CAR T-Cell Therapy and the Emerging Threat of Secondary Cancers: A Targeted Look

OBJECTIVES: Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy for certain blood cancers, involving the modification of a patient’s T cells to target cancer cells. In November 2023, the FDA warned of a potential risk of secondary blood cancers linked to CAR T-cell therapy, requiring some manufacturers to add a boxed warning to their product information. This study aims to understand and report the risk of secondary malignancies associated with CAR T-cell therapy, based on available evidence to balance these risks against its therapeutic benefits.

METHODS: We conducted a targeted literature search in PubMed and Google Scholar using the evidence synthesis tool MaiA. The search included articles published from November 2023 to June 2024, focusing on secondary malignancies due to CAR T therapy. We included clinical trials, case studies, systematic reviews, observational studies, and reviews. Two independent reviewers extracted data from the articles, which were charted in an Excel sheet

RESULTS: According to our gathered literature, the most common secondary malignancy after CAR-T therapy was leukemia, comprising 2.7% of all reported cases. This includes myelodysplastic syndromes and T-cell large granular lymphocytic leukemia. Secondary myeloid neoplasms such as acute myeloid leukemia (AML), hematopoietic neoplasms excluding leukemias and lymphomas including lymphoproliferative disorder were also noted. Skin cancers were the second most common, accounting for 0.4% of reported cases. Other reported solid tumors included prostate cancer, nervous system tumors, and respiratory neoplasms. Most of the reported secondary malignancies were associated with CAR T products namely axicabtagene ciloleucel and tisagenlecleucel.

CONCLUSIONS: Cancer treatments like chemotherapy and radiation can cause genetic mutations in healthy cells, resulting in secondary malignancies. Since most CAR T therapy treated patients have undergone previous treatments, pre-existing mutations can lead to secondary malignancies. Evaluating these risks against other therapeutic approaches is crucial for understanding the outcomes, risks, and benefits of CAR T therapies.