Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children with High-Risk First-Relapse B-Acute Lymphoblastic Leukemia: A Randomized Clinical Trial

Importance: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL). Objective: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab versus consolidation chemotherapy before allogeneic hematopoietic stem cell transplantation. Design, Setting, and Participants: In this randomized phase 3 clinical trial, patients were enrolled November 2015–July 2019 (data cutoff: July 17, 2019). Investigators at 47 centers in 13 countries enrolled children >28 days and <18 years with high-risk first-relapse B-ALL in morphological complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization. Intervention: Patients were randomized to receive one cycle blinatumomab (n=54; 15 μg/m2/day, 4 weeks, continuous intravenous infusion) or chemotherapy (n=54) for third consolidation. Main Outcomes and Measures: The primary endpoint was event-free survival (events represented by relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy endpoint was overall survival. Other secondary endpoints included minimal residual disease remission and incidence of adverse events. Results: 108 patients were randomized (median age 5.0 [IQR: 6.5; 4.0-10.5], 51.9% female, 97.2% M1 marrow). Enrollment was terminated early for benefit of blinatumomab based on a pre-specified stopping rule. After a median of 22.4 months of follow-up (IQR: 26.1, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank p<0.001; hazard ratio [HR], 0.33 [95%CI, 0.18‒0.61]). In very high-risk patientsrelapsing <18 months from diagnosis, HR was 0.21 (95%CI, 0.07‒0.59). Deaths occurred in 8 (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95%CI, 0.18–1.01). Minimal residual disease remission was observed in more patients in the blinatumomab versus consolidation chemotherapy group (90% [44/49] versus 54% [26/48]; difference, 35.6% [95%CI, 15.6, 52.5]). No fatal adverse events were reported. In the blinatumomab versus consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, and the incidence of grade ≥3 adverse events was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients (3.7%; neurologic) in the blinatumomab group. Conclusions and Relevance: Among children with high-risk first-relapse B-ALL, treatment with one cycle of blinatumomab compared with standard intensive multi-drug chemotherapy before allogeneic hematopoietic stem cell transplantation resulted in an improved event-free survival at a median of 24 months of follow-up.