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The FDA has identified more cases of secondary T-cell malignancies following treatment with chimeric antigen receptor (CAR) T-cell therapies, cases that led the agency to demand new boxed warnings on approved agents in the class.

With about 27,000 doses of the six B-cell maturation antigen (BCMA)- or CD19-directed CAR-T products having been administered in the U.S. for hematologic cancers, the overall rate of secondary T-cell malignancies seems to be quite low, even if the 22 reported cases are all deemed to be related to treatment, noted Nicole Verdun, MD, and Peter Marks, MD, PhD, of the FDA's Center for Biologics Evaluation and Research, in a perspective published in the .

Among the 14 cases for which adequate data are currently available, the secondary cancers, including T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma, started developing within 2 years after administration of the CAR T cells, with about half developing within the first year.

"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," Verdun and Marks wrote. "For instance, the lentiviral vector constructs, despite integrating in a semirandom fashion into the genome, have affinity for areas of the genome in which active gene expression is taking place, which may pose a risk for insertional oncogenesis."

While the cases were reported in conjunction with five of the CAR-T products -- idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), and axicabtagene ciloleucel (Yescarta), with the exception being brexucabtagene autoleucel (Tecartus) -- Verdun and Marks observed that the small number of cases spread among the various agents "preclude conclusions about the strength of an association with any specific product."

These drugs are approved for various indications in hematologic cancers, including B-cell precursor acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma.

In three cases in which genetic sequencing has been performed, the CAR transgene was detected in the malignant clone, indicating that the CAR-T agent was likely involved in the development of the T-cell cancer, the authors noted.

However, they also pointed out that relying on postmarketing reporting could lead to underestimation of the number of these cases, and the FDA plans to provide updates "as substantive new information becomes available."

For now, Verdun and Marks said their agency is recommending that patients and clinical trial participants treated with these CAR-T products be monitored for new cancers throughout their lives, since it is currently unknown how long recipients of these agents remain at risk.

"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," they suggested. "Comprehensive tumor-testing strategies might also generate information on the risk for and nature of these cancers and provide additional mechanistic insights."

Finally, they emphasized that the risk of T-cell cancers developing after the use of these products appears to be low, and appropriate labeling can help clinicians have conversations with patients about the benefits and risks associated with treatment options.

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