Selecting the optimal bridging therapy for B-ALL: A multicenter comparison of blinatumomab, inotuzumab ozogamicin, and CAR-T prior to allo-HSCT

Abstract Background: The incorporation of novel immunotherapeutic and cellular approaches—including blinatumomab, inotuzumab ozogamicin, and CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy—has substantially improved remission rates and enabled more patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) to undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite their increasing use, the optimal bridging strategy prior to HSCT remains undefined. Methods: In this multicenter retrospective study, we included consecutive R/R B-ALL patients who received blinatumomab (BLI), inotuzumab ozogamicin(INO), or CD19-directed CAR-T therapy—including brexucabtagene autoleucel and a second-generation investigational CAR-T product incorporating an FMC63-derived scFv and 4-1BB as the co-stimulatory domain—as bridging treatment prior to allo-HSCT between 2018 and 2025. Multivariable analyses were performed using the Cox proportional hazards model. All statistical analyses were conducted using R software (version 4.2.1). Results: A total of 262 patients with relapsed/refractory (R/R) B-ALL who underwent allo-HSCT were included. The median age was 20 years (range, 2–69), and 147 patients (56.1%) were male. Prior to transplantation, 124 patients (47.3%) had received blinatumomab (BLI), 141 (53.8%) had received CAR-T therapy, and 16 (6.1%) had received inotuzumab ozogamicin (INO); 18 patients had received ≥2 immunotherapies (BLI+CAR-T, n=11; BLI+INO, n=2; CAR-T+INO, n=4; all three, n=1). Donor types included 31 matched sibling donors (MSD, 11.8%), 4 matched unrelated donors (10/10 URD, 1.5%), and 227 haploidentical donors (86.6%). The median time to neutrophil and platelet engraftment was 12 and 13 days, respectively. CMV viremia was observed in 30.0% of patients, and EBV viremia in 18.3%. Baseline characteristics were comparable among the BLI, INO, and CAR-T groups. Univariate analysis revealed no significant differences in neutrophil (p=0.1) or platelet (p=0.6) engraftment between patients who received immunotherapy and those who did not. Similarly, no significant differences in 1-year overall survival (OS) or disease-free survival (DFS) were observed for BLI (OS: 87% vs. 91%, p=0.4; DFS: 72% vs. 76%, p=0.7), CAR-T (OS: 89% vs. 89%, p=0.8; DFS: 75% vs. 74%, p>0.9), or INO (OS: 84% vs. 89%, p=0.7; DFS: 65% vs. 75%, p=0.5). Post-HSCT Epstein–Barr virus (EBV) reactivation rates were comparable across groups (BLI: 34.4% vs. 28.5%, p=0.2; CAR-T: 29.4% vs. 33.5%, p=0.3; INO: 32.6% vs. 31.2%, p>0.9). However, cytomegalovirus (CMV) reactivation was significantly more frequent in patients who had received CAR-T therapy (56.3% vs. 39.3%, p<0.001).The incidence of grade II–IV acute graft-versus-host disease (aGVHD) did not differ significantly according to prior immunotherapy (BLI: 45% vs. 54%, p=0.171; CAR-T: 55% vs. 44%, p=0.081; INO: 44% vs. 50%, p=0.821). Multivariate analysis showed that none of the three immunotherapies were independently associated with OS, DFS, or II–IV aGvHD. II–IV aGvHD was identified as a significant adverse factor for OS (HR 3.19, 95% CI 1.27–8.03, p=0.011). Haploidentical donor was independently associated with improved DFS (HR 0.385, 95% CI 0.08–1.82, p=0.020). Conclusion: In this cohort of R/R B-ALL patients undergoing allo-HSCT, BLI, CAR-T, and INO showed comparable survival outcomes and safety profiles when used as bridging immunotherapy. Notably, CAR-T recipients exhibited a higher incidence of post-HSCT CMV reactivation, underscoring the need for enhanced CMV prophylaxis and surveillance in this subgroup.