• Sustainability
  • DE&I
  • Pandemic
  • Finance
  • Legal
  • Technology
  • Regulatory
  • Global
  • Pricing
  • Strategy
  • R&D/Clinical Trials
  • Opinion
  • Executive Roundtable
  • Sales & Marketing
  • Executive Profiles
  • Leadership
  • Market Access
  • Patient Engagement
  • Supply Chain
  • Industry Trends

FDA Urges Caution Following Boxed Warning Requirements on CAR T-Cell Therapies


FDA leadership notes that the overall rate of secondary T-cell cancers among patients administered CAR T-cell therapies appears to be low, even if all reported cases are assumed to be related to treatment.

Image credit: Iryna | stock.adobe.com

Image credit: Iryna | stock.adobe.com

FDA leadership is emphasizing the benefits of chimeric antigen receptor (CAR) T-cell therapy still outweigh the risks of secondary cancers, but are urging clinicians to remain vigilant in monitoring patients administered the treatments after the agency recently required the addition of Boxed Warnings to all approved CAR T-cell therapies.1

Six CAR T-cell therapies have been approved by the FDA to date, for cancers that include relapsed or refractory B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin lymphoma, and multiple myeloma.

The FDA has approved six CAR T-cell therapies since 2017 for the treatment of hematologic cancers. Credit: National Cancer Institute

The FDA has approved six CAR T-cell therapies since 2017 for the treatment of hematologic cancers. Credit: National Cancer Institute

In a commentary published by The New England Journal of Medicine, Peter Marks, MD, PhD, director of the FDA Center for Biologics Evaluation and Research (CBER) and Nicole Verdun, MD, director of CBER Office of Therapeutic Products, noted the use of CAR T-cell therapies require a careful benefit-risk assessment.1

“The demonstrated efficacy of the current generation of approved CAR T products comes along with several well-described safety concerns that are noted in the products’ labeling, including risks of cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, various forms of cytopenia, and hypogammaglobulinemia,” Marks and Verdun wrote. “Better understanding of some of these risks has led to improved outcomes, such as for patients who develop cytokine release syndrome.”1

On January 19, 2024, the FDA notified several manufacturers that Boxed Warnings need to be added to these products, citing additional cancer risks associated with treatment. All FDA-approved CAR T-cell therapies and licensed BCMA-directed and CD19-directed genetically modified autologous CAR T-cell immunotherapies were required to add the warnings, including Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, and Yescarta.2 Since the initial letters, the FDA has tweaked its letter to Gilead regarding Tecartus, which is no longer being listed as causing T cell malignancies.3

In November 2023, the FDA announced plans to investigate the potential risks of secondary cancer linked to CAR T-cell therapy. The agency made this decision based on reports of T-cell malignancies in patients administered BCMA- or CD19-directed autologous CAR T-cell immunotherapies.

“Given the relatively recent deployment of these therapies, the (FDA) has issued draft guidance recommending that people who receive CAR T cells engineered with integrating vectors be monitored for extended periods for adverse events, including cancers,” Marks and Verdun wrote. “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.”1

By the end of 2023, the FDA had received reports of 22 cases of T-cell cancers following treatment with CAR T products, including T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. Of these reports, 14 cases had adequate data available, all of which manifested between one and 19 months after the administration of CAR T cells, with approximately half occurring within the first year after administration of five of the six approved CAR T-cell therapies.

The FDA noted that the small number of cases and varied product use prevent conclusions regarding the association of secondary cancers with any specific CAR T-cell therapy, with some of the cases still under investigation.

“With more than 27,000 doses of the six approved products having been administered in the United States, the overall rate of T-cell cancers among people receiving CAR-T therapies appears to be quite low, even if all reported cases are assumed to be related to treatment,” Marks and Verdun wrote. “But relying on postmarketing reporting may lead to underestimates of such cases. The FDA is attempting to gather as much information as possible on each of the reported cases, but in many instances, adequate samples of the lymphomas have not been retained for testing by means of polymerase chain reaction or genome sequencing. Determination of whether the T-cell cancer is associated with the CAR construct therefore most likely won’t be possible for every case reported to date.”1

The FDA said it will issue updates as substantive new information becomes available and urges clinicians to report the occurrence of any new cancer in patients administered CAR T-cell therapy.

“Appropriate product labeling will be a resource that can help clinicians manage conversations with patients about the benefits and risks associated with treatment options,” Marks and Verdun concluded.1


1. Verdun, N; Marks, P. Secondary Cancers after Chimeric Antigen Receptor T-Cell Therapy. Journal Article. New England Journal of Medicine. DOI: 10.1056/NEJMp2400209. Published January 24, 2024.

2. FDA Roundup: January 23, 2024. FDA. January 23, 2024. Accessed January 24, 2024. https://www.fda.gov/news-events/press-announcements/fda-roundup-january-23-2024

3. Gilead's Tecartus gets revised safety demand amid FDA's push for CAR-T boxed warnings. Fierce Pharma. January 24, 2024. Accessed January 25, 2024. https://www.fiercepharma.com/pharma/fda-tweaks-tecartus-secondary-cancer-labeling-change-demand-classwide-boxed-warning

Related Videos
Ashley Gaines
Related Content