Results of a phase III study suggest that the addition of the immunotherapy agent blinatumomab—a bispecific T-cell engager targeting CD19—to standard chemotherapy may help to prevent relapse in more children with B-cell acute lymphoblastic leukemia (B-ALL), the most common pediatric cancer, according to data presented by lead study author Rachel Elizabeth Rau, MD, Associate Professor of Pediatrics at Seattle Children’s Hospital and the University of Washington, at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition1 and simultaneously published in The New England Journal of Medicine.2
Interim analysis of the AALL1731 study, conducted by the Children’s Oncology Group (COG), demonstrated that the addition of blinatumomab to risk-adapted chemotherapy improved the 3-year disease-free survival rate to 96%, compared with 87.9% in the chemotherapy-alone group, a 61% reduction in events (hazard ratio [HR] = 0.39). The improved disease-free survival was due to a significantly reduced risk of bone marrow–involving relapses in the group randomly assigned to receive blinatumomab. The beneficial effect of blinatumomab was observed across all evaluated demographic, racial, and cytogenetic subsets, as well as varying minimal (also known as measurable) residual disease (MRD) levels, effectively neutralizing many historically poor risk factors of pediatric B-ALL.
Authors of the study emphasized that these results could establish blinatumomab as a new standard of care for most newly diagnosed pediatric patients with National Cancer Institute (NCI) standard-risk B-ALL. “The addition of blinatumomab to chemotherapy represents a transformative advance, offering children with NCI standard-risk B-ALL significantly improved outcomes while maintaining an acceptable safety profile,” said Dr. Rau.
Background
As Dr. Rau reported, despite a relatively favorable prognosis for pediatric B-ALL, outcomes have remained static for more than 20 years. Large, well-designed trials such as AALL09323 and AALL11314 have highlighted the limits of cytotoxic chemotherapy, showing that intensifying or adding chemotherapy agents provided no meaningful improvement in survival rates. Moreover, these approaches often resulted in unacceptably high rates of severe and fatal toxicities.
Recognizing the need for a therapeutic agent with a distinct mechanism of action and a nonoverlapping toxicity profile, AALL1731 incorporated blinatumomab. Emerging data from relapsed and refractory B-ALL populations suggest its efficacy and tolerability, paving the way for its evaluation in front-line therapy.
Study Design and Risk Stratification
AALL1731 enrolled more than 4,000 children with NCI standard-risk B-ALL from July 2019 to mid-2024. Participants were stratified into three groups based on their relapse risk:
Favorable Risk: These patients have favorable cytogenetics and MRD < 1% in the blood at day 8 of induction therapy and < 0.01% in the bone marrow at the end of induction. They received standard chemotherapy without randomization.
Average Risk: These patients meet neither the favorable-risk criteria nor the high-risk criteria. These patients have undetectable MRD by flow cytometry but detectable MRD by high-throughput sequencing. This group was randomly assigned to receive either standard chemotherapy or chemotherapy plus two cycles of blinatumomab.
High Risk: These patients have unfavorable cytogenetics, neutral cytogenetics with central nervous system (CNS) involvement, or higher MRD thresholds. This group was randomly assigned to receive intensified chemotherapy with or without blinatumomab, except for a small subset with MRD > 0.1% after consolidation, who received nonrandomized chemotherapy plus blinatumomab due to existing U.S. Food and Drug Administration approval in this setting.
Improved Outcomes Across All Subgroups
The interim analysis, conducted when 40% of expected events had occurred, revealed evidence of efficacy, leading the study’s data and safety monitoring committee to recommend early termination of randomization. Key findings follow:
Improved Disease-Free Survival: The 3-year disease-free survival rate was 96% in the blinatumomab group compared with 87.9% in the chemotherapy-alone group, corresponding to a hazard ratio of 0.39 (61% reduction in events). Similar benefits were observed across both the average-risk and high-risk groups.
Reduction in Relapse Risk: Blinatumomab significantly lowered the cumulative incidence of relapse, particularly in bone marrow–involving relapses. However, its activity in preventing isolated CNS relapses was limited, reflecting blinatumomab’s known limited efficacy in CNS settings.
Efficacy Across Subgroups: Post hoc analysis revealed consistent benefits across demographic, racial, and cytogenetic subsets, as well as across different MRD thresholds. According to Dr. Rau, these findings suggest that blinatumomab may neutralize core diagnostic features associated with a poor prognosis in B-ALL.
Safety and Toxicity
Blinatumomab was well tolerated in the trial, according to Dr. Rau, who reported no treatment-related deaths during blinatumomab cycles. In addition, severe toxicities, including cytokine-release syndrome and neurotoxicity, were infrequent with blinatumomab.
However, the study identified an increased risk of grade 3 or higher sepsis and catheter-related infections in the average-risk group receiving blinatumomab. Although some infections occurred during blinatumomab treatment, most were observed in subsequent chemotherapy blocks. Of note, Dr. Rau added, the rates of severe (grade 4) and fatal (grade 5) infections were rare and did not differ significantly between treatment arms.
Implications for Clinical Practice
According to Dr. Rau, findings from the AALL1731 could mark a major shift in the treatment paradigm for pediatric B-ALL, adding to a growing body of evidence that supports the integration of blinatumomab into front-line therapy.
“Blinatumomab effectively addresses long-standing treatment gaps, achieving better outcomes for most newly diagnosed NCI standard-risk patients,” Dr. Rau said. “Although it has not been formally evaluated in NCI high-risk B-ALL, a group enriched for adolescent patients, results from similar populations suggest potential applicability,” she added. “With these results, the oncology community moves closer to redefining standard treatment protocols for B-ALL, balancing efficacy with tolerability,” Dr. Rau concluded.
Expert Point of View
Wendy Stock, MD, the Anjuli Seth Nayak Professor of Medicine at UChicago Medicine, praised the findings of the AALL1731 trial, highlighting the transformative potential of blinatumomab in standard-risk B-cell acute lymphoblastic leukemia (B-ALL). “Blinatumomab’s impact on patients with standard-risk B-ALL is spectacular, and even two cycles of postremission blinatumomab for these patients resulted in significant improvements in progression-free survival,” Dr. Stock told The ASCO Post.
While acknowledging the increased risk of infectious complications in the blinatumomab arm, Dr. Stock underscored the overall benefit-risk profile of the treatment. “The benefits of blinatumomab, I believe, far outweigh the risks,” she noted. “The infectious risks could potentially be mitigated by careful evaluation of immune status and potential antibiotic prophylaxis, but this will have to be more carefully evaluated in future studies.”
DISCLOSURE: Dr. Rau reported financial relationships with Jazz Pharmaceuticals, AbbVie, and Servier. Dr. Stock reported no conflicts of interest.
REFERENCES
1. Rau RE, et al: 2024 ASH Annual Meeting & Exposition. Abstract 1. Presented December 8, 2024.
2. Gupta S, et al: N Engl J Med. December 7, 2024 (early release online).
3. Angiolillo AL, et al: J Clin Oncol 39:1437-1447, 2021.
4. Salzer WL, et al: J Clin Oncol 38:2628-2638, 2020.
