Understanding the Implications of the FDA’s New Boxed Warning for CAR T-Cell Therapy


In November 2023, the FDA announced an investigation of CAR T-cell therapy based on several reported secondary T-cell malignancies.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as groundbreaking therapy for certain types of cancer, offering hope to patients who have exhausted traditional therapies. CAR T-cell therapy involves reprogramming a patient’s own T cells to recognize and destroy cancer cells. CAR T-cell therapy has shown remarkable success in treating certain types of blood cancers, particularly B-cell malignancies such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, and certain types of non-Hodgkin lymphoma.1

Silver Spring, MD, USA - June 25, 2022: The FDA White Oak Campus, headquarters of the United States Food and Drug Administration, a federal agency of the Department of Health and Human Services (HHS).

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However, recent developments have prompted the FDA to issue a new boxed warning for CAR T-cell therapy, sparking discussions and concerns within the medical community. The FDA is requiring a boxed warning update to the label for the 6 CAR T-cell therapies on the market, saying, “T-cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies.”2

The treatments impacted include idecabtagene (Abecma; Bristol Myers Squibb), lisocabtagene (Breyanzi; Bristol Myers Squibb), ciltacabtagene (Carvykti; Janssen Biotech), tisagenlecleucel (Kymriah; Novartis), brexucabtagene (Tecartus; Kite), and axicabtagene (Yescarta; Gilead).2

More than 27,000 patients with blood cancers have been treated with CAR T-cell therapy since their approval in 2017.3 In November 2023, the FDA announced an investigation of CAR T-cell therapy based on several reported secondary T-cell malignancies.4

As of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers that occurred after treatment with CAR T-cell therapy. Malignancies that have been reported include T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. There are currently 14 cases with adequate data available showing the malignancies have manifested within 2 years of CAR T-cell therapy, with half of the cases occurring within the first year after CAR T-cell therapy. In 3 cases, the CAR transgene was seen in a malignant clone, indicating that CAR T-cell therapy was involved in the development of T-cell cancers. Due to the limited number of patients experiencing secondary malignancies following CAR T-cell administration, it is difficult to claim a causal relationship between occurrence of malignancy following CAR T-cell therapy.3

On January 19, the FDA announced the addition of a boxed warning to the labels of CAR T-cell therapies, requiring manufacturers to add the warning to the prescribing information. This warning highlights the potential risks of developing secondary T-cell malignancies with CAR T-cell therapies and manufacturers were given 30 days to submit any changes to the prescribing information.2

For patients considering CAR T-cell therapy, the addition of a boxed warning underscores the importance of informed decision-making and thorough discussions with health care providers. Although CAR T-cell therapy has demonstrated remarkable efficacy in treating certain cancers, patients must weigh the potential benefits against the risks of adverse events.

The FDA’s decision to issue a boxed warning for CAR T-cell therapy highlights the importance of balancing innovation with patient safety in the field of oncology. Although the warning calls attention to the potential risks associated with CAR T-cell treatment, it also emphasizes the need for monitoring, early intervention, and continued research to maximize the benefits of this novel therapy. By addressing safety concerns and enhancing patient care practices, the medical community can navigate the complexities of CAR T-cell therapy while striving to improve outcomes for patients with cancer.

Despite the development of a new boxed warning, CAR T-cell therapy remains a promising avenue for cancer treatment. Continued research efforts should be focused on refining CAR T-cell engineering, optimizing patient selection criteria, and developing novel strategies to mitigate treatment-related toxicities to provide patients with a safe and efficacious management of therapy.


1. National Cancer Institute. CAR T cells. Accessed January 27, 2024. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

2. FDA. 2024 Safety and availability communications. January 24, 2024. Accessed February 1, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/2024-safety-and-availability-communications

3. Verdun N, Marks P. Secondary cancers after chimeric antigen receptor T-cell therapy. N Engl J Med. Published online January 24, 2024. doi:10.1056/NEJMp2400209

4. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. November 28, 2023. Accessed February 2, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous

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