In January 2024, the FDA mandated new boxed warnings for all approved B-cell maturation antigen (BCMA)- or CD19-directed autologous CAR T-cell therapies, highlighting the serious risk of T-cell malignancies. This decision was based on reports of secondary T-cell cancers occurring in patients treated with these therapies. However, by the end of the year, the necessity of this warning was seriously questioned by clinicians and researchers, as studies suggested a low risk of second primary malignancies (SPMs) after therapy.
Kai Rejeski, MD, of the Sloan Memorial Kettering Cancer Center, expressed skepticism about the increased risk for developing SPMs with CAR T-cell therapy compared to other treatment modalities. A systematic literature review and meta-analysis published by Rejeski and colleagues in September 2024 showed that the rate of SPM was 5.8% among 5,517 patients who received CAR T-cell therapy, with T-cell malignancies accounting for just 1.5% of SPMs. This rate was similar to that of standard-of-care therapies.
The FDA's decision was informed by 22 cases of T-cell cancers that occurred after treatment with CAR-T products, emerging from about 27,000 doses administered in the U.S. for hematologic cancers. Despite these cases, a review article in JAMA Oncology by Saurabh Dahiya, MD, and colleagues in December 2024 emphasized that the benefits of CAR-T therapy against the primary cancer appear to outweigh the small risk for SPCs, advocating for cautious reassurance in most cases.
The FDA's investigation into the "serious risk" of T-cell malignancies in patients who received BCMA- or CD19-directed autologous CAR T-cell therapy was first announced in November 2023. FDA leaders discussed the reasoning behind the cancer risk warnings in a perspective article published in the New England Journal of Medicine, highlighting the potential for oncogenesis caused by genomic integration or other mechanisms with the current generation of retroviral vectors.
As the use of CAR T-cells for indications outside hematology and oncology is considered, new strategies involving targeting insertion of the CAR construct to specific loci might help reduce the risk of cancers due to integration of the CAR construct at oncogenic loci within the genome.
