel (n = 10), Ciltacabtagene autoleucel (n = 13), and Idecabtagene vicleucel (n = 5).

3. Discussion

3.1. Pathogenesis of CAR-T Therapy Induced Cardiotoxicity

CAR T-cells identify and interact with antigen-expressing tumor cells, triggering their proliferation and inducing a pro-inflammatory cytokine surge into the bloodstream. This leads to a systemic inflammatory response that causes endothelial injury and capillary leakage, manifesting as CRS. Our findings suggest that most cardiotoxic events were associated with CRS, with the highest incidence seen with Axicel. Symptoms include fever, tachycardia, hypotension, and hypoxia, and it can escalate to potentially life-threatening multi-organ dysfunction [11].

The murine model has emphasized the critical role of in situ monocyte and macrophage cells in the secretion of inflammatory cytokines, specifically interleukin-1 (IL-1) and interleukin-6 (IL-6) [12,13]. Blocking the signaling pathways of IL-1 and IL-6 can lead to a downregulation of pro-inflammatory cytokines. Various trials are underway to evaluate the effectiveness of medications such as Tocilizumab (an anti-IL-6 monoclonal antibody) and Anakinra (an IL-1 antagonist) in treating cytokine release syndrome [14,15].

Cardiotoxicity occurs due to the release of cardiac cytokines such as TNF-α and IFN-γ, endothelial dysfunction, direct inflammation of the myocardium, and cytokine release syndrome (CRS). Histopathological reports of cardiac death related to MAGE-A3-specified CAR T-cell therapy for melanoma and myeloma revealed the highest concentrations in the myocardium and pericardial fluid, suggesting extensive myocardial necrosis and lymphoid CD3+ T infiltration. Notably, CD3+ T-cell infiltration was specific to the myocardium, suggesting a potential for direct T-cell-mediated cardiac injury and toxicity. Further research is needed to confirm these findings [16].

3.2. Clinical Manifestation of Cardiovascular Side Effects Associated with CAR T-Cell Therapy

3.2.1. Cytokine Release Syndrome and Hypotension

Hypotension is a common and potentially serious side effect driven by CRS.

The American Society for Transplantation and Cellular Therapy published a consensus grading system for CRS. Symptoms typically manifest within days, and occasionally weeks, following CAR T-cell infusion, correlating with the peak in vivo expansion of T-cells observed in some translational studies. Research has aimed to identify which high-risk groups for severe CRS to facilitate targeted prevention strategies for. The principal risk factor for severe CRS is a high disease burden, which indicates a more significant antigenic load. Other important factors include the dose of infused cells, the presence of comorbidities, and the early onset of CRS (within the first three days). Ongoing translational research seeks to identify and validate predictive biomarkers for CRS.

Increased cytokine release syndrome (CRS) levels were associated with higher levels of soluble IL-2 receptor, peak IL-6, peak ferritin, peak C-reactive protein (CRP), and elevated blood CAR T-cell counts. Some studies have indicated that the severity of CRS and the increase in serum cytokines are related to the disease burden, with a higher disease burden predicting more significant toxicity [17].

A meta-analysis of thirteen studies assessing the incidence of hypotension in CAR T-cell therapy. The overall pooled proportion of hypotension was 28.6% (95% CI: 0.158–0.414). There was considerable heterogeneity among the studies included in the analysis, indicated by an I² value of 96% (p < 0.01), and a random-effects model was employed. In the subgroup analysis, the incidence of hypotension was 31.5% (95% CI: 0.169–0.461) for the CD19 subgroup, while it was 18.4% (95% CI: 0.132–0.235) for other subgroups [18].

In clinical trials on CAR T-cell therapies such as ZUMA-1, JULIET, and ZUMA-2, hypotension of any grade was described in 16–59% of the analyzed population, with up to 22% requiring vasopressor support [19,20,21].

3.2.2. Heart Failure

Our study suggests that the second most common event recorded was heart failure, with the highest number of events noted in Axicel. Cytokine release can lead to vascular leakage and significantly positive fluid balances, potentially resulting in capillary leak syndrome. This syndrome is characterized by a triad of symptoms: hypotension, edema, and hemoconcentration with hypoproteinemia.

However, data collection on cardiovascular complications has mainly been retrospective, and not all patients underwent echocardiography during their hypotensive episodes, making it difficult to rule out left-ventricular systolic dysfunction (LVSD). It has also been suggested that LVSD in this context may represent a nonspecific stress-induced phenomenon or Takotsubo cardiomyopathy [22].

