Bispecific T-cell redirecting antibody (BsAb) therapies are a class of immunotherapies that use bivalent antibodies engineered to contain 2 antigen-binding sites that target cancer cell–specific antigens and native T-cell-specific antigens to colocalize T-cells to tumor sites, leading to the destruction of cancer cells by the immune system.1,2 As of 2025, BsAb therapies are available for treatment of relapsed, refractory leukemia, lymphoma, and multiple myeloma.1 The advent of BsAb therapies has shown significant promise for patients; however, data regarding the effects of these therapies on the cardiovascular system are limited. In this study, we sought to characterize cardiovascular adverse events (CVAEs) following treatment with BsAb therapies.
We retrospectively identified adult patients who received BsAb therapy at Northwestern Medicine between 2022 and 2024. Clinical data were collected via chart review. CVAEs were retrospectively adjudicated according to guidelines3 and defined as the first occurrence of any of the following through 6 months of follow-up: 1) cancer therapy–related cardiac dysfunction (CTRCD), defined as new left ventricular ejection fraction (LVEF) reduction to <40% (severe), new LVEF reduction by ≥10% points to an LVEF of 40% to 49% (moderate), or symptomatic heart failure requiring intensification of diuretic and/or heart failure therapy; 2) new-onset atrial fibrillation among patients without histories of atrial fibrillation; and 3) myocardial infarction (MI), defined by a presentation consistent with acute coronary syndrome. Mild CTRCD (defined by LVEF >50%, decline in global longitudinal strain, or increases in cardiac biomarkers without symptoms) was not classified as a CVAE but was noted as a comparator. Baseline characteristics were compared between patients with and those without CVAEs using the chi-square test, Fisher exact test, 2-sample Student’s t-test, or Wilcoxon test as appropriate. The 6-month cumulative incidence of CVAEs was estimated using the Kaplan-Meier function; competing risks were not used, as no deaths occurred prior to 6 months. The Northwestern University Institutional Review Board approved this study.
Overall, 140 patients received BsAb therapies, including 79 patients with multiple myeloma treated with teclistamab, 38 patients with leukemia treated with blinatumomab, and 20 patients with lymphoma treated with glofitamab, epcoritamab, or mosunetuzumab. Baseline characteristics of the study cohort are shown in Table 1. The mean age of the cohort was 64 ± 17 years, and 51.4% of patients (72 of 140) were woman. Almost one-third (32.3%) of patients (50 of 133) identified as non-White. The median number of cycles of BsAb therapy received was 4 (Q1-Q3: 2-9). Prior to receiving BsAb therapy, 42.1% of patients (59 of 140) received anthracycline therapy, 41.4% (58 of 140) received carfilzomib, 26.4% (37 of 140) received chimeric antigen receptor (CAR) T-cell therapy, and 40.0% (56 of 140) underwent stem cell transplantation.
Table 1.
Baseline Characteristics of the Study Cohort, Stratified by Cardiovascular Events Within 6 Months of BsAb Therapy
| n | All (N = 140) | Cardiovascular Adverse Events |
P Valuea | ||
|---|---|---|---|---|---|
| No (n = 124) | Yes (n = 16) | ||||
| Age, y | 140 | 63.9 ± 16.5 | 63.4 ± 16.4 | 67.8 ± 17.1 | 0.32 |
| Female | 140 | 72 (51.4) | 62 (50.0) | 10 (62.5) | 0.35 |
