T-cell neoplasias and secondary malignancies after CAR-T cell therapy: current knowledge, risk factors, and implications from CAR-T engineering strategies

Widespread use of CAR-T cell therapies for treatment of B cell malignancies has resulted in a frameshift in treatment strategies and improved patient outcomes since the first CAR-T product was FDA approved in 2017. Currently over 30,000 patients have been treated with approved CAR-T cell products, with many more likely to be treated in future, both as standard of care therapy as well as on clinical trials. As more patients are treated, development of rare complications has begun to emerge, and the incidence of second primary malignancies after CAR-T cell therapy is evolving from a hypothetical to a realized concern. Furthermore, in November 2023, the FDA issued a warning regarding the potential for CAR-T cell-derived T cell neoplasias to arise as a result of CAR-T manufacturing. Here we review patient risk factors for development of second primary malignancies including T cell neoplasias, CAR-T engineering strategies that may increase this risk, and the current body of literature surrounding incidence of second primary malignancies and case reports of T cell neoplasias arising after CAR-T cell therapy.