Cardiovascular Events Following CAR T-Cell Therapy Are Common, Especially in Conjunction With CRS

Presentation

A 67-year-old male with refractory diffuse large B-cell lymphoma (DLBCL) after two lines of therapy, resolved sinus arrhythmia, and controlled essential hypertension is ready to undergo CAR T-cell therapy with lisocabtagene maraleucel. His physical examination included the following measures: blood pressure (BP), 135/85 mm Hg; white blood cell count (WBC), 4.6-5.0 x 10⁹/L; hemoglobin (Hgb),  9.2-10.3 g/dL; platelet count, 200,000-250,000 µL; lactate dehydrogenase (LDH) level, 300 IU/L; and his electrolyte count, calcium level, and renal and hepatic function were all normal. He had a palpable left inguinal mass of 3 cm and generally appeared well. The required pre-testing showed no restrictive or obstructive disease on pulmonary function tests and normal sinus rhythm on electrocardiogram (EKG). His pre-testing transthoracic echocardiogram demonstrated normal left ventricular size, normal left ventricular systolic function with ejection fraction of 62%, normal global longitudinal strain, moderately increased localized left ventricular wall thickness, minimal mitral regurgitation, and mild aortic stenosis. In addition, there was no evidence of obstruction, effusion, pulmonary hypertension, or severe valvular stenosis.

The patient was referred to a cardiologist at the authorized treatment center to establish care prior to his admission. The cardiologist evaluated the patient’s studies and confirmed that no heart failure symptoms were present. Both the patient’s brain natriuretic protein (BNP) level and the treadmill stress test were normal. The cardiologist discussed risks and benefits of CAR T-cell therapy with the patient, noting that both the patient and the oncology team must be accepting of risks. However, because of the suboptimal response expected with traditional lymphoma therapy for this patient and because of the volume of disease, CAR T-cell therapy was discussed as a reasonable approach. The patient was cleared for treatment and went on to receive lymphodepleting chemotherapy: fludarabine 30 mg/m²/day intravenously (IV), and cyclophosphamide 300 mg/m²/day IV for 3 days, followed by 2 days of rest. Lisocabtagene maraleucel was administered (50 to 110 × 10⁶) on Day 5, after which the patient developed a fever of 100.4°F.

Work-up, Diagnosis, and Treatment

Day 5 (post-infusion):

Initial vital signs for the patient were as follows: BP 110/85 mm Hg; heart rate (HR), 87; respiratory rate (RR), 20; temperature, 100.4°F; and oxygen saturation (SpO2), 99% on room air. A full infectious workup (chest x-ray, blood, and urine cultures) was negative, and the patient was non-neutropenic. The patient was given 650 mg of Tylenol orally and observed.  

Day 6:

The patient was still under observation for cytokine release syndrome (CRS)-associated symptoms, and he developed tachycardia with mild shortness of breath. His SpO2 decreased to 95% on room air, and his blood pressure dropped to 90/70 mm Hg. An EKG showed sinus tachycardia, but a repeat echocardiogram showed no change from his baseline; troponin and creatine phosphokinase (CPK) levels were normal. The patient was started on low-flow oxygen by nasal cannula and given bolus IV fluids, and a cardiologist was consulted to evaluate the patient. Given the fever, hypotension not requiring pressors and hypoxia, and cytokine panel demonstrating interleukin (IL)-6 elevation, the patient received 8 mg/kg of tocilizumab for grade 2 CRS. The patient was responsive to treatment with repeat vital signs: BP, 110/90 mm Hg; SpO2 back to 99% on room air; RR, 20; temperature, 98.8°F; and HR, 82. A repeat EKG showed normal sinus rhythm, and the patient’s shortness of breath resolved.

