Replacing two cycles of intensive chemotherapy with blinatumomab significantly improved event-free survival in children with newly diagnosed high-risk B-cell acute lymphoblastic leukemia (ALL), while also reducing several serious treatment-related toxicities. Schrappe et al reported results from the phase III AIEOP-BFM ALL 2017 trial in The New England Journal of Medicine.
Blinatumomab is a bispecific T-cell engager that targets CD19 on B cells. Although the drug has improved outcomes when added to chemotherapy in several ALL settings, the investigators asked a different question: whether blinatumomab could replace part of intensive chemotherapy without sacrificing disease control.
“We have shown that blinatumomab can safely replace chemotherapy as first-line treatment of pediatric high-risk B-cell ALL,” the investigators wrote. They noted that most previous studies had evaluated blinatumomab as an addition to chemotherapy rather than as a substitute for part of it.
Study Details
The international randomized trial included 709 patients younger than 18 years with newly diagnosed, Philadelphia chromosome–negative, high-risk B-cell ALL. After consolidation and one cycle of intensive chemotherapy, 358 patients were assigned to two 28-day cycles of blinatumomab and 351 to two additional cycles of intensive chemotherapy.
High-risk disease was defined by several factors, including poor early treatment response, elevated measurable residual disease (MRD), and certain unfavorable genetic features. The primary endpoint was event-free survival, with events including resistance to protocol treatment, relapse, a second cancer, or death from any cause. At the analysis reported in the study, median follow-up was 2.9 years.
Key Findings
Estimated 4-year event-free survival was 83% with blinatumomab compared with 70.3% with intensive chemotherapy. Blinatumomab reduced the risk of an event by 49% (hazard ratio [HR] = 0.51; P = .0002).
Relapse was also less common with blinatumomab. The estimated 4-year cumulative incidence of relapse was 11.8% with blinatumomab and 21.4% with chemotherapy. Overall survival was similar between the groups, with estimated 4-year survival of 93.6% and 91%, respectively.
Among patients with detectable MRD before treatment, MRD clearance occurred in 69.2% after the first cycle of blinatumomab compared with 32.3% after the second cycle of intensive chemotherapy.
Treatment-related infections were substantially less frequent with blinatumomab, occurring in 23.9% of patients compared with 69.4% in the chemotherapy group. Life-threatening adverse events occurred in 2 patients (0.5%) in the blinatumomab group and in 16 patients (4.7%) receiving intensive chemotherapy. One patient in the blinatumomab group died from acute pancreatitis, although the investigators could not determine whether the event was related to prior asparaginase exposure.
Blinatumomab was associated with more neurotoxic events, however, which occurred in 12% of patients compared with 3.2% receiving intensive chemotherapy. Grade 2 or higher cytokine-release syndrome occurred in 1.1% of patients receiving blinatumomab and in none receiving intensive chemotherapy.
Reducing chemotherapy has historically raised concerns about compromising leukemia control. In this trial, however, replacing two intensive chemotherapy cycles with blinatumomab improved event-free survival while reducing several important toxicities.
“These findings provide a basis for evaluating immunotherapy-based replacement strategies across broader B-cell ALL risk groups,” they concluded. “Future therapeutic regimens may be the first to allow substantial reduction of potentially toxic treatment in patients with ALL.”
Martin Schrappe, MD, of the Department of Pediatrics I, University Hospital Schleswig-Holstein, Campus Kiel, Germany, is the corresponding author of the study.
DISCLOSURE: For full disclosures of the study authors, visit nejm.org.
