Addition of blinatumomab to chemotherapy improves outcomes for children with B-cell ALL
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Key takeaways:
- The addition of blinatumomab to chemotherapy improved DFS for children with B-cell ALL.
- Researchers stopped trial randomization early because of the efficacy observed.
SAN DIEGO — The addition of blinatumomab to chemotherapy extended DFS for children with newly diagnosed B-cell acute lymphoblastic leukemia, according to results of a randomized phase 3 trial presented at ASH Annual Meeting and Exposition.
Researchers halted trial randomization early because of the superior efficacy they observed.
“I don't think any of us predicted how much better blinatumomab (Blincyto, Amgen) would be,” Rachel E. Rau, MD, associate professor of pediatrics at University of Washington and pediatric hematologist-oncologist at Seattle Children’s Hospital, told Healio. “We had planned the study to detect an approximate 35% reduction in relapses, which we would be able to detect after [randomly assigning] about 2,500 patients.”
Results of the first planned interim efficacy analysis — conducted after 40% of expected events had occurred — showed blinatumomab reduced relapses by 61%.
“These results indicate that all pediatric [patients with B-cell ALL] — except those with the most favorable predicted outcome with chemotherapy alone — should have blinatumomab added to therapy,” Rau said.
Background and methods
Approximately 90% of children with newly diagnosed B-cell ALL survive; however, because it is the most common childhood cancer, it is the second leading cause of pediatric cancer death, Rau said.
Trials over the past 2 decades have not markedly improved outcomes.
“We learned from those studies that mere intensification of standard chemotherapy was unlikely to dramatically improve outcomes,” Rau said. “[Although] blinatumomab was still a relatively new drug at the time, early studies of it suggested it was overall well tolerated and was already showing a promising efficacy signal, and thus [it] was deemed an appropriate agent to study in our population.”
The AALL1731 study enrolled 4,236 children aged 1 to 10 years with standard-risk B-cell ALL. All trial participants had initial white blood cell count less than 50,000/µL.
Rau, along with Sumit Gupta, MD, PhD, FRCPC, associate professor at University of Toronto and staff physician at The Hospital for Sick Children, and colleagues stratified participants into three categories based on relapse risk: favorable, average and high. Children in the favorable group received standard chemotherapy and did not continue to randomization. Those in the high group moved on in the trial.
Children classified as average got further stratified based on end-of-induction bone marrow high-throughput sequencing of immunoglobulin loci minimal residual disease. Those who had undetectable levels received chemotherapy and did not continue to randomization. Others proceeded to randomization.
The first planned analysis included 1,440 children (median age, 4.3 years; interquartile range, 2.8-6.4; 52.6% boys; 69% white) in four categories: average control (n = 418), average treatment (n = 417), high control (n = 304) and high treatment (n = 301).
Researchers randomly assigned them within their classification groups to chemotherapy alone or with two 28-day cycles of blinatumomab (15 mg/m² daily via IV).
DFS served as the primary endpoint.
Results and next steps
Median follow-up was 2.5 years (interquartile range, 1.6-3.2).
Results showed a significantly higher 3-year DFS rate among children assigned blinatumomab than those assigned chemotherapy alone (96% vs. 87.9%; HR = 0.39; 95% CI, 0.24-0.64).
The 3-year DFS improvement with blinatumomab remained consistent when researchers focused analyses on the average-risk group (97.5% vs. 90.2%; HR = 0.33; 95% CI, 0.15-0.69) and the high-risk cohort (94.1% vs. 84.8%; HR = 0.45; 95% CI, 0.24-0.85).
Researchers categorized blinatumomab as overall “well tolerated.” Five children — three assigned to blinatumomab and two assigned chemotherapy alone — died in remission. All deaths occurred among those with high relapse risk. None of the deaths occurred during blinatumomab cycles and no deaths were deemed attributable to blinatumomab.
Among children assigned blinatumomab, 0.3% developed grade 3 or worse cytokine release syndrome after the first course of treatment and 0.7% experienced seizures.
The trial “definitively establishes” that the addition of blinatumomab to risk-adapted chemotherapy improves DFS for this patient population and suggests the agent is a new treatment standard in this setting, Rau, Gupta, and colleagues wrote.
Future research should examine long-term adverse events and whether blinatumomab could replace a portion of chemotherapy, Rau said.
“[Although] this is an exciting advancement for the field, blinatumomab is expensive and must be administered via a continuous IV infusion,” she added. “Thus, there are patients who may not have access to it either due to cost or feasibility. This must be addressed and will take the concerted efforts of many — including pediatric oncologists, pharmacists, nursing, cancer consortia, government and regulatory agencies — because every child who would benefit from blinatumomab should have access.”
Perspective
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Cynthia E. Dunbar, MD
B-cell ALL is the most common childhood cancer. It also is one of the most treatable. However, some children still relapse following standard chemotherapy, and then they have a much grimmer outcome. This trial assessed whether the addition of blinatumomab — a bispecific CD3/CD19 T-cell engager — can improve DFS in standard-risk childhood ALL. The results definitively demonstrate a benefit with the addition of this immunotherapeutic drug, achieving 97% DFS at 3 years on the blinatumomab-chemotherapy arm compared with 90% with standard therapies alone. This trial will establish the addition of blinatumomab for childhood ALL as standard of care.These immune cell engagers can result in cytokine release syndrome and other severe immune activation consequences. However, it appears that children seem to be less susceptible to those than adults — at least in terms of severity. And at least in this study, although some of these complications did occur, they didn't result in mortality and were easily treatable.
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Rau RE, et al. Abstract 1. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.
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