FDA Requires New Boxed Warning for CAR-T Therapies


The FDA orders new warnings for CAR-T cell therapies due to reports of T-cell malignancies, including fatal cases, applying to BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies.

The Food and Drug Administration (FDA) has ordered new black box warnings for CAR-T cell therapies following a review of reports highlighting the risk of T-cell malignancies, with some cases of fatal outcomes. The new warning applies to all BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies.

Since 2017, CAR-T therapies have demonstrated deep and durable responses in patients with lymphoma, leukemia, or multiple myeloma. The labeled warnings for CAR-T therapies already contain cautionary language about the risk of secondary malignancies.

In letters to the manufacturers of CAR-T therapies on January 19th, the FDA stated that boxed warnings, the strongest type of labeled warning, must be included in the prescribing information.

CAR T-cell therapy utilizes T cells, which are essential in directing the immune response, to combat cancer by customizing treatments for each patient. This involves collecting the patient's own T cells and modifying them in the lab to create chimeric antigen receptors (CARs) on their surface. These CARs are designed to target and attach to specific antigens found on cancer cells.

Currently, six CAR-T therapies are approved in the US:

  • Kymriah (tisagenlecleucel)
  • Yescarta (brexucabtagene autoleucel)
  • Carvykti (ciltacabtagene autoleucel)
  • Breyanzi (lisocabtagene maraleucel)
  • Abecma (idecabtagene vicleucel)
  • Tecartus (brexucabtagene autoleucel)

The FDA initiated an investigation into CAR-positive lymphoma in November. Reports of T-cell malignancies were received from clinical trials and post-marketing adverse event reporting. Still, agency officials stated that the benefits of CAR-T treatments, approved for lymphoma, leukemia, and multiple myeloma, outweigh the potential dangers.

In a January 8th update briefing, Peter Marks, M.D., Ph.D., director of FDA's Center for Biologics Evaluation and Research, emphasized the need for CAR-T makers to monitor clinical trial participants and patients receiving CAR-T post-approval throughout their entire lives to identify any new malignancies and test for the CAR gene when they occur.

The International Society for Cell and Gene Therapy published an expert consensus statement on CAR-T risks, advocating for ongoing evaluation while maintaining access to these therapies. “ISCT and its leaders firmly agree that the benefits of CAR-T therapies continue to outweigh potential risks in the vast majority of cases and recommends that centres with cell therapy expertise should continue to make commercial CAR-T products available to patients when it appears to be the best option available,” ISCT wrote in the statement.

The ISCT also pointed out that CAR-T cell immunotherapies have been given to 34,000 patients worldwide and that 20 cases of T cell malignancies have been reported. However, more information is needed to fully understand the risk, such as patient characteristics, genetic mutations, and timing of development.

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