FDA Requires Boxed Warning for Risk of T-Cell Malignancies With Approved CAR T-Cell Therapies


The FDA has mandated that the boxed warning for all approved CAR T-cell therapies be updated to include the serious risk of T-cell malignancies.



The FDA has mandated that the boxed warning for all approved CAR T-cell therapies be updated to include the serious risk of T-cell malignancies. The agency is also requiring updates to other sections of the labels pertaining to warnings and precautions, post-marketing experience, and patient counseling information and medication guide.1

The FDA indicated that patients and participants in clinical trials receiving CAR T-cell therapy should be monitored life-long for secondary malignancies. The FDA added that the manufacturers should be contacted if a new malignancy occurs after treatment with any of the products listed below as all currently approved BCMA-directed and CD19-directed CAR T-cell products carry a serious risk of T-cell malignancies.

  1. Idecabtagene vicleucel (Abecma)
  2. Lisocabtagene maraleucel (Breyanzi)
  3. Ciltacabtagene autoleucel (Carvykti)
  4. Tisagenlecleucel (Kymriah)
  5. Brexucabtagene autoleucel (Tecartus)
  6. Axicabtagene ciloleucel (Yescarta)

“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 in the Clinical Research Division at Fred Hutchinson Cancer Center and an assistant professor in the Division of Hematology and Oncology at the University of Washington in Seattle, said in a statement to OncLive®. Banerjee, a multiple myeloma specialist, continued, “If our hypotheses are true about prior therapies like bendamustine or lenalidomide [Revlimid] being the real risk factors, then the risk of secondary malignancies may be lower as CAR T-cell therapy 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.”

The class-wide safety labeling changes were initiated by the FDA in January 2024,2 but the risk for secondary T-cell malignancies was first flagged in November 2023 in patients who received BCMA- or CD19-directed autologous CAR T-cell therapy. The reports came from clinical trials and/or post-marketing adverse effect data.3

“I’m often asked whether it’s possible that T-cell malignancies are being underreported in the post–CAR T-cell therapy setting, and I think that’s extremely unlikely. We follow these patients carefully for 15 years after CAR T-cell therapy––our center has a dedicated coordinator and nurse practitioner to review their charts and contact their local doctors to evaluate for late toxicities just like this,” Banerjee added. “Furthermore, T-cell malignancies are quite rare and often treated at academic centers…Cases like this would be noticed rather quickly and published if physicians suspected a link between prior CAR T-cell therapy and a current malignancy.”

Following further investigation by the Adverse Event Reporting System, the FDA listed post-treatment T-cell malignancy as a potential signal of serious risk/new safety information for this therapeutic class in the July – September 2023 quarterly report. The agency concluded that mature T-cell malignancies, including CAR-positive tumors, may occur within weeks of infusion and may prove fatal.4

“Many therapies that these patients receive [such as] transplantation, bendamustine, lenalidomide, and more have been associated with secondary cancers. Ciltacabtagene autoleucel’s package insert in myeloma was also recently updated to include the risk of secondary myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML], but many of these patients had received years of prior lenalidomide, a drug that is well known to predispose patients to secondary MDS or AML,” Banerjee said.

“I have no doubt that future analyses will show that patients who receive CAR-T therapy have higher rates of second cancers than those who don’t. Why? Because of a principle similar to immortal time bias, whereby certain complications can only develop if the patient is alive to develop them. This has been well shown in multiple myeloma––patients who develop second malignancies after their myeloma diagnosis are paradoxically more likely to have had deep responses to therapy and to have lived longer,” Banerjee explained.

However, when asked whether screening should be implemented to help reduce individual risk, Banerjee responded, “Screening T cells ahead of CAR T-cell infusion is not something we routinely do, and I’d argue that the benefits of CAR T-cell therapy would still outweigh the risks even in a patient who had clonal hematopoiesis of indeterminate potential or low-level T-cell abnormalities beforehand.”


  1. FDA requires boxed warning for T cell malignancies following treatment with BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. FDA. April 18, 2024. Accessed April 19, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-requires-boxed-warning-t-cell-malignancies-following-treatment-bcma-directed-or-cd19-directed
  2. 2024 safety and availability communications. FDA. Updated April 18, 2024. Accessed April 19, 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 23, 2023. Accessed April 19, 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. July - September 2023 I Potential signals of serious risks/new safety information identified by the FDA Adverse Event Reporting System (FAERS). FDA. Updated January 2, 2024. Accessed April 19, 2024. https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/july-september-2023-potential-signals-serious-risksnew-safety-information-identified-fda-adverse
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