FORTRESS-CART: Focused Observation and Risk Testing for Robust Evaluation of Safety in Chimeric Antigen Receptor T-Cell Therapy (CAR-T): Real-World Predictors of Second Primary Malignancies (SPMs) Among Patients Treated With CAR-T.

BACKGROUND

Chimeric antigen receptor-T (CAR-T) cell therapies are highly effective in treating hematologic malignancies. Cases of second primary malignancies (SPMs) have been reported post-treatment, although risk factors remain unclear. This real-world study evaluated predictors of SPMs among patients treated with CAR-T.

METHODS

Patients with multiple myeloma (MM) or lymphoma/leukemia treated with CAR-T were identified from the Komodo Research Database (January 1, 2016-June 30, 2024). Incidences of SPMs and hematologic SPMs were evaluated following CAR-T infusion (index date) and predictors were evaluated 12 months pre-index. LASSO regression was used to identify predictors of SPMs and hematologic SPMs, separately. Multivariate Cox regression was used to assess the magnitude and direction of each predictor.

RESULTS

Among 2,609 patients receiving CAR-T (MM: 683, lymphoma/leukemia: 1,926) and over a median follow-up of 14.5 months, the incidences of SPMs and hematologic SPMs were 11.8% and 5.0%, respectively (0.3% for peripheral T-cell lymphoma). Median time-to-event was approximately 8 months for SPMs and hematologic SPMs. Adjusting for other predictors in the models, there was no association between CAR-T indicated for MM versus lymphoma/leukemia and the risk of SPMs (hazard ratio: 0.85, P = .32). Relative to lymphoma/leukemia, MM was associated with a significantly lower risk of hematologic SPMs (hazard ratio: 0.24, P < .05).

CONCLUSIONS

This study found no association between CAR-Ts used in MM versus lymphoma/leukemia and the risk of subsequent SPMs, while a lower risk of hematologic SPMs was observed in patients with MM. T-cell malignancies were infrequent. Ongoing research into potential risk factors of SPMs following CAR-T could help inform individualized management strategies.