Temporal Association and Risk Window for Secondary Malignancies Post CAR-T

In November 2023, the U.S. FDA reported potential risks of T-cell lymphomas following BCMA-directed or CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy. Initial disproportionality analysis (DA) of the FDA Adverse Events Reporting System (FAERS) database yielded mixed results across six FDA-approved CAR-T therapies. Subsequent real-world (RW) data analysis suggested that background incidence of T-cell malignancies may have influenced these findings. This study explored comprehensive temporal analysis of short term and long-term toxicities specifically secondary T-cell lymphomas (STCL) following CAR-T therapy.

Methods: This follow-up study analyzed updated data from RW datasets focused on two FDA-approved CAR-T therapies: tisagenleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). The TriNetX Global database, encompassing 178 healthcare organizations from more than 20 countries and 223,703,950 patient records, served as our primary RW data source. Analysis included the incidence of STCL at multiple time points post-CAR-T therapy: 1 month, 1-3 months, 3-6 months, 6 months to 1 year and beyond 1 year.

Results: The RW database revealed a target patient population with 960 individuals receiving tisagenleucel and 1,560 receiving axicabtagene ciloleucel . For tisagenleucel the data reveals a relatively low incidence of secondary T cell lymphoma with only 10 cases (1.04%) occurring within the 1-3 month period following treatment and no cases reported in other time frames. Notably, no cases were reported in the first one month or beyond three months post CAR-T. In contrast, axicabtagene ciloleucel (n=1560) demonstrated a relatively higher overall incidence of secondary T-cell Lymphoma occurrence. A total of 40 cases (2.56%) were reported at any time after therapy, with the majority (30 cases, 1.9%) manifesting within the first month post-treatment. An additional 10 cases (0.64%) were observed in the 3-6 month period with no cases reported in the 1-3 month window or beyond the 6 month time frame following therapy. The lifetime incidence of secondary T-cell lymphoma was 1.04% for tisagenleucel and 2.56% for axicabtagene ciloleucel. Axicabtagene ciloleucel demonstrated both a higher incidence (2.56% vs. 1.04%) with earlier onset and a second peak (3-6 month post therapy) as compared to tisagenleucel .

Conclusions: This study revealed that there is reasonable temporal association between secondary T-cell Lymphoma and tisagenleucel and axicabtagene ciloleucel therapy. However significant differences exist in the temporal patterns and overall incidence of STCL following tisagenleucel and axicabtagene ciloleucel therapy and are important for understanding the potential short and long-term risks and onset windows associated with these innovative cancer treatments. These findings underscore the importance of vigilant patient monitoring particularly in the first six months post-CAR-T, and suggest that risk profiles may vary substantially among different CAR-T products. The clustering of cases within specific time windows (1-3 months for tisagenleucel; <1 month and 3-6 months for axicabtagene ciloleucel) warrants further investigation into potential mechanisms underlying these temporal patterns. These insights can serve to inform efforts to optimize long-term patient management strategies and refine risk assessment protocols in CAR-T therapy and appropriate follow-up protocols for patients undergoing CAR-T cell therapy.