Comparative clinical outcomes and single-cell profiling of CD19 CAR-T versus blinatumomab for relapsed/refractory B-ALL.
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BACKGROUND: CD19-targeting chimeric antigen receptor T-cells (CAR-T) and blinatumomab represent two leading immunotherapies for relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL). Despite sharing the same target, their differential clinical efficacy and underlying mechanisms remain unclear. METHODS: This retrospective study enrolled 106 r/r B-ALL patients (61 CD19 CAR-T vs 45 blinatumomab) between February 2020 and August 2023. The complete response (CR) rate, long-term survival, and therapeutic toxicities were compared between the two cohorts. Additionally, we conducted scRNA-seq on nine samples of patient-derived CAR-T/ blinatumomab-elicited T cells after infusion and performed a head-to-head comparison in vitro. RESULTS: Overall, the CR or CR with incomplete count recovery (CR/CRi) rate by day 28 after infusion was 96.6% (56/58) in the CAR-T cohort and 77.8% (35/45) in the blinatumomab cohort (p=0.008). With a median follow-up of 10 months (IQR 5.0-19.4), overall survival (OS) and leukemia-free survival (LFS) were comparable. In patients with higher tumor burden (minimal residual disease >20%), CAR-T was associated with a longer LFS (HR 0.453, 95% CI 0.226 to 0.908, p=0.026) compared with blinatumomab. In patients with relapsed disease, CAR-T showed prolonged LFS (HR 0.415, 95% CI 0.221 to 0.778, p=0.006) and a trend toward improved OS (p=0.088). All toxicities were reversible, and any adverse events (AEs) were similar (98.4% vs 88.9%), but severe AEs (grade ≥3) were higher with CAR-T, especially cytokine release syndrome (42.6% vs 13.3%, p<0.001). In addition, scRNA-seq data provided correlative evidence of functional enrichment of effector cells in CAR-T samples during peak expansion at 2 weeks post infusion. Head-to-head comparison in vitro is consistent with the possibility that CAR-T cells may sustain effector function and cytotoxicity following tumor engagement, whereas blinatumomab-elicited T cells tended to show relatively higher exhaustion and reduced cell recovery. CONCLUSIONS: Our findings suggest that CD19 CAR-T therapy is associated with a higher CR/CRi rate compared with blinatumomab, particularly in patients with high tumor burden and relapsed disease, despite a higher severe toxicity profile.