FDA Requests Class-Wide Boxed Warning for CAR T-Cell Agents Regarding Secondary T-Cell Malignancy Risk


The FDA has called to add a class-wide boxed warning for CAR T-cell therapies to alert patients of the risk of developing secondary T-cell malignancies.



Following a safety probe, the FDA has called to add a class-wide boxed warning for CAR T-cell therapies to alert patients and clinicians of the potential risk of developing secondary T-cell malignancies following treatment with these agents. The announcement will affect all 6 FDA-approved CAR T-cell therapies, including ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), axicabtagene ciloleucel (Yescarta), and brexucabtagene autoleucel (Tecartus).1

On January 19, 2024, the FDA sent 6 letters to the manufacturers of the approved CAR T-cell agents, noting that these agents had been deemed to be associated with the risk of developing secondary malignancies. The manufacturers will have 30 days to submit proposed changes to their agents’ safety labels or file a rebuttal in the case they do not agree with the FDA.1

“We have become aware of the risk of T-cell malignancies, with serious outcomes, including hospitalization and death, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies. FDA identified postmarketing adverse event [AE] and clinical trial reports describing occurrence of mature T-cell malignancies, including CAR-positive tumors, following treatment with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies,” the FDA wrote in all the letters.2

"We will continue to be vigilant about this potential risk, but I do not advise any changes to our practice," Rahul Banerjee, MD, FACP, an assistant professor at the Fred Hutchinson Cancer Center, and an assistant professor in the Division of Hematology and Oncology at the University of Washington, both in Seattle, said in an email to OncLive. "If our hypotheses are true about prior therapies like bendamustine or lenalidomide being the real risk factors, then the risk of secondary malignancies may actually be lower as CAR-T is moved into earlier lines of therapy. We will continue to watch for these toxicities very carefully as a field with this point in mind."

On November 28, 2023, the FDA announced that it was further investigating the safety of CAR T-cell agents following reports of T-cell malignancies, including CAR-positive lymphoma, in patients who received treatment with BCMA- or CD19-directed autologous CAR T-cell immunotherapies. The reports stemmed from clinical trials and AE data sources. The agency noted that the potential risk of secondary malignancies is labeled as a class warning in the United States prescribing information for all FDA approved BCMA-directed and CD19-directed genetically modified autologous T-cell immunotherapies, as it is with all gene therapy products with integrating vectors.3

In their statement, the FDA also noted that the initial approvals of all the CAR T-cell agents included postmarketing requirements to conduct 15-year long-term follow-up observational safety studies to further determine the long-term safety profile and risk of secondary malignancies following treatment with these agents.3

At the time, the FDA wrote, “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action.”3

"This particular boxed warning didn't come as a surprise, but the specificity of the initial FDA statement in November absolutely did," Banerjee said. "The risk of second malignancies is already something I discuss with patients routinely for many therapies, including CAR T, but also with stem cell transplantation and lenalidomide. Going forward, I'll mention the boxed warning briefly as an extra detail in these discussions but won't change the gist of what I describe."

Moreover, according to a perspective piece published in the New England Journal of Medicine on January 24, 2024, coauthored by Peter W. Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research and Nicole Verdun, MD, the super office director of the FDA’s Office of Therapeutic Products, the FDA had become aware of 22 cases of T-cell cancers that occurred after treatment with CAR T agents as of December 31, 2023. This included instances of T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. They went on to note that such cases have been reported in 5 of the 6 CAR T-cell agents—although not specifying which ones—and that of the 14 cases with available adequate data, the cancers manifested within 2 years after administration of CAR T-cell therapy (range, 1 to 19 months), with approximately 50% occurring within the first year.4

Marks and Verdun went on to say that in 3 cases for which genetic sequencing data were available, the CAR transgene was detected in the malignant clone, indicating that the CAR T-cell agent was likely involved in the development of the T-cell malignancy. However, they also noted that, “With more than 27,000 doses of the 6 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. But relying on postmarketing reporting may lead to underestimates of such cases.”4

In response to the FDA’s investigation, similar reviews of CAR T-cell agents are underway worldwide, including by the United Kingdom’s Medicines and Healthcare products Regulatory Agency, the European Union’s European Medicines Agency, and the South Korean Ministry of Food and Drug Safety.4

"As of now, I'd strongly advise against trying to screen patients to minimize the risk of second cancers," Banerjee said. "There's so much we don't know about the real risk factors at play here - is it the CAR-T therapy itself, or is it the patient's prior therapies and the fact that they're now living longer? CAR T offers patients the potential for deep and durable remissions. Compared with other novel immune effector cell-based therapies such as bispecific antibodies, CAR T is a single infusion with much less time toxicity from continued drug administration every few weeks. In multiple myeloma, the median progression-free survival in the [phase 1/2] CARTITUDE-1 trial [NCT03548207] was almost 3 years without any maintenance therapy - this would have been unimaginable to tell patients even just a few years ago."


  1. Manalac T. FDA calls for boxed warnings on CAR-T therapies regarding secondary cancer risks. BioSpace. January 23, 2024. Accessed January 25, 2024. https://www.biospace.com/article/fda-calls-for-boxed-warnings-on-car-t-therapy-labels-regarding-secondary-cancer-risks/?keywords=cancer
  2. 2024 Safety and Availability Communications. FDA. January 2024. Accessed January 25, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/2024-safety-and-availability-communications
  3. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. FDA. November 28, 2023. Accessed January 25, 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
  4. Verdun N, Marks P. Secondary cancers after chimeric antigen receptor T-cell therapy. N Eng J Med. Published online January 24, 2024. Accessed January 25, 2024. doi:10.1056/NEJMp2400209
  5. Asanga P. Global regulators increase CAR T scrutiny in wake of FDA’s investigation. BioSpace. January 22, 2024. Accessed January 25, 2024. https://www.biospace.com/article/global-regulators-increase-car-t-scrutiny-in-wake-of-fda-s-investigation-/
Related Videos
Francesco Di Meo, PhD
Jay Spiegel, MD
Tatyana Feldman, MD