FDA Requests Warnings on CAR-T Cell Therapies, Citing Secondary Cancers

Certain CAR-T cell therapies could potentially come with Boxed Warnings after the FDA's request to the respective manufacturing companies.

The Food and Drug Administration (FDA) is requesting that approved BCMA- or CD19-targeted CAR-T cell therapies now come with a warning after the agency received reports of T-cell malignancies, including CAR-positive lymphoma, in patients who have been treated with the class of blood cancer drug.

The FDA began investigating these secondary malignancies in November 2023, and issued letters on Jan. 19 to the pharmaceutical companies of CAR-T cell therapies requesting that the labeling for drugs include warnings of the secondary malignancies and that the patient counseling information and medication guide also mention the risk for cancers.

FDA Requests Boxed Warning

Specifically, the FDA requested that the drug makers include a Boxed warning — formerly known as a “Black Box Warning” — on CAR-T cell therapy products. According to the National Institutes of Health, this is “the highest safety-related warning that medications can have assigned by the Food and Drug Administration.”

“We consider this information to be ‘new safety information’ as defined in section 505-1(b)(3) of the FDCA. Furthermore, we consider the serious risk of T cell malignancy to be applicable to all BCMA- and CD19-directed genetically modified autologous T cell immunotherapies,” the FDA wrote in letters to each of the pharmaceutical companies.

Five out of the six FDA-approved CAR-T cell therapies received the Safety Labeling Change Notification Letters. They were:

• Abecma (idecabtagene vicleucel)
• Breyanzi (lisocabtagene maraleucel)
• Carvykti (ciltacabtagene autoleucel)
• Kymriah (tisagenlecleucel)
• Yescarta (axicabtagene ciloleucel)

The pharmaceutical companies have 30 days after receiving the letter to either submit to the agency a supplement proposing changes to the labeling or to respond to the FDA that they do not believe a label change is warranted. In that case, they must submit a rebuttal statement detailing why the change is not warranted, according to the letters.

Drug Manufacturers, Experts, Patients Respond to the FDA’s Request

According to Reuters, Novartis and J&J, the manufacturers of Kymriah and Carvykti, respectively, said that they will include the risk of T-cell malignancies. However, Novartis also stated that it has not identified a causal relationship between Kymriah and these secondary diseases.

READ MORE: Chance or CAR-T: Expert Weighs in on FDA Investigation

Gilead, the manufacturer of Yescarta and Tecartus, plans to work with the FDA on the next steps regarding labeling updates and also mentioned that they found no evidence that their drugs cause secondary diseases, according to Reuters.

Reuters also reported that Bristol Myers Squibb, the company behind Abecma and Breyanzi, is “evaluating next steps on the labels for Abecma and Breyanzi.”

Experts are also voicing their opinions on the FDA’s label change request.

On X, the platform formerly known as Twitter, Bruce L. Levine, Barbara and Edward Netter Professor in Cancer Gene Therapy, Perelman School of Medicine at the University of Pennsylvania, said, “I think since T-cell malignancies were reported to the (FDA Adverse Event Reporting System), (it) forced FDA’s hand. (In my honest opinion), this doesn’t change risk equation, standing by recommendations in our Nature Medicine commentary.”

Levine included a photo of a commentary published in the journal by him and colleagues titled, “The benefits of CAR-T therapies continue to outweigh the potential risks in the vast majority of cases.”

David Mitchell, a patient with multiple myeloma and founder of Patients for Affordable Drugs, an organization focused on decreasing the cost of prescription drugs, said on X, “As a multiple myeloma patient who’s likely a candidate for CAR-T when I fail on my current 4-drug combo, I believe strongly (that the FDA) did the right thing adding the warning. Patients need to know about the secondary cancers to make informed decisions.”

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