| Body mass index, kg/m2 | 124 | 26.6 (23.7-30.6) | 26.8 (23.9-30.6) | 25.2 (21.5-31.0) | 0.46 |
| Ethnicity | 133 | 0.25 | |||
| White | 90 (67.7) | 80 (67.8) | 10 (66.7) | ||
| African American | 18 (13.5) | 14 (11.9) | 4 (26.7) | ||
| Hispanic | 15 (11.3) | 15 (12.7) | 0 (0.0) | ||
| Asian | 10 (7.5) | 9 (7.6) | 1 (6.7) | ||
| Cardiac history and risk factors | |||||
| Heart failure | 140 | 11 (7.9) | 8 (6.5) | 3 (18.8) | 0.08 |
| Arrhythmia | 140 | 7 (5.0) | 4 (3.2) | 3 (18.8) | <0.01 |
| Coronary artery disease | 140 | 13 (9.3) | 10 (8.1) | 3 (18.8) | 0.17 |
| Myocardial infarction | 140 | 0 (0) | 0 (0) | 0 (0) | NA |
| Hypertension | 140 | 66 (47.1) | 55 (44.4) | 11 (68.8) | 0.07 |
| Diabetes mellitus | 140 | 31 (22.1) | 27 (21.8) | 4 (25.0) | 0.75 |
| Hyperlipidemia | 140 | 47 (33.6) | 39 (31.5) | 8 (50.0) | 0.14 |
| Cerebral vascular accident | 140 | 1 (0.7) | 1 (0.8) | 0 (0) | 0.75 |
| End-stage renal disease | 140 | 5 (3.6) | 2 (1.6) | 3 (18.8) | 0.011 |
| Tobacco use | 137 | 0.14 | |||
| Never | 87 (63.5) | 80 (66.1) | 7 (43.8) | ||
| Former | 43 (31.4) | 35 (28.9) | 8 (50.0) | ||
| Current | 7 (5.1) | 6 (5.0) | 1 (6.3) | ||
| Statin use | 140 | 51 (36.4) | 43 (34.7) | 8 (50.0) | 0.23 |
| Beta-blocker use | 140 | 55 (39.3) | 50 (40.3) | 5 (31.3) | 0.48 |
| ACE inhibitor use | 140 | 12 (8.6) | 10 (8.1) | 2 (12.5) | 0.63 |
| ARB use | 140 | 21 (15.0) | 19 (15.3) | 2 (12.5) | 1.00 |
| ARNI use | 140 | 1 (0.7) | 1 (0.8) | 0 (0) | 1.00 |
| Aspirin use | 140 | 26 (18.6) | 23 (18.5) | 3 (18.8) | 1.00 |
| SGLT2 inhibitor use | 140 | 5 (3.6) | 4 (3.2) | 1 (6.3) | 0.46 |
| GLP-1 receptor agonist use | 140 | 2 (1.4) | 2 (1.6) | 0 (0) | 1.00 |
| CCB use | 140 | 30 (21.4) | 27 (21.8) | 3 (18.8) | 1.00 |
| Malignancy and treatment history | |||||
| Type of cancer | 140 | 0.14 | |||
| Diffuse large B-cell lymphoma | 18 (12.9) | 14 (11.3) | 4 (25.0) | ||
| Multiple myeloma | 80 (57.1) | 73 (58.9) | 7 (43.8) | ||
| Acute lymphocytic leukemia | 38 (27.1) | 34 (27.4) | 4 (25.0) | ||
| Burkitt lymphoma | 1 (0.7) | 0 (0) | 1 (6.3) | ||
| Mantle cell lymphoma | 1 (0.7) | 1 (0.8) | 0 (0) | ||
| Other | 2 (1.4) | 2 (1.6) | 0 (0) | ||
| BsAb therapy | 140 | 0.19 | |||
| Blinatumomab | 41 (29.3) | 37 (29.8) | 4 (25.0) | ||
| Glofitamab | 6 (4.3) | 4 (3.2) | 2 (12.5) | ||
| Teclistamab | 79 (56.4) | 72 (58.1) | 7 (43.8) | ||
| Epcoritamab-bysp | 13 (9.3) | 10 (8.1) | 3 (18.8) | ||
| Mosunetuzumab-axgb | 1 (0.7) | 1 (0.8) | 0 (0) | ||
| Number of BsAb cycles | 134 | 4 (2-9) | 4 (2-9) | 2 (1-5) | 0.13 |
| Days between BsAb cycles 1 and 2 | 109 | 42 (39-48) | 42 (39-48) | 42.5 (37-48) | 0.60 |
| Chest radiation | 136 | 1 (0.7) | 1 (0.8) | 0 (0) | 1.00 |
| Anthracycline exposure | 140 | 59 (42.1) | 52 (41.9) | 7 (43.8) | 0.89 |
| Total anthracycline dose, mg/m2 | 59 | 175 (90-250) | 163 (90-188) | 175 (80-300) | 0.65 |
| Anthracycline dose > 250 mg/m2 | 59 | 14 (23.7) | 11 (21.2) | 3 (42.9) | 0.34 |
| Prior carfilzomib | 140 | 58 (41.4) | 53 (42.7) | 5 (31.3) | 0.38 |
| Prior cyclophosphamide | 140 | 2 (1.4) | 2 (1.6) | 0 (0) | 1.00 |
| Prior tyrosine kinase inhibitor | 140 | 10 (7.1) | 8 (6.5) | 2 (12.5) | 0.32 |
| Prior CAR T-cell therapy | 140 | 37 (26.4) | 31 (25.0) | 6 (37.5) | 0.28 |
| Prior stem cell transplantation | 140 | 56 (40.0) | 51 (43.2) | 5 (38.5) | 0.74 |
Values are mean ± SD, n (%), or median (Q1-Q3). Laboratory values reflect the first result after admission and before BsAb treatment.