Burstein et al. [23]. examined CD19 CAR T-cell therapy patients; 24% developed cardiovascular dysfunction, requiring inotropic support with high-grade CRS.

Among the patients in the analysis who required inotropic support due to hypotension, at least 41% developed new LVSD. In this study, a deterioration in left-ventricular systolic function was defined as either a decrease in ejection fraction > 10% or fractional shortening > 5% compared to baseline or as an ejection fraction < 55% or fractional shortening of less than 28% when previously normal at baseline. Long-term follow-up also showed cardiac systolic and diastolic dysfunction in 7% (n = 7) of patients at discharge, with persistent dysfunction observed in just 1% (n = 1) at 6 months. In a small group of patients for whom serum cardiac biomarkers were measured, significant abnormalities were noted: 92% had elevated levels of B-type natriuretic peptide (median 580 pg/mL), 79% had elevated lactate levels (median 3.05 mmol/L), and 52% had low mixed venous saturations (median 68.5%).

In a study conducted by Shalbi et al., [24]. cardiac dysfunction was defined as either a >10% absolute decrease in left-ventricular ejection fraction (LVEF) compared to baseline or the new onset of LVSD of grade ≥ 2 with an LVEF < 50%. Cardiac dysfunction was observed in 6 out of 52 patients. Notably, four of these six patients had grade 3–4 severe cytokine release syndrome (CRS), suggesting that CRS plays a role in the development of cardiovascular dysfunction.

Alvi et al. [25]. conducted a retrospective study involving 137 adult patients examining the cardiovascular complications associated with CAR T-cell therapy. Following the infusion, 54% of those assessed (n = 29) had elevated troponin levels, indicating myocardial injury. Cardiovascular events occurred in 12% of the patients (n = 17), with six individuals experiencing cardiovascular death due to new-onset heart failure. Additionally, another six patients developed decompensated cardiac failure.

In our study, the second most common cardiotoxic event was the development of heart failure (n = 113). The highest incidence was observed in patients treated with Axicabtagene ciloleucel (n = 58), followed by those treated with Tisagenlecleucel (n = 41). Notably, Axicabtagene ciloleucel reported the highest number of cases of cytokine release syndrome (CRS) (n = 174), suggesting a possible association between CRS and heart failure.

3.3. Arrhythmias Related to CAR T-Cell Therapy

The most frequently observed abnormalities in these patients include asymptomatic prolonged QTc and atrial fibrillation [26,27]. These findings align with our study.

Arrhythmias may arise as a direct result of cytokines affecting the electrical system. This phenomenon is similar to those observed in patients with inflammatory diseases such as rheumatoid arthritis or myocarditis [28].

Increases in circulating cytokines directly impact cardiomyocytes and stimulate the heart through an activated sympathetic nervous system. This stimulation leads to changes in calcium and potassium channels, which prolong the action potential duration. Additionally, systemic inflammation, particularly interleukin-6 (IL-6)‘s influence, may be a significant risk factor for QT prolongation [29,30].

Elevated C-reactive protein (CRP) levels have been linked to both the onset and persistence of atrial fibrillation [31]. Potential mechanisms for this association may include disrupted calcium homeostasis caused by interleukins (ILs) and tumor necrosis factor-alpha (TNF-α), as well as the downregulation of connexins 43 and 40 due to IL-6 [32].

Cytotoxins released from activated CAR T-cells significantly shorten action potential duration (APD), slow conduction velocity (CV), and impulse block reentrant arrhythmias. Additionally, this study indicated that macrophages play a significant role in these effects. This suggests that developing agents targeting the cytotoxins released by CAR T-cells and macrophages could help reduce the risk of arrhythmias associated with CAR T-cell therapy [33].

In our study of arrhythmias associated with CAR T-cell therapy, we found that atrial fibrillation was the most frequently reported cardiotoxic effect, occurring in 122 cases. This was followed by ventricular arrhythmias (108 cases) and bradyarrhythmias (41 cases). Notably, Axicabtagene ciloleucel reported the highest number of atrial fibrillation cases (59) and bradyarrhythmias (17). Interestingly, out of the 108 reported ventricular arrhythmias, Brexucabtagene autoleucel had the highest occurrence, with 40 cases, distinguishing it from other therapies.

