Landmark Phase III Trial Results Show Blincyto Plus Chemotherapy Boosts Three-Year Survival in Pediatric Standard-Risk B-Cell ALL
The Phase III AALL1731 trial demonstrated that adding Blincyto (blinatumomab) to chemotherapy significantly improved three-year disease-free survival in pediatric patients with standard-risk B-cell acute lymphoblastic leukemia.
Credit: Arif Biswas | stock.adobe.com
Efficacy results from the first pre-specified interim analysis of the Phase III AALL1731 trial (NCT03914625) show that the addition of Blincyto (blinatumomab; Amgen) to chemotherapy significantly improved three-year disease-free survival (DFS) in newly diagnosed pediatric patients with standard-risk (SR) B-cell acute lymphoblastic leukemia (B-ALL).1,2 The results of the trial, also published by The New England Journal of Medicine,3 further cement the role of Blincyto as a transformative treatment in lowering relapse rates and enhancing outcomes in this pediatric patient population, according to trial investigators.
"The AALL1731 study results are truly practice-changing, further solidifying blinatumomab's role as the standard of care for a large number of children with B-ALL," co-chair of the Children's Oncology Group AALL1731 trial Sumit Gupta, MD, PhD, FRCPC, oncologist and clinician investigator, Division of Haematology/Oncology at The Hospital for Sick Children (SickKids), associate professor of pediatrics at the University of Toronto, said in a press release. "These breakthrough data showing a significant improvement in disease-free survival are poised to bring substantial clinical value to children with newly diagnosed B-ALL."1
Blincyto, a bispecific T-cell engager molecule, was approved by the FDA on June 14, 2024, to treat CD19-positive Philadelphia chromosome-negative B-cell precursor ALL in the consolidation phase in patients aged one month and above.4 It also has approved indications for adult and pediatric patients aged one month or older with CD19-positive B-ALL in first or second complete remission with measurable residual disease (MRD) greater than or equal to 0.1% and for adult and pediatric patients aged one month or older with relapsed or refractory CD19-positive B-ALL.
“Treatment with blinatumomab has been shown to improve outcomes in children with relapsed (B-cell ALL),” the study authors wrote. “The E1910 trial showed that the addition of blinatumomab to standard chemotherapy improved relapse-free survival and overall survival among adults with newly diagnosed disease. Whether the addition of blinatumomab would also improve outcomes in children with newly diagnosed B-cell ALL was unclear.”3
Enrollment Criteria
Investigators enrolled patients with newly diagnosed SR B-cell ALL, with or without Down’s syndrome, who did not have testicular leukemia or frank central nervous system disease. SR disease was defined as being older than 1 year of age and younger than 10 years of age at diagnosis and having a white-cell count of fewer than 50,000 per microliter. Patients with Down’s syndrome and an elevated risk of relapse for B-cell ALL and patients with localized B-cell lymphoblastic lymphoma were deemed eligible but did not undergo randomization and their data were not reported in the interim analysis.
Trial Design
The randomized, controlled AALL1731 trial was conducted at centers in Australia, Canada, New Zealand, and the United States with a protocol approved by the pediatric central institutional review board of the National Cancer Institute (NCI), as well as by local institutional review boards. The legal guardian of each patient enrolled in the trial provided written informed consent. Trial data were reviewed biannually at preplanned intervals by an independent data and safety monitoring committee.
Investigators enrolled 4,264 patients newly diagnosed with NCI SR B-ALL. A total of 2,334 patients were risk stratified following induction therapy as being either SR-Average or SR-High. At the planned interim efficacy analysis, which had a data cutoff date June 30, 2024, 1,440 of eligible and evaluable patients were randomly assigned to treatment.
Patients were randomly assigned in a 1:1 ratio and stratified as per SR B-cell ALL with an average risk of relapse and without Down’s syndrome; SR B-cell ALL with an average risk of relapse and with Down’s syndrome; and SR B-cell ALL with a high risk of relapse.
