FDA to Investigate Risk of T-Cell Malignancy After CAR T-Cell Therapy


The FDA has received reports of multiple T-cell malignancies in patients after approved CAR-T treatment.

The FDA has announced that it will be investigating the risk of T-cell malignancies in patients that have received B cell maturation antigen (BCMA)-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies.1

The FDA stated that it has received reports from clinical trials and/or postmarketing adverse event (AE) data sources of cases of T-cell malignancies after treatment. The agency has determined that the apparent risk is applicable to all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T-cell therapies, including the approved therapies Abecma (idecabtagene vicleucel), Breyanzi (lisocabtagene maraleucel), Carvykti (ciltacabtagene autoleucel), Kymriah (tisagenlecleucel), Tecartus (brexucabtagene autoleucel), and Yescarta (axicabtagene ciloleucel).

According to the FDA Adverse Event Reporting System (FAERS) database, there have been 12 instances of T-cell lymphoma in patients treated with approved CAR T-cell therapies. These cases have been seen in patients treated with Kymriah (n = 7), Yescarta(n = 3), Carvykti (n = 1), and Breyanzi (n = 1).

Instances of T-cell malignancy with serious outcomes, including hospitalization and death, will be investigated for patients treated with these therapies, and regulatory action may be taken according to the findings.

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In its statement, the FDA stated that the overall benefits of these products continue to outweigh their potential risks for their approved uses. The potential risk of developing secondary malignancies is labeled as a class warning in the US prescribing information for all gene therapy products with integrating vectors (lentiviral or retroviral). All initial approvals of these products require sponsors to conduct 15-year long-term follow-up studies to assess safety and the risk of secondary malignancies.

The announcement comes soon after the FDA pushed back ide-cel's Prescription Drug User Fee Act date from December 16, 2023, to a yet unspecified date and announced an Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the supplemental biologics license application for the approved therapy.2

The sBLA was submitted with the intention of expanding ide-cel from its current FDA-approved indication, which covers adults with triple-class exposed relapsed/refractory multiple myeloma (r/r MM) who have received 4 or more previous lines of treatment, to earlier-line settings. Bristol Myers Squibb (BMS) and 2seventybio expect that the AdComm meeting will be focused on a review of overall survival (OS) data from the phase 3 KarMMa-3 clinical trial (NCT03651128) evaluating ide-cel in patients with r/r MM that have received 2 to 4 previous lines of treatment. The OS results constituted a secondary end point for KarMMa-3; the trial’s primary end point was previously met when a statistically significant improvement in progression-free survival (PFS) was demonstrated in comparison to standard-of-care (SOC) regimens.

1. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. News release. FDA. November 28, 2023. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous?utm_medium=email&utm_source=govdelivery
2. Bristol Myers Squibb and 2seventy bio Provide Update on U.S. FDA Review of sBLA for Abecma (idecabtagenevicleucel) in Earlier Lines of Therapy for Triple-Class Exposed Relapsed or Refractory Multiple Myeloma. News release. 2seventy bio, Inc. November 20, 2023. Accessed November 20, 2023. https://ir.2seventybio.com/news-releases/news-release-details/bristol-myers-squibb-and-2seventy-bio-provide-update-us-fda
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