CAR-T Warning for Secondary Malignancies: Warranted or Not?

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FDA boxed warning led to multiple studies on the issue in 2024

by
Mike Bassett, Staff Writer, MedPage Today
January 5, 2025

Early in 2024, we reported on the FDA’s call for new boxed warnings on the labeling of all approved chimeric antigen receptor (CAR) T-cell therapies for the potential risk for secondary T-cell malignancies. In this report, we follow up on what has happened since.

In January 2024, the FDA mandated new boxed warnings on approved B-cell maturation antigen (BCMA)- or CD19-directed autologous CAR T-cell therapies to include the serious risk of T-cell malignancies. By the end of the year, the necessity of the warning was seriously questioned by clinicians and researchers.

A boxed warning now reads “T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies” for six approved CAR T-cell therapies:

Since the FDA first announced it was investigating reports of secondary T-cell cancers occurring in patients treated with CAR-T cell therapies, however, research has highlighted the rarity of this outcome. Study after study suggested a low risk of second primary malignancies (SPMs) after therapy.

“Currently, I would not say that there is strong evidence that, relative to other treatment modalities, there is an increased risk for developing SPMs with CAR T-cell therapy,” Kai Rejeski, MD, of the Sloan Memorial Kettering Cancer Center in New York City, told MedPage Today. “I think what that really does is question, to some extent, the black-box warning label by the FDA.”

In September 2024, Rejeski and colleagues published a systematic literature review and meta-analysis that showed that CAR T-cell therapy carried a risk of SPM that was no worse than with other standard-of-care therapies.

With a median follow-up of 21.7 months, the rate of SPM was 5.8% among 5,517 patients who received CAR T-cell therapy — a rate that didn’t vary according to disease type or CAR T-cell product used. T-cell malignancies accounted for just 1.5% of SPMs. Limiting the analysis to four clinical trials comparing CAR T-cell therapy and standard-of-care therapies yielded similar rates of SPM (5.0% vs 4.9%), according to Rejeski’s group.

In a perspective article published in the New England Journal of Medicine (NEJM) to coincide with the January 2024 mandate, FDA leaders discussed the reasoning behind the cancer risk warnings and detailed the 22 cases of T-cell cancers the agency had been aware of that occurred after treatment with CAR-T products.

The 22 cases emerged from about 27,000 doses of these products having been administered in the U.S. for hematologic cancers. Among the 14 cases with adequate data, the secondary cancers (e.g., T-cell lymphoma [TCL], T-cell large granular lymphocytosis, peripheral TCL, and cutaneous TCL) started developing within 2 years after administration of the CAR T-cells, with about half developing within the first year.

In December 2024, a review article in JAMA Oncology from Saurabh Dahiya, MD, of the Stanford University School of Medicine, and colleagues said that while associations have been made between CAR-T therapy and the development of secondary primary cancer (SPC), “causal associations are largely lacking, aside from rare cases of transgene-positive T-cell lymphomas.”

“The benefits of CAR-T therapy against the primary cancer appear to outweigh the small risk for SPCs, and cautious reassurance is warranted in most cases,” they stressed. They cited an analysis of FDA Adverse Events Reporting System data that concluded that the incidence of SPCs was only 4.3%, “which remains relatively low compared with the opportunity cost of forgoing CAR-T therapy.”

“We favor proceeding with CAR-T therapy when clinically indicated, given the miniscule risk of SPCs as well as the lack of definitive evidence of causality,” Dahiya’s group concluded.

The FDA investigation into what it called a “serious risk” of T-cell malignancies in patients who received BCMA- or CD19-directed autologous CAR T-cell therapy was first announced in November 2023.

“Although CAR-T products have to date been associated with fewer cancers than products made with the previous generation of viruses used for gene therapy transduction, the potential for oncogenesis caused by genomic integration or other mechanisms still exists with the current generation of retroviral vectors,” wrote the FDA’s Nicole Verdun, MD, and Peter Marks, MD, PhD, in their January 2024 NEJM perspective article.

“Moving forward, particularly as the use of CAR T-cells for indications outside hematology and oncology is considered, new strategies involving targeting insertion of the CAR construct to specific loci might help reduce the risk of cancers due to integration of the CAR construct at oncogenic loci within the genome,” the pair added.