4. Materials and Methods

We conducted a retrospective post-marketing pharmacovigilance review using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, a publicly accessible database, and the Medical Dictionary for Regulatory Activities (MEDRA). This database contains information on the suspected pharmacological agent, its indication, patient characteristics, reported adverse events, and outcomes. We examined the adverse effects of CAR-T and TCE since their FDA approval in the United States and in non-US populations. The data was queried from FDA approval until 5 January 2024.

Until May 2024, only six CAR-T products, such as Idecabtagene vicleucel, Ciltacabtagene autoleucel, Axicabtagene ciloleucel, Tisagenlecleucel, Lisocabtagene maraleucel, and Brexucabtagene autoleucel, were FDA-approved for the treatment of RRMM and lymphoma. We collected all the adverse effects of the above-mentioned medications since their FDA approval until 1st May. Cardiotoxicities were defined as coronary artery disease (CAD), myocardial infarction (MI), arrhythmias, such as bradyarrhthymia, atrial fibrillation, and ventricular arrhythmia, heart failure, and hypotension.

Patients with known cardiovascular disease or high baseline risk (e.g., reduced LVEF, coronary artery disease) may benefit from a tailored monitoring strategy. This could include baseline and serial troponin and BNP levels, echocardiographic assessments, and telemetry monitoring during peak CRS periods. Prophylactic use of corticosteroids and earlier administration of IL-6 inhibitors like tocilizumab may be considered in such high-risk populations based on clinical discretion. Patients with known cardiovascular disease or high baseline risk (e.g., reduced LVEF, coronary artery disease) may benefit from a tailored monitoring strategy. This could include baseline and serial troponin and BNP levels, echocardiographic assessments, and telemetry monitoring during peak CRS periods. Prophylactic use of corticosteroids and earlier administration of IL-6 inhibitors like tocilizumab may be considered in such high-risk populations based on clinical discretion [25].

We used descriptive analysis using numbers and percentages for categorical variables. Incomplete data entries, such as the drug involved not being reported, were removed.

5. Conclusions

Current data suggest that cardiovascular toxicities associated with CAR T-cell therapy primarily occur early and are linked to cytokine release syndrome (CRS). However, CAR T-cell therapy’s potential for long-term and late-onset cardiovascular adverse effects is still not fully understood. In a retrospective review conducted by Cordeiro et al. [34]., which analyzed a cohort of 86 patients who survived beyond one year after receiving CAR T-cell infusion, several late adverse events were identified. These included significant cytopenias, hypogammaglobulinemia, infections, subsequent malignancies, immune-related issues, graft-versus-host disease in patients who had previously undergone allogeneic stem cell transplants, and neurologic or psychiatric events. Notably, no recorded cardiovascular complications that led to late morbidity or mortality were recorded in Cordeiro et al.’s analysis. Although comprehensive long-term follow-up data on CAR T-cell therapy is still lacking regarding long-term toxicity and complications, current evidence suggests that most cardiovascular issues associated with this innovative therapy are likely to be transient, occurring early and shortly after infusion.

We warrant precardiac work, which would screen the population, identify those at higher risk, closely monitor them, and treat them at an earlier stage. Screening guidelines are warranted, including serial electrocardiograms during treatment, serial echocardiograms, and cardiac imaging for close monitoring of this population. Prospective studies have shown that pre-treatment cardiac assessment can aid in identifying subclinical dysfunction, enabling early interventions such as fluid management, vasopressor use, and immunomodulatory therapy, which may mitigate severe complications [23,24].

Limitations: Our findings provide real-world evidence for the incidence and spectrum of cardiotoxicities associated with various CAR-T products. By highlighting the predominance of arrhythmias and heart failure linked to CRS, our results support incorporating cardiac risk stratification and toxicity surveillance protocols into future consensus guidelines. Furthermore, product-specific toxicity patterns (e.g., higher ventricular arrhythmias with Brexucabtagene) could guide therapeutic selection or pre-infusion optimization. As a spontaneous voluntary reporting system, it leads to underreporting and duplicate entries, which affect generalizability. The limited availability of patient-specific demographics and missing information can lead to confounding and causality effects.

Despite the limitations mentioned above, we wanted to bring the cardiotoxic effects of CAR-T to the attention of future clinical trials and research.

This warrants further clinical trials, allowing us to study the population better.