The analysis found that 31 of 145 adult patients had a total of 41 events. MACE often occurred within the same time frame as cytokine release syndrome (CRS), a recognized and potentially serious complication of CAR T-cell therapy. Patients who had MACE tended to be younger men with higher rates of cardiac risk factors at the time of treatment.
The findings suggest that patients treated with CAR T-cell therapy may benefit from cardiovascular surveillance, Marielle Scherrer-Crosbie, MD, PhD, of the University of Pennsylvania in Philadelphia, and coauthors reported in JACC: CardioOncology.
“We determined that baseline creatinine and grade 3 or 4 CRS were independently associated with MACE,” the authors concluded.
“CAR T-cell therapy has opened a new field in the treatment of hematologic malignancies and is now under investigation for other indications, including solid tumors,” the group continued. “Given that CAR T-cell use will only increase in the future and that no recommendations for monitoring and follow-up of left ventricular function and MACE currently exist, prospective studies are needed to ascertain the incidence and predictors of MACE.”
The higher rate of cardiac risk factors in patients who had MACE emphasizes the need to understand the patient population treated with CAR T-cell therapy, said the author of an accompanying editorial.
“The adult patient population in which this therapy was used had refractory and relapsed lymphomas that were often treated with multiple rounds of anthracycline-based chemotherapy and chest radiation, which are well established as having cardiotoxic effects,” wrote Anna B. Catino, MD, of the University of Utah in Salt Lake City.
As indications for CAR T-cell therapy expand, patients might have received other cardiotoxic agents or undergone stem-cell transplants, which are associated with an increased risk of cardiovascular events, she added. Conditioning therapy prior to CAR T-cell infusion may also increase the risk of MACE.
The pathophysiology of CAR T-cell-associated cardiotoxicity might be complex, and many of the details remain unknown. However, the review by Scherrer-Crosbie and colleagues showed a clear association between CRS and MACE, said Catino. Prospective data from systematic cardiac monitoring is essential to improve understanding about the frequency and pathophysiology of CAR T-cell-related cardiotoxicity.
Two retrospective analyses showed high rates of cardiovascular complications in pediatric patients treated with CAR T-cell therapy. One of the studies showed that more than a third of patients developed cardiogenic shock, cardiomyopathy, or other cardiovascular complications. In the other, 24 of 98 patients developed hypotension requiring inotropic support, and 10 of the 24 had echocardiographic evidence of left ventricular (LV) systolic dysfunction.
A recent retrospective analysis of 137 adults treated with CAR T-cell therapy reported cardiovascular events in 17 patients (12%), including six deaths, all of which occurred in association with grade ≥2 CRS. Elevated troponin was documented in 29 patients, eight of whom had decreased LV function, with most associated with CRS.
Scherrer-Crosbie and coauthors sought to gain more insight into the frequency and natural history of cardiovascular events in adults treated with CAR T-cell therapy at the University of Pennsylvania, where the treatment originated.
The study involved consecutive patients treated from August 2010 to January 2019. The study population consisted of 36 patients with acute lymphocytic leukemia, 43 with diffuse large B-cell lymphoma, and 66 with chronic lymphocytic leukemia. They had a median age of 60. A total of 176 episodes of CRS occurred in 104 patients, and the median time to onset of CRS was 6 days after CAR T-cell infusion. During a median follow-up of 456 days, 61 patients died, all but two of noncardiac causes.
The median time to occurrence of MACE was 11 days after CAR T-cell infusion for the 41 events. The MACE subgroup had a median follow-up of 753 days. The estimated MACE rates were 17% at 30 days, 19% at 6 months, and 21% at 12 months. The 41 events consisted of 22 episodes of heart failure, 12 episodes of atrial fibrillation, two cases of acute coronary syndrome, two cardiac deaths, one episode of supraventricular tachycardia, and one episode of nonsustained ventricular tachycardia.
By multivariable competing-risk analysis, three factors had independent associations with MACE (P<0.001 for all):
- Baseline creatinine: HR 15.54 per 1 mg/dL increase, 95% CI 3.7-65.86
- Grade 3 CRS: HR 8.42, 95% CI 3.48-20.40
- Grade 4 CRS: HR 29.86, 95% CI 9.80-90.94
Disclosures
Scherrer-Crosbie and coauthors and Catino reported having no relevant relationships with industry.
Primary Source
JACC: CardioOncology
