Background Acute B-cell lymphoblastic leukemia (B-ALL) is an aggressive malignancy where minimal residual disease (MRD) negativity dictates long-term survival. While blinatumomab effectively induces remission in newly diagnosed (ND) and relapsed/refractory (R/R) disease, its real-world efficacy for deep MRD eradication in Philadelphia chromosome-positive (Ph+) and -negative (Ph-) B-ALL is unestablished. For Ph+ patients receiving blinatumomab-tyrosine kinase inhibitors (TKIs) combinations, comparative complete molecular response (CMR) rates between ND and R/R cohorts are particularly lacking.

Methods We conducted a multicenter retrospective analysis of 113 adult B-ALL patients treated with blinatumomab (Sep 2021-Jul 2025). MRD was assessed by flow cytometry (negativity: aberrant blasts <0.01%). In Ph+ patients, BCR::ABL1 transcripts were quantified by PCR on the international scale (IS), with CMR defined as IS ≤0.01%. Treatment cohorts: 23 newly diagnosed and 12 refractory/relapsed patients received induction therapy; others received consolidation or MRD-guided therapy. Primary endpoints were complete remission/complete remission with incomplete hematological recovery (CR/CRi) and progression-free survival (PFS); secondary endpoints included overall survival (OS), MRD negativity detected by flow cytometry, CMR, and safety. Group comparisons used Fisher's/χ² tests (categorical) or Mann-Whitney U test (continuous). Survival analyses employed Kaplan-Meier with log-rank testing. All analyses used SPSS v26.0 (α=0.05).

Results The cohort comprised 64 Ph-negative and 49 Ph-positive B-ALL patients. Baseline characteristics including age, sex distributions, and NCCN risk stratifications were comparable between Ph subgroups (all p>0.05), though Ph-positive patients exhibited significantly higher rates of central nervous system involvement (16.7% vs. 1.5%; p=0.0098).

All 23 ND patients achieved complete remission, significantly higher than the CR rate of 66.7% (8/12) observed in the R/R group (p=0.0095). Overall flow-MRD negativity occurred in 83.3% of responders in the induction group (25/30). Among ND patients with evaluable MRD (n=23), flow cytometry (<0.01% threshold) revealed 18 MRD-negative and five MRD-positive cases post-induction. Over a median follow-up of 13.0 months (95% CI 7.2–14.8) in this subgroup, MRD-negative patients maintained 100% 12-month PFS and OS with no events observed, whereas MRD-positive patients showed significantly inferior outcomes: 12-month PFS 0%, 12-month OS 53.3%, and 0% survival beyond 24 months (log-rank p< 0.001).

Combination therapy of blinatumomab and TKIs induced CMR in 55.6% of Ph+ ND patients (5/9) and 80% of R/R Ph+ cases (4/5). Flow-based MRD clearance with MRD-directed therapy occurred in 85.7% (18/21) of Ph- patients. In Ph+ patients: isolated molecular MRD clearance was achieved in 54.5% (6/11) of those without detectable flow-MRD; whereas all 7 patients with dual-detectable MRD achieved flow clearance, but molecular disease persisted in 5 patients (71.4%). On MRD-directed therapy, no association was observed between BCR::ABL isoforms (P190/P210) and CMR conversion rates (P190: 53.8% vs. P210: 40.0%; p>0.05).

After a median follow-up of 13.0 months (range 7.2–14.4), survival analysis of 35 induction therapy patients (23 ND, 12 R/R) revealed significantly higher PFS in ND versus R/R cohorts (1-year: 82.5% vs 55.6%; 2-year: 68.8% vs 27.8%; log-rank p=0.033). PFS trajectories were comparable between Ph+ and Ph- subgroups. The entire cohort had 1- and 2-year OS rates of 83.3% and 70.7%, with no significant differences by disease status (ND vs R/R: p=0.179) or Ph subtype (p=0.945).

Adverse events affected 64.6% (73/113), predominantly reversible neutropenia (57.5%) and infections (43.3%). Cytokine release syndrome occurred in 4.4% (all grade 1). One grade 3 immune effector cell-associated neurotoxicity syndrome resolved with corticosteroids and temporary therapy interruption. No treatment-related mortality.

Conclusions Blinatumomab induces high remission rates and deep MRD clearance in newly diagnosed B-ALL but yields inferior outcomes in relapsed disease. Its suboptimal molecular efficacy in Ph+ ALL may reflect unoptimized TKI use during MRD therapy, whereas next-generation TKIs in R/R Ph+ patients correlate with enhanced CMR rates. Future Ph+ B-ALL clinical trials should prioritize MRD-guided TKI-blinatumomab combinations to accelerate molecular clearance and improve survival.

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2025
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