Patients randomly assigned to receive Blincyto and chemotherapy were administered two cycles of Blincyto as a continuous intravenous infusion at a dose of 15 μg per square meter of body-surface area per day (maximum dose, 28 μg per day) for 28 days, before and following first interim maintenance phase of treatment. Further, one dose of intrathecal methotrexate was administered on the first day of each Blincyto cycle.
Results
The first pre-specified interim analysis for efficacy showed Blincyto achieved the primary endpoint of DFS. The data and safety monitoring committee recommended that study randomization be stopped early because of the benefit observed in the Blincyto cohort compared with the chemotherapy-only cohort.
Three-year DFS was found to be 96.0% for patients administered chemotherapy plus Blincyto compared with 87.9% for patients only administered chemotherapy. The hazard ratio (HR) was 0.39 [95% confidence interval (CI) 0.24-0.64], which translates to a 61% decrease in the risk of disease relapse, secondary malignant neoplasm, or remission death with Blincyto, according to the investigators.
In SR-Average patients, the three-year DFS rate was 97.5% in the Blincyto cohort compared to 90.2% in the chemotherapy only cohort (HR 0.33, CI 0.15-0.69). Among SR-High patients, the three-year DFS rate was 94.1% in the Blincyto cohort compared to 84.8% in the chemotherapy only cohort (HR 0.45, 95% CI 0.24-0.85).
“We showed that even among subgroups with baseline disease-free survival of 85 to 90%, the addition of blinatumomab conferred notable efficacy, preventing two thirds of relapses,” the study authors wrote. “Indeed, among patients with an average or high risk of relapse who received blinatumomab and chemotherapy, the 3-year disease-free survival exceeded 94%, which was similar to what had been previously shown in the most favorable risk group. This improvement seemed to be maintained across subpopulations. Although post hoc, the subgroup analyses showed consistency in the magnitude of effect across leukemic cytogenetic risk groups and regardless of MRD at the end of induction therapy as assessed by multiparameter flow cytometry or high-throughput sequencing.”3
In total, investigators emphasized that at three years, more patients administered Blincyto remained alive and cancer free compared to chemotherapy alone. They added that these results show the first evidence that supports the use of Blincyto in the consolidation phase among newly diagnosed pediatric patients with Philadelphia chromosome-negative B-ALL.
"Relapsed ALL remains a major cause of pediatric cancer mortality, with nearly half of the relapses occurring in children with standard-risk B-ALL," co-chair of the Children's Oncology Group AALL1731 trial Rachel E. Rau, MD, pediatric hematologist-oncologist at Seattle Children's Hospital and associate professor of pediatrics at the University of Washington, said in the release. "These findings underscore the progress made with blinatumomab in preventing relapse and support its role as a critical addition to current therapeutic strategies."1
References
1. Blincyto® (Blinatumomab) Added to Chemotherapy Significantly Improves Survival in Newly Diagnosed Pediatric Patients With B-Cell Precursor Acute Lymphoblastic Leukemia (B-ALL). News release. Amgen. December 7, 2024. Accessed December 9, 2024. https://www.amgen.com/newsroom/press-releases/2024/12/blincyto-blinatumomab-added-to-chemotherapy-significantly-improves-survival-in-newly-diagnosed-pediatric-patients-with-bcell-precursor-acute-lymphoblastic-leukemia-ball
2. A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia. ClinicalTrials.gov. Updated December 4, 2024. Accessed December 9, 2024. https://clinicaltrials.gov/study/NCT03914625
3. Gupta S., et al. Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. N Engl J Med 2024. DOI: 10.1056/NEJMoa2411680.
4. FDA Approves Blincyto® (Blinatumomab) In CD19-Positive Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia (B-ALL) in the Consolidation Phase. Amgen. June 14, 2024. Accessed December 9, 2024. https://www.amgen.com/newsroom/press-releases/2024/06/fda-approves-blincyto-blinatumomab-in-cd19positive-philadelphia-chromosomenegative-bcell-precursor-acute-lymphoblastic-leukemia-ball-in-the-consolidation-phase
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