FDA Requires Boxed Warnings for Secondary Cancer for Approved CAR-T Therapies

Nicole Verdun, MD

Update - April 19, 2024 - The FDA is requiring that boxed warnings for T-cell malignancies after treatment with chimeric antigen receptor (CAR) T-cell therapy be added to all approved CAR T therapies.¹

These products include Bristol Myers Squibb (BMS) and 2seventybio’s idecabtagene vicleucel (ide-cel; marketed as Abecma); BMS’s lisocabtagene maraleucel (liso-cel; marketed as Breyanzi); Janssen and Legend Biotech’s ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti); Novartis’s tisagenlecleucel (tisa-cel; marketed as Kymriah); Kite Pharma’s brexucabtagene autoleucel (brexu-cel; marketed as Tecartus); and Kite Pharma’s axicabtagene ciloleucel (axi-cel; marketed as Yescarta).

The boxed warnings note that “T-cell malignancies may occur following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies,” with each product’s name listed in the letter. The agency also requests additional references to T-cell malignancies be added to the 'WARNINGS AND PRECAUTIONS' sections of for each of the 6 CAR-T products' labels: “T cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including [product name]. Mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes.”²

In its new communication, the FDA stated that it will also mandate amendments to other sections of their labels, including the warnings and precautions, postmarketing experience, patient counseling information and medication guide sections.¹

READ MORE: FDA Approves Janssen and Legend Biotech’s Carvykti for Expanded Indication in Earlier Line Multiple Myeloma

The FDA previously announced in November 2023 that it was investigating the risk of T-cell malignancies in patients who have received BCMA-directed or CD19-directed autologous CAR T-cell immunotherapies.⁷ At the time, according to the FDA Adverse Event Reporting System (FAERS) database, there had 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). Despite this, at the time of this announcement, the FDA stated that the overall benefits of the marketed CAR-T products continue to outweigh their potential risks for their approved uses.³

Later, in January 2024, the FDA requested that black box warnings related to secondary cancer risks be added to the approved CAR T-cell therapies and issued separate letters to each of the relevant companies for the therapies on January 19, 2024.²

“Since [the product was approved], 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,” Nicole Verdun, MD, the director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research, the signed author of the letters, wrote in each.² “FDA identified postmarketing adverse event and clinical trial reports describing [the] occurrence of mature T-cell malignancies, including CAR-positive tumors, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies... Furthermore, we consider the serious risk of T-cell malignancy to be applicable to all BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies.”

REFERENCES
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. April 18, 2024. News release. FDA. 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. 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. 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