Background
Phase III RCT (n=405), Ph-negative heavily pretreated B-cell precursor ALL (refractory to primary induction or salvage, first relapse with remission <12 mo, second or later relapse, or relapse after allogeneic HCT). Randomized 2:1 to blinatumomab vs chemotherapy.
Interventions and follow up
Arm A: Blinatumomab (CD19/CD3 BiTE) CIV — induction 9 μg/d wk 1, 28 μg/d wk 2-4, off wk 5-6; consolidation wk 1-4 Q6wk
Arm B: Investigator-choice chemotherapy (FLAG ± anthracycline; high-dose cytarabine; high-dose methotrexate; or clofarabine-based)
Primary endpoint: OS
Median follow-up: 11.7 mo (A) vs 11.8 mo (B)
Arm B: Investigator-choice chemotherapy (FLAG ± anthracycline; high-dose cytarabine; high-dose methotrexate; or clofarabine-based)
Primary endpoint: OS
Median follow-up: 11.7 mo (A) vs 11.8 mo (B)
Results
mOS: 7.7 vs 4.0 mo (A vs B); HR 0.71, 95%CI 0.55-0.93, P=.01
CR within 12 wks: 34% vs 16% (blinatumomab vs chemotherapy)
HSCT: 24% in each group underwent allogeneic transplant
CR within 12 wks: 34% vs 16% (blinatumomab vs chemotherapy)
HSCT: 24% in each group underwent allogeneic transplant
Adverse events
Hematologic/cytopenias (grade ≥3): Neutropenia 38% vs 58% (A vs B); cytopenias more frequent with chemotherapy.
Infections (grade ≥3): 34% vs 52%.
Blinatumomab-specific: Cytokine release syndrome 4.9% grade ≥3; neurologic events 9.4% grade ≥3.
Other: Elevated liver enzymes 13% vs 15%. Any grade ≥3 event 87% vs 92%; fatal AEs 19% vs 17%.
Infections (grade ≥3): 34% vs 52%.
Blinatumomab-specific: Cytokine release syndrome 4.9% grade ≥3; neurologic events 9.4% grade ≥3.
Other: Elevated liver enzymes 13% vs 15%. Any grade ≥3 event 87% vs 92%; fatal AEs 19% vs 17%.
Conclusions
Blinatumomab significantly improved OS and CR rate versus standard chemotherapy in relapsed/refractory Ph-negative B-cell precursor ALL, establishing it as standard of care.
Key Limitations
Open-label; heterogeneous chemotherapy comparator. CRS and neurotoxicity require inpatient monitoring and step-dosing. Continuous-infusion logistics burdensome. Limited to Ph-negative disease; subsequent HCT confounds OS.
Clinical Context
Confirmatory trial supporting full FDA (2017) and EMA approval of blinatumomab for relapsed/refractory B-cell precursor ALL. ESMO guidance positions blinatumomab as preferred salvage and as a bridge to allogeneic HCT; also approved for MRD-positive ALL.