In an international, randomised, controlled, phase III AALL1731 study conducted by the Children’s Oncology Group (COG) involving children with standard-risk B-cell acute lymphoblastic leukaemia (ALL), the addition of blinatumomab to standard chemotherapy resulted in a significant improvement in disease-free survival (DFS) over chemotherapy alone. This improvement was consistent across subgroups defined according to patient-related or disease-related characteristics, owing mainly to a decrease in relapse involving the bone marrow.
These outcomes were similar to those previously observed in patients with only the most favourable risk characteristics according to Dr. Mignon Loh of the Seattle Children’s Hospital in Seattle, WA, US, and colleagues who presented the findings at the 66th ASH Annual Meeting along with a simultaneous publication in The New England Journal of Medicine on 7 December 2024.
B-cell ALL is the most common childhood cancer. Cure rates for ALL have increased dramatically over the past five decades. However, progress has slowed, with several attempts to intensify traditional chemotherapeutic agents having failed to further increase cure rates. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children.
Blinatumomab is a bispecific, single-chain molecule that targets the CD19 antigen expressed on the surface of B-lineage cells and redirects CD3-positive T cells for CD19-selective lysis. Treatment with blinatumomab has been shown to improve outcomes in children with relapsed B-cell ALL. The E1910 study showed that the addition of blinatumomab to standard chemotherapy improved relapse-free survival (RFS) and overall survival (OS) 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. This international, randomised, controlled, COG study involved children with standard-risk B-cell ALL, as defined by the US National Cancer Institute (NCI). The primary objective was to determine whether the addition of two non-sequential cycles of blinatumomab to standard chemotherapy would improve outcomes in patients with standard-risk B-cell ALL who had an average or high risk of relapse on the basis of clinical features.
Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two non-sequential 28-day cycles of blinatumomab. The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomisation (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomisation.
At a median follow-up of 2.5 years, the estimated 3-year DFS (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time 72 days; 95% confidence interval 36 to 108; p < 0.001 by stratified log-rank test). The estimated 3-year DFS among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a high relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%.
Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone.
The addition of blinatumomab improved outcomes predominantly through decreasing relapse involving the bone marrow. In contrast, the cumulative incidence of isolated central nervous system (CNS) relapse remained essentially unchanged. The most likely explanation for this finding is the known limited CNS activity of blinatumomab. Further improvements in relapse prevention will require an increased focus on identifying patients at highest risk for CNS relapse and new methods of targeting the CNS without adversely affecting neurocognitive outcomes.
The authors commented whether the efficacy of blinatumomab allows for removal of even more elements of traditional chemotherapy without compromising cure rates among patients with newly diagnosed B-cell ALL remains unclear. Deintensification of chemotherapy may decrease the short- and long-term burden of ALL treatment, but studies that balance potential decreases in morbidity and improvements in quality-of-life with the amount of risk that patients, caregivers, and providers are willing to take are needed. Given the aforementioned lack of CNS activity of blinatumomab, particular care is warranted when considering the removal of elements of traditional chemotherapy that have marked CNS activity.
Other unanswered questions merit consideration. Longer-term follow-up is required to ensure that improved outcomes with blinatumomab are maintained over time. Furthermore, paediatric patients with NCI-defined high-risk B-cell ALL were not included. Nevertheless, the patients in this study with standard-risk B-cell ALL who had a high risk of relapse were treated with the same chemotherapy backbone that is used for NCI-defined high-risk B-cell ALL, which together with the results of the E1910 study strongly suggest that patients with high-risk B-cell ALL may also benefit from receiving blinatumomab. Other groups are currently studying the effect of blinatumomab in higher-risk paediatric patients and will provide further data.
Another consideration is that CD19-directed therapies such as blinatumomab, along with CAR T-cell, have become standard components of therapy for relapsed disease, but such treatments may not be equally effective in patients previously exposed to blinatumomab. None of the patients who had relapse in this study were known to be CD19-negative.
Studies that have incorporated one to more than four cycles of blinatumomab have now shown substantial efficacy. The appropriate number of blinatumomab cycles and their timing remain unclear, but the results of the current and the E1910 studies provide standard chemoimmunotherapy backbones against which alternative strategies can be evaluated.
The logistic burden of administering blinatumomab remains substantial; barriers may be considerable for families who have limited resources or are living in remote or rural areas. Interventions targeting these barriers will be crucial to avoid disparities. The use of subcutaneous blinatumomab has shown efficacy in early studies and may improve treatment access in the future. Finally, the long-term effects of blinatumomab and other immunotherapies are poorly characterised.
The study was supported by grants from the NCI of the National Institutes of Health, the St. Baldrick’s Foundation, and in part by Amgen.
Reference
Gupta S, Rau RE, Kairalla JA, et al. Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. NEJM; Published online 7 December 2024. DOI: 10.1056/NEJMoa241168