Discussion

Although previous cardiac dysfunction, such as arrhythmias, do not exclude a patient from receiving commercial CAR T-cell therapies, a high number of patients who received CAR T-cell therapies have developed CV-related adverse events, such as left ventricle dysfunction, elevated troponin, arrhythmia, and sudden cardiac death.¹ There is a growing body of evidence that draws a correlation between development of CRS (especially > grade 2) post-infusion with decreased cardiac function and arrhythmias.² A retrospective meta-analysis of 2,059 patients across 25 studies found that the pooled incidence rates of overall CV events (including a decline in left ventricle ejection fraction (LVEF) of 10%-30%²) and CV events associated with grade 2 or greater CRS were 25.6% and 14.2%, respectively.³ Alvi and colleagues found that sufficient cardiac reserve pre-CAR T-cell therapy could be essential to avoiding these life-threatening complications.²

Regarding CRS, corrected QT interval (QTc) prolongation/torsades de pointes, tachyarrhythmia, and ischemic heart disease seem to be the most prevalent CV events that occur concurrently with CRS, with cardiomyopathy being the least associated.¹ Data showed that earlier identification of CRS and subsequent administration of tocilizumab was associated with improved risk for CV events, with a 1.7-fold increased risk with each 12-hour increment of delay in administration.²

In their retrospective observational study, Alvi and colleagues² found that 12% to 28% of patients experienced a major CV event such as decompensated heart failure and death, shortly after infusion (median: 6-21 days post-infusion). Although not all included patients were tested at baseline for cardiac troponin levels, elevated troponin levels post-therapy were found in 54% of all patients and 94% of patients who experienced severe CV adverse events. Of note, patients with elevated troponin levels also had higher burdens of CV risk factors and were notably older. Researchers found that 55% of those of those patients with elevated troponin levels post-therapy had some sort of CV complication compared with only 4% of patients with normal troponin levels. Researchers also identified CRS (≥ grade 2) to be associated with both elevated troponin levels (83%) and reduced LVEF (28%).

Lisocabtagene maraleucel is associated with several CRS-related cardiac-specific side effects, of which providers should be aware. Cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) are all serious events that can occur. Manufacturer recommendations are that two doses of tocilizumab should be available prior to administration of lisocabtagene maraleucel. Tachycardia is the most common any-grade adverse event (of the cardiac-related events) associated with lisocabtagene maraleucel in the TRANSFORM Study, occurring in 15% of patients (N=89); 1.1% of patients experienced ≥ grade 3.⁶ Although no patients in the TRANSCEND Study experienced ≥ grade 3 tachycardia after lisocabtagene maraleucel infusion, 25% of patients (N=268) experienced any grade of tachycardia. In addition, arrhythmia was experienced by 6% of patients and cardiomyopathy by 1.5% of patients in TRANSCEND.

Based on these findings and other prospective data, baseline assessments should include medical history, clinical examination, EKG, echocardiogram, and in some, cardiac troponin testing. N-terminal pro-brain natriuretic peptide (NT-pro BNP) testing also is recommended to ensure diagnosis of any previously unknown CV disease.¹

Prospective trials examining CV events post CAR T-cell therapy are ongoing and aim to define the rates of occurrence and risk factors for developing a CV event (NCT04026737, NCT04870853), as well as determine the value of cardiac imaging in diagnosis of CV events (NCT051304489).

References:

1. Totzeck M, Michel L, Lin Y, et al. Cardiotoxicity from chimeric antigen receptor-T cell therapy for advanced malignancies. European Heart Journal. 2022;43:1928-40.
2. Alvi RM, Frigault MJ, Fradley MG, et al. Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T). J Am Coll Cardiol. 2019;74(25):3099-3108.
3. Chen L-R, Li Y-J, Zhang Z, et al. Cardiovascular effects associated with chimeric antigen receptor T cell therapy in cancer patients: A meta-analysis. Front Oncol. 2022;12:924208.
4. Hanna KS, Kaur H, Alazzeh MS, et al. Cardiotoxicity associated with chimeric antigen receptor (CAR)-T cell therapy for hematologic malignancies: A systematic review. Cureus. 2022;14(8):e28162.
5. Ahmed T. Cardiovascular risk profile of chimeric antigen receptor T-cell therapy. Cureus. 2020;12(3):e7436.
6. Bristol-Myers Squibb. Breyanzi (lisocabtagene maraleucel) package insert. 2022. https://packageinserts.bms.com/pi/pi_breyanzi.pdf