Simple SummaryTo date, quantitative and comprehensive information summarizing the differences in the efficacy and safety of anti-CD19 chimeric antigen receptor (CAR) T-cells with CD28 co-stimulatory domains or 4-1BB co-stimulatory domains for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) is lacking. Our study utilized a model-based meta-analysis (MBMA) to accurately measure the differences between the anti-CD19 CAR T-cell therapies for B-ALL with CD28 and 4-1BB co-stimulatory domains. We discovered that the median overall survival (OS) and progression-free survival (PFS) for the 4-1BB co-stimulatory domain were longer than those for anti-CD19 CAR T-cell therapy with a CD28 co-stimulatory domain. Additionally, anti-CD19 CAR T-cells with the CD28 co-stimulatory domain showed a higher incidence of neurotoxic adverse effects. This study provides quantitative information that can be used to compare the different co-stimulatory domains of anti-CD19 CAR T-cells for treating B-ALL.AbstractThis study quantified the differences in the efficacy and safety of different stimulation domains of anti-CD19 chimeric antigen receptor (CAR) T therapy for B-cell acute lymphoblastic leukemia (B-ALL). Clinical trials related to anti-CD19 CAR T-cell therapy for B-ALL were searched in public databases from database inception to 13 November 2021. The differences in overall survival (OS) and progression-free survival (PFS) of B-ALL patients treated with anti-CAR T-cell therapy containing 4-1BB and CD28 co-stimulatory domains were compared by establishing a parametric survival function. The overall remission rate (ORR), the proportion of people with minimal residual disease (MRD)-negative complete remission (CR), the incidence of cytokine release syndrome (CRS), and the neurotoxicity across different co-stimulatory domains was assessed using a random-effects model. The correlation between the ORR, MRD-negative CR, PFS, and OS was tested. The results showed that the median OS of anti-CAR T-cell treatment containing 4-1BB and CD28 co-stimulatory domains was 15.0 months (95% CI: 11.0–20.0) and 8.5 months (95% CI: 5.0–14.0), and the median PFS was 7.0 months (95% CI: 4.0–11.5) and 3.0 months (95% CI: 1.5–7.0), respectively. Anti-CD19 CAR T-cells in the 4-1BB co-stimulatory domain showed superior benefits in patients who achieved ORR. The incidence of neurotoxicity was significantly higher in the CD28 co-stimulatory domain of anti-CD19 CAR T-cells than in the 4-1BB co-stimulatory domain. In addition, the ORR and MRD-negative CR were strongly correlated with OS and PFS, and PFS and OS were strongly correlated. The 4-1BB co-stimulatory domain suggested a better benefit–risk ratio than the CD28 co-stimulatory domain in B-ALL.