Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia

Abstract

IMPORTANCE Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell 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 vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. DESIGN, SETTING, AND PARTICIPANTSIn this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts Ն5% and <25%) at randomization. INTERVENTION Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m 2 /d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation. MAIN OUTCOMES AND MEASURESThe primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events.RESULTS A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (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 vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group.CONCLUSIONS AND RELEVANCE Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up.

Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

“…The main adverse effects are cytokine release syndrome and neurotoxicity, which coincide with T cell activation. Two randomized studies in children, adolescents, and young adults with intermediate-risk or high-risk relapsed/refractory B-ALL showed blinatumomab to have benefits over intensive consolidation chemotherapy [ 129 , 130 ]. The loss of CD19 expression is a major mechanism of resistance to blinatumomab treatment and is also observed with CAR T cell therapy.…”

Blinatumomab in Pediatric Acute Lymphoblastic Leukemia—From Salvage to First Line Therapy (A Systematic Review)

“…The results of both phase III RCTs in children with first relapse of ALL confirm the superiority of blinatumomab in achieving MRD-negativity before HSCT and even show evidence for an advantage in overall survival [38,39], while inducing less severe adverse events compared to conventional chemotherapy. These results definitely warrant the inclusion of blinatumomab into relapse protocols before HSCT.…”

“…Overall, adverse events are much less common under blinatumomab compared to conventional chemotherapy [38,39]. Additionally, even specific blinatumomab-related toxicities, such as CRS and neurotoxicity, only rarely necessitate the interruption of therapy [20,31,35].…”

“…It took a further two years until the publication of the phase I/II trial [21]. The first results of RCTs for the use of blinatumomab in children with first relapse of ALL were published this year [38,39]. Current front-line trials are investigating blinatumomab in children with standard-risk ALL (NCT03914625, NCT02877303); others only apply blinatumomab to standard-risk patients with residual disease at the end of induction therapy (NCT03117751) or intermediate and high-risk ALL (NCT0363276).…”

“…The second trial is reported by Locatelli and colleagues [39]. Centers in Europe, Australia and Israel enrolled 108 children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥ 5% and <25%) at randomization: (NCT02393859).…”