The FDA will investigate all currently approved CAR T-cell treatments, as well as BCMA-directed and CD19-directed genetically modified autologous CAR T-cell therapies, for the risk of secondary T-cell malignancies.
The FDA has announced plans to launch an investigation into the potential risk of secondary cancer associated with the use of chimeric antigen receptor (CAR) T-cell therapies. The investigation was prompted following reports from clinical trials and tracking of postmarketing adverse events for T-cell malignancies, including CAR-positive lymphoma, among patients administered BCMA- or CD19-directed CAR-T cell immunotherapies.1
“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,” the FDA said in a press release.
The agency will investigate all currently approved CAR T-cell treatments, as well as BCMA-directed and CD19-directed genetically modified autologous CAR T-cell therapies.
The FDA said that T-cell malignancies were observed in patients administered several products in the class, but the agency did not identify a specific treatment. Approved CAR T-cell treatments include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta).
“As with all gene therapy products with integrating vectors (lentiviral or retroviral vectors), the potential risk of developing secondary malignancies is labeled as a class warning in the U.S. prescribing information (USPIs) for approved BCMA-directed and CD19-directed genetically modified autologous T cell immunotherapies,” the FDA wrote in a statement. “The initial approvals of these products included postmarketing requirements (PMRs) under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) to conduct 15-year long term follow-up observational safety studies to assess the long-term safety and the risk of secondary malignancies occurring after treatment.”1
The agency added that patients and individuals enrolled in clinical trials who are currently receiving treatment with CAR T-cell therapies should be monitored throughout their lives for new malignancies. Manufacturers should report any cases of new malignancies and obtain a patient sample to test for the presence of the CAR transgene, according to the FDA.
The FDA has approved six CAR T-cell therapies since 2017 for the treatment of hematologic cancers, including lymphomas, some forms of leukemia, and multiple myeloma. Despite promising response rates in clinical trials, fewer than half of patients have demonstrated long-term durable responses, with limited data demonstrating the true efficacy and broad feasibility of CAR T-cell treatments outside of the clinical trial setting, according to a study published by Blood Advances.2 The study noted that alternative treatments may have similar efficacy to CAR T-cell therapies in select clinical scenarios. This is highly relevant given the cost of these treatments, which can rise higher than $450,000.3
“Despite the encouraging response rates, [progression-free survival (PFS)], and [overall survival (OS)] of the CAR T cohort, greater than two-thirds ultimately progressed after CAR T cells,” the study authors wrote.2 “Moreover, after adjusting for poor prognostic variables in both cohorts, including elevated LDH, bulky disease, extranodal sites, elevated ECOG status, and refractory disease, the superiority of CAR T therapy was less pronounced for PFS and OS. Indeed, patients who received alternate therapy had a significantly increased incidence of elevated LDH and refractory disease compared with those patients who were referred for CAR T cells. Furthermore, the subgroup analysis performed on patients with elevated LDH and bulky disease demonstrated that CAR T therapy did not significantly improve PFS and OS.”
Manufacturers will have an opportunity to present data showing the benefits of CAR T-cell therapies outweigh the risks at the upcoming American Society of Hematology meeting in San Diego, California next month.
1. FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies. FDA. News release. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous
2. Sermer D, et al. Outcomes in patients with DLBCL treated with commercial CAR T cells compared with alternate therapies. Blood Adv (2020) 4 (19): 4669–4678. https://doi.org/10.1182/bloodadvances.2020002118. Published October 1, 2020. Accessed November 29, 2023.
3. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. National Cancer Institute. Webpage. Updated March 10, 2022. Accessed November 29, 2023.