Inotuzumab ozogamicin vs blinatumomab bridging optimization and second CD19 CAR-T efficacy in Relapsed/Refractory B-ALL

Abstract

Abstract Introduction: Despite advances with CD19 chimeric antigen receptor T-cells (CAR-T) in relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), optimal strategies to bridge patients to CAR-T and manage post-CAR-T relapse remain undefined. The study explored differential efficacy of antibody-based bridging with inotuzumab ozogamicin (INO) versus blinatumomab (BITE) and outcomes of second CAR-T infusions in a real-world cohort. Methods: Twenty-two R/R B-ALL patients treated at our institution (Feb 2020- Mar 2025) with CD19 CAR-T were stratified by bridge agent: INO (n=16) or BITE (n=6; 3 received concurrent intrathecal [IT] chemotherapy for CNS disease). Four received second CAR-T after primary CAR-T failure. Multivariate regression identified factors associated with efficacy and relapse. Results: Our cohort of 22 R/R B-ALL patients (median age 39 years; range 16-69) exhibited 59.1% extramedullary disease (EMD) prevalence and 36.4% BCR::ABL1 positivity, with bridging therapy achieving an overall response rate (CR/PR) of 87.5% in the INO group (n=16; BM blast reduction 85%) versus 66.7% in the Blinatumomab group (n=6; p=0.28), while Blinatumomab combined with intrathecal chemotherapy demonstrated 100% CNS clearance efficacy in all EMD-CNS+ cases. Following CD19 CAR-T infusion, the day 90 CR rate reached 75.0% for INO-bridged and 66.7% for Blinatumomab-bridged patients (p=0.62), though multivariable analysis identified baseline EMD (HR 3.9; 95%CI 1.2-12.7) and epigenetic mutations (DNMT3A/ASXL1/TET2; HR 4.2; 95%CI 1.4-12.9) as significant relapse predictors. All subjects exhibited peripheral blood CAR-T expansion detectable via ddPCR, in INO-bridged group reaching a median peak level of 53400 copies/μg DNA by (range: 21800-153680) at median peak time of day 8 after CAR-T infusion, while in Blinatumomab-bridged reaching a median peak level of 46700 copies/μg DNA by (range: 14390-10240) at median peak time of day 7after CAR-T infusion. Among four patients receiving second CAR-T after primary failure, 75% (3/4) achieved CR when bridge therapy was optimized through agent-switch or combination strategies (e.g., INO switched to Blinatumomab), yielding a median PFS of 8 months. Safety monitoring showed 77.3% experienced grade 1-2 CRS, 22.7% grade 1 ICANS, and two grade 3 VOD cases in the INO cohort. The 1-year overall survival remained comparable between bridging arms (INO:80% vs Blinatumomab:83%; p=0.91). Conclusion： INO achieves superior marrow debulking in high-tumor-burden patients, while Blinatumomab with intrathecal chemotherapy facilitates complete CNS disease eradication; retreatment with CD19 CAR-T induces remission in 75% of primary-refractory cases when bridging is optimized via agent-switch or combination strategies, albeit with limited durability; and critically, epigenetic mutations (DNMT3A/ASXL1) constitute the highest-risk molecular subgroup, mandating development of novel maintenance therapies.