Unanswered questions following reports of secondary malignancies after CAR-T cell therapy: an ASTCT, EBMT, ISCT, CIBMTR, and PICI commentary

A recent commentary published in Nature Medicine addresses emerging reports of T cell malignancies after CAR-T cell therapy, the overall benefits over potential risks, and importance of supporting the FDA’s long-term follow up recommendations for treated patients. This commentary provides a well-timed and common response from members of the American Society for Transplantation and Cellular Therapy (ASTCT), the European Society for Blood and Marrow Transplantation (EBMT), the International Society for Cell & Gene Therapy (ISCT), the Center for International Blood and Marrow Transplant Research (CIBMTR), and the Parker Institute for Cancer Immunotherapy (PICI).

To date, the FDA is investigating 20 reports of T cell malignancies following treatment with BCMA- or CD19-directed CAR-T cell immunotherapies. Several key abstracts presented at the 2023 American Society for Hematology (ASH) reported lymphomas and leukemias after CAR-T therapy, suggesting potential genetic mutations in genes such as TET2 and JAK3 present in clonally expanded cell as contributors. Additionally, CIBMTR data on 11,345 CAR-T recipients showed 3 reported T cell malignancies. Despite the 20 cases in the FDA Adverse Events Reporting System (FAERS) database, the observed rate of T cell malignancies is comparatively low among the estimated 34,400 CAR-T recipients.

One central question revolves around establishing a causal link between CAR-T therapy and rare instances of T cell malignancy. The lack of comprehensive information on reported cases presents a challenge, the authors state. These dat includes critical patient characteristics such as age, prior therapies, immune status, and time from CAR-T infusion to T cell lymphoma development. Although CAR-T products mandate 15 years of monitoring, an unknown number of patients may not adhere to recommended follow-ups, potentially leading to undetected or unknown early warning signs. Since both FAERS and CIBMTR reporting is voluntary, this results in a lack of reliable numerator or denominator for assessment. With an estimated 34,400 patients globally receiving commercial FDA-approved CAR-T cells, the FDA FAERS database includes outcomes for just under 8,000 patients, indicating potential gaps in reporting.

The authors also consider CAR-T cell therapy in the context of commonly used therapies such as chemotherapy and radiotherapy, which carry a higher long-term risk of genotoxicity and predisposition to secondary cancers compared with what has been reported after CAR T cell therapy thus far. Other treatments such as hematopoietic stem cell transplant increase the risk of secondary cancers, influenced by factors such as patient age, underlying disease, prior therapies, type of transplant, and post-transplant treatments. For patients with Hodgkin lymphoma and non-Hodgkin lymphoma undergoing autologous stem cell transplantation, the risk of secondary hematological malignancies is estimated to be 8–29%. Furthermore, a review of 340 patients receiving gene-modified T cells found no increased risk of subsequent malignancy with retroviral genetically modified T cells. Even in cases of subsequent malignancies, assessments showed no transgene-positive samples, and testing for replication-competent retrovirus in patient samples was negative.

Despite uncertainties regarding the genotoxicity risks associated with retroviral or lentiviral insertion in CAR-T cell therapies for advanced hematological malignancies, the authors, including current and past leaders of prominent organizations in the field, emphasize the need for thorough investigation and transparency. They express the view that, as leaders in the field, the benefits of CAR-T therapies outweigh potential risks in most cases. While awaiting FDA investigation results, they advocate for centers with cell therapy expertise to continue offering commercial CAR-T products when deemed the best option based on confirmed safety information. The authors stress support for FDA long-term follow-up recommendations, urging participation in safety studies and prompt reporting of subsequent malignancies, emphasizing the importance of ongoing research based on the latest safety information.

Reference:

Levine, B.L., Pasquini, M.C., Connolly, J.E. et al. Unanswered questions following reports of secondary malignancies after CAR-T cell therapy. Nat Med (2024). https://doi.org/10.1038/s41591-023-02767-w