FDA Requires Boxed Warning for Secondary Cancers on CAR-T Therapies

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Pictured: FDA signage at its headquarters in Maryland/iStock, hapabapa

The FDA announced on Thursday that it will officially require an update to the boxed warnings of CAR-T cell therapies, which should now also alert patients and prescribers to a heightened risk of developing secondary T cell malignancies.

All six commercially available CAR-T therapies will be affected, including Bristol Myers Squibb’s Abecma (idecabtagene vicleucel) and Breyanzi (lisocabtagene maraleucel), Johnson & Johnson’s Carvykti (ciltacabtagene autoleucel), Novartis’ Kymriah (tisagenlecleucel), as well as Gilead’s Tecartus (brexucabtagene autoleucel) and Yecarta (axicabtagene ciloleucel).

The FDA will also mandate amendments to other sections of their labels, including the warnings and precautions, postmarketing experience, patient counseling information and medication guide sections.

Patients and clinical trial participants being given these products should also be followed “life-long” for the potential development of secondary T cell cancers, according to the regulator’s announcement.

The FDA first revealed that it was looking into the potential safety issues of BCMA- or CD19-directed autologous CAR-T therapies in November 2023, noting at the time that it had flagged a “serious risk” of secondary T cell malignancies “in patients treated with several products in the class.” These cases were detected from both clinical trials and postmarket reporting.

In January 2024, the regulator called on CAR-T manufacturers to implement a class-wide boxed warning to their products, reflecting the increased risk of secondary malignancies. In its letter to the companies, the FDA did not explicitly cite a causal link between the products and the adverse event, though it did note that the secondary cancers could lead to “serious outcomes, including hospitalization and death.”

A few days later, two FDA officials published a perspective piece in The New England Journal of Medicine, revealing more details from its safety probe. The officials revealed they found the CAR transgene in three cases of secondary malignancies, indicating that “the CAR-T product was most likely involved in the development of the T-cell cancer.”

The FDA’s boxed warning announcement on Thursday comes as CAR-T cell therapies continue to break new ground, demonstrating their potential in more treatment settings and new indications.

In March 2024, the FDA greenlit BMS’ Breyanzi for the treatment of chronic lymphocytic leukemia and small lymphocytic leukemia, making it the first CAR-T therapy approved in these indications. Earlier this month, the regulator also cleared the use of BMS’ Abecma and J&J’s Carvykti in earlier lines of treatment for multiple myeloma.

Beyond cancer, CAR-T therapies have also shown promise in the treatment of autoimmune diseases. In February 2024, a small study published in The New England Journal of Medicine showed that CD19 CAR-T treatment could elicit strong clinical benefit in patients with systemic lupus erythematosus, systemic sclerosis and idiopathic inflammatory myositis.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

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