Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia

Abstract

IMPORTANCE Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile.OBJECTIVE To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high-and intermediate-risk first relapse of B-ALL. DESIGN, SETTING, AND PARTICIPANTSThis trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669).INTERVENTIONS All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. MAIN OUTCOME AND MEASURESThe primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025. RESULTS Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group.CONCLUSIONS AND RELEVANCE Among children, adolescents, and young adults with high-and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpret...

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.…”

“…In newly published RCTs, Brown and colleagues describe blinatumomab-related adverse events with overall 22% CRS, 11% encephalopathy and 4% seizures but only one case of grade ≥3 CRS or seizure each and two cases of higher-grade encephalopathy. Other rates of notable serious adverse events were much less common in the blinatumomab group compared to the chemotherapy group: infection (15% vs. 65%), febrile neutropenia (5% vs. 58%), sepsis (2% vs. 27%) and mucositis (1% vs. 28%) [38].…”

“…In March 2021, the first results of two randomized controlled trials investigating blinatumomab in pediatric patients with ALL were published back to back in JAMA. Brown and colleagues describe the effect of postreinduction therapy consolidation with blinatumomab versus chemotherapy in patients with first relapse of ALL [38]. All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive two cycles of blinatumomab or two cycles of multiagent chemotherapy, each followed by HSCT.…”

MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL

“…After the first cycle of randomized therapy, the MRD neg rate was 75% for the blinatumomab group vs. 32% for the chemotherapy group ( p < 0.001). Finally, for the blinatumomab group, 70% proceeded to allogeneic HCT, compared with 43% for the chemotherapy group ( p < 0.001) [ 96 ].…”