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; BsAb = bispecific T-cell redirecting antibody; CAR = chimeric antigen receptor; CCB = calcium-channel blocker; GLP-1 = glucagon-like peptide 1; SGLT2 = sodium-glucose cotransporter 2.
P values were determined using the chi-square test, Fisher exact test, 2-sample Student’s t-test, or Wilcoxon test as appropriate.
Among patients who received BsAb therapies, the cumulative incidence for any CVAE was 12.3% (95% CI: 7.2%-18.5%). This included moderate to severe CTRCD, 6.6% (95% CI: 2.9%-11.6%); atrial fibrillation, 5.4% (95% CI: 2.2%-9.9%); and MI, 0.8% (95% CI: 0.0004%-3.1%). Mild CTRCD, not included in the CVAE definition, occurred in 5.8% (95% CI: 2.3%-10.6%) of patients. The median time to CVAE development was 47 days (Q1-Q3: 15-107 days) following cycle 1 of BsAb therapy. Seventy-five percent of CVAEs (12 of 16) occurred during cycle 1 of therapy. Overall, 34.3% of patients (48 of 140) developed cytokine release syndrome (CRS) following BsAb therapy (grade 1 in 37 patients, grade 2 in 8 patients, grade 3 in 2 patients, and grade 4 in 1 patient). Three of these patients developed CRS (all grade 1) following cycle 1 and experienced CVAEs. There was no significant association between post-BsAb CRS development and subsequent CVAE (P = 0.69).
Few studies have comprehensively assessed CVAEs in patients with multiple myeloma, lymphoma, and leukemia treated with BsAb therapy. Previous retrospective studies were limited to patients with leukemia treated with blinatumomab.4 In this single-center analysis, the cumulative incidence of CVAEs, including atrial fibrillation, moderate to severe CTRCD, and MI within 6 months of cycle 1 of treatment with BsAb was 12.3% (95% CI: 7.2%-18.5%). There was no association between post-BsAb CRS and subsequent CVAEs. This is in contrast to CAR T-cell therapy, for which many studies have shown a relationship between CRS and CVAE development.5
Limitations of this study include its retrospective design and lack of a control arm. Additionally, as BsAb therapy is currently used as non-first-line therapy for refractory and relapsed malignancies, most of the patients in this study had received extensive previous treatment with anthracyclines, CAR T-cell therapy, and/or stem cell transplantation, which are known to cause CVAEs. Although our study cohort is representative of the type of real-world high-risk patient who would receive BsAb therapy after multiple prior lines of cardiotoxic therapy, given this study’s retrospective design, it is unknown whether the observed cardiotoxicities are a result of delayed toxicities from prior treatments, a direct result of BsAb therapy, or a combination. Further prospective and mechanistic studies are needed to address this question and the differences in CRS-associated CVAEs between CAR T-cell and BsAb therapy. Overall, the relatively low rate of CVAEs following BsAb treatment in this cohort is reassuring for the cardiovascular management of these patients.
Funding Support and Author Disclosures
Dr Karmali is a consultant for AbbVie, Genentech/Roche, Genmab, and Bristol Myers Squibb. Dr Akhter is a Speakers Bureau member for Zoll and Cleerly. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
- 1.Baik A., Oluwole O.O., Johnson D.B., et al. Mechanisms of cardiovascular toxicities associated with immunotherapies. Circ Res. 2021;128(11):1780–1801. doi: 10.1161/CIRCRESAHA.120.315894. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Stein-Merlob A., Ganatra S., Yang E.H. T-cell immunotherapy and cardiovascular disease: chimeric antigen receptor T-cell and bispecific T-cell engager therapies. Heart Fail Clin. 2022;18(3):443–454. doi: 10.1016/j.hfc.2022.02.008. [DOI] [PubMed] [Google Scholar]
- 3.Lyon A., Lopez-Fernandez T., Couch L.S., et al. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS) Eur Heart J. 2022;43(41):4229–4361. doi: 10.1093/eurheartj/ehac244. [DOI] [PubMed] [Google Scholar]
- 4.Jung S., Lee S.R., Yang D.H., et al. Efficacy and safety of blinatumomab treatment in adult Korean patients with relapsed/refractory acute lymphoblastic leukemia on behalf of the Korean Society of Hematology ALL Working Party. Ann Hematol. 2019;98(1):151–158. doi: 10.1007/s00277-018-3495-2. [DOI] [PubMed] [Google Scholar]
- 5.Munir M., Sayed A., Addison D., Epperla N. Cardiovascular toxicities associated with novel cellular immune therapies. Blood Adv. 2024;8(24):6282–6296. doi: 10.1182/bloodadvances.2024013849. [DOI] [PMC free article] [PubMed] [Google Scholar]