Real-world comparative outcomes of CAR-T cell therapy versus bispecific T-cell engagers in patients with relapsed acute lymphoblastic leukemia

Abstract Introduction: The emergence of novel immunotherapies and cellular therapies has transformed the treatment landscape for hematological malignancies such as acute lymphoblastic leukemia (ALL). As these therapies become more widely adopted in clinical practice, comparative evidence is needed to inform treatment selection and guide patient care. We conducted a national, real-world analysis of clinical outcomes between current FDA-approved CAR-T cell therapies (CAR-T) and bispecific T-cell engagers (BiTEs) in patients with relapsed ALL (R-ALL). Methods: We conducted a retrospective cohort study using real-world data from the TriNetX United States Research Database, a federated network of de-identified electronic health records (EHRs) from over 70 healthcare organizations. The study period included all relevant data from August 1st, 2005, to August 1st, 2025, or a standard 20-year lookback period. Propensity score matching was used to adjust for confounders, and time-to-event analysis was performed using Cox proportional hazards models with additional Kaplan-Meier survival analyses where appropriate. Statistical significance was determined by p < 0.001. Our primary outcome was overall survival, and several additional secondary outcomes were explored. Results: 8,250 R-ALL patients were identified, of whom 252 were exposed to CAR-T only and 1,131 were exposed to BiTEs only. Propensity score matching identified 226 patients per cohort thereafter. The Cox proportional hazards model demonstrated no statistically significant survival benefit between CAR-T and BiTEs, and median overall survival was not met in either cohort. Median follow-up for CAR-T was 23.6 months, and for BiTEs was 27.6 months; however, CAR-T recipients were less likely to progress to further lines of treatment (HR 0.410, CI 0.329-0.511, p<0.0001) at data cutoff. Additionally, although the risks of hospitalization were comparable between CAR-T and BiTE recipients, CAR-T demonstrated lower overall inpatient mortality (HR 0.628, CI 0.496-0.795). On secondary analysis, CAR-T was found to have a higher risk of cytokine release syndrome (CRS; RR 2.735, CI 1.934-3.869) and immune effector cell-associated neurotoxicity syndrome (ICANS; RR 4.700, CI 2.436-9.068) than BiTEs. Lastly, CAR-T use was found to have higher rates of hypogammaglobulinemia (RR 1.813, CI 1.465-2.244) and IVIG use (RR 1.58, CI 1.302-1.916). Conclusion: In this real-world, retrospective multi-cohort analysis, we report comparative outcomes associated with CAR-T versus BiTEs in R-ALL. Most notably, those exposed to CAR-T alone were less likely to require further lines of therapy; however, CAR-T was associated with greater hematotoxicity. As the use of these novel agents expands, ongoing evaluation of these analyses will be essential to inform treatment sequencing and optimize patient care.