Low CV Risk With ‘Living’ Cancer Therapies, Meta-analysis Shows

Cellular immunotherapies for cancer are associated with a low rate of serious adverse cardiac events in patients with advanced malignancies of the blood, bone marrow, or lymph nodes, a meta-analysis suggests.

Left ventricular dysfunction and supraventricular arrhythmia were the most commonly observed cardiac events—both with pooled rates of less than 9%—in more than 1,500 patients treated with autologous chimeric antigen receptor (CAR) T-cell therapy products.

“The key takeaway is the need for cardio-oncological surveillance with a focus on left ventricular function and arrhythmias,” senior author Lorenz H. Lehmann, MD (University Hospital Heidelberg, Germany), said in an email.

Sometimes referred to as genetically engineered “living therapy,” the treatments are derived from a patients’ own T cells that have been modified with the addition of CAR to seek out and destroy cancer cells. At present, there are six such therapies approved in the United States for B-cell lymphomas and multiple myeloma, with the field evolving rapidly.

Lehmann and colleagues say that long-term registry-based studies that incorporate cardiac testing and recording of cardiac events are needed. Their meta-analysis, published October 7, 2024, in JAMA Network Open, adds needed data on the short- and mid-term cardiotoxicity profile of CAR T-cell therapy, they note. Just how long surveillance is needed to be clear about the full spectrum of cardiac risk, however, is unclear.

“We would expect that cardiotoxic effects by CAR T-cells are early events,” Lehmann said. “However, most of these patients are heavily pretreated. That’s why they would need a long-term surveillance strategy, probably 2, 5, and 10 years after successful cancer therapy.”  

Sarju Ganatra, MD (Lahey Hospital and Medical Center, Beth Israel Lahey Health, Burlington, MA), who commented on the meta-analysis for TCTMD, said the data are important given the increasing use of these agents on the background of research on the individual CAR T-cell therapies that captured complications in carefully selected trial populations.

“Real-world patients are going to have a lot of preexisting conditions and are not going to be as pristine as what we see in trials, so putting all these smaller studies together in a meta-analysis gives us a broader picture and sheds more light on the potential for side effects on the heart,” he said.

While the frequencies of left ventricular dysfunction and supraventricular arrhythmias across the studies in the meta-analysis aren’t surprising, Ganatra said they are important for cardiologists to be aware of because prompt diagnosis and treatment may help to recover function and reverse abnormal rhythms.

In many cases, Ganatra said, the culprit is cytokine release syndrome (CRS), an overly aggressive immune response triggered by the immunotherapy that is not uncommon in people receiving CAR T-cell products, but can and should be treated appropriately.

“We know what we know, but we also don't know what we don't know with these therapies,” he added. For those reasons, he said he agrees with the investigators that longer-term surveillance is needed to understand how immunotherapies impact vulnerable patients, many of whom have, as Lehmann noted, already been heavily treated for their cancers before even encountering CAR T-cell therapy.

CV Risk Factors Prevalent

For the meta-analysis led by David Koeckerling, MD (University Hospital Heidelberg), the researchers analyzed data from 13 studies that included 1,528 patients (median age 61 years; 44% women) with a median follow-up of 487 days.

All had refractory or relapsed hematologic malignant neoplasms and were being treated with at least one CAR T-cell therapy: axicabtagene ciloleucel (Yescarta; Kite), tisagenlecleucel (Kymriah; Novartis), brexucabtagene autoleucel (Tecartus; Kite), lisocabtagene maraleucel (Breyanzi; Bristol Myers Squibb), or idecabtagene vicleucel (Abecma; Bristol Myers Squibb). Approximately 80% of patients received the therapies for lymphoma. Overall, 85% of all patients had previously undergone anthracycline therapy, 17.5% radiotherapy, and 27% stem-cell transplant. A sizeable portion of patients had CV risk factors, including diabetes in 12.5%, hypertension in 37.5%, hypercholesterolemia in 32%, and a smoking history in 35%.

The pooled prevalence of CV complications was lowest for MI at 0.62%, followed by CV death at 0.63% and HF events at 3.87%. Pooled prevalence rates of supraventricular arrhythmia were 8.68% and ventricular arrhythmia was 7.79%. The pooled prevalence of all-cause mortality was 30%.

The investigators say the left ventricular dysfunction data should be interpreted with caution given that the retrospective studies did not incorporate systematic serial echocardiographic evaluation and the information on recovery of ventricular function was limited.

In an accompanying editorial, Vlad G. Zaha, MD, PhD (University of Texas Southwestern Medical Center, Dallas), notes that the study raises many questions that will be important to future research.

“Placing this study in the context of evolving immunotherapy technologies, such as bispecific T-cell effectors and off-the-shelf allogeneic CAR T-cell and CAR natural killer cell therapies, the recommendation of using prospective, multicenter, international registries for cardiovascular complications is an opportune one, because the cardiometabolic and immuno-oncological paths show extensive connections that influence the immediate and potentially the long-term therapeutic outcomes,” he writes.

Ganatra agreed that a larger, systematic approach to tracking CV complications in CAR T-cell recipients is much needed, adding that it would be helpful “to house this kind of registry under an international society where everyone can contribute and learn from each other.”

The International Cardio-Oncology Society currently houses some registries to keep tabs on CV complications from several types of cancer therapies, he added, but does not currently track those related to CAR T-cell treatments.