Addition of Blinatumomab Improves 3-Year DFS Rates in Standard-Risk Pediatric B-ALL

According to an interim analysis, adding blinatumomab (Blincyto) to risk-adapted chemotherapy significantly improved 3-year disease-free survival (DFS) rates, compared with chemotherapy alone, in pediatric patients with newly diagnosed, standard-risk B-cell acute lymphoblastic leukemia (B-ALL) at average or high risk for relapse, according to findings from the first efficacy interim analysis of the Children’s Oncology Group Study AALL1731 (NCT03914625).¹

Findings, which were presented during a press briefing preceding the 2024 ASH Annual Meeting, also demonstrated that the combination was considered to be well tolerated.

Blinatumomab plus chemotherapy significantly improved 3-year DFS rates and was well tolerated in pediatric patients with standard-risk pediatric B-ALL.

At a median follow-up of 2.5 years, the 3-year DFS rate in the overall population (n = 1440) was 96% with blinatumomab plus chemotherapy vs 87.9% with chemotherapy alone (HR, 0.39; 95% CI, 0.24-0.64 P < .0001). In the standard risk–average population, these respective rates were 97.5% (n = 417) and 90.2% (n = 418; HR, 0.33; P = .0019). In the standard risk–high population, respective rates were 94.1% (n = 301) and 84.8% (n = 304; HR, 0.45; P = .0126).

Additionally, blinatumomab plus chemotherapy reduced rates of bone marrow relapse vs chemotherapy alone in the overall population (P < .0001), as well as in the standard risk–average (P = .0019) and standard risk–high (P = .0024) populations. Patients who received blinatumomab also had a numerically lower cumulative incidence of central nervous system (CNS) relapses vs those who received chemotherapy alone (P = .8510).

“The improvement in DFS was secondary to a significant reduction in bone marrow relapses,” lead study author Rachel E. Rau, MD, stated in a presentation of the data. “We did not see similar reduction in the [rarer] event of an isolated CNS relapse. This finding was not surprising, given blinatumomab’s known limited activity in the CNS.”

Rau is an associate professor of pediatrics at the University of Washington and a pediatric hematologist-oncologist at Seattle Children’s Hospital in Washington.

Study AALL1731 Design

Starting in July 2019 and continuing until June 2024, AALL1731 enrolled patients with National Cancer Institute (NCI) standard-risk B-ALL between 1 and younger than 10 years of age at diagnosis with white blood cell counts below 50,000/μL. Patients with CNS3 involvement, testicular leukemia, or those pretreated with steroids were excluded from the study.

Enrolled patients started therapy with a standard 3-drug induction regimen. At the end of the induction period (EOI), patients (excluding those with Philadelphia chromosome (Ph)–positive ALL) were assigned to 1 of 3 stratification groups based on their expected NCI risk of relapse: standard risk–favorable (favorable cytogenetics, peripheral blood minimal residual disease [MRD] levels < 1% at day 8, and bone marrow MRD levels < 0.01% at EOI) vs standard risk–high (unfavorable cytogenetics or neutral cytogenetics/CNS2 or MRD levels ≥ 0.01%/≥ 1% double trisomy) vs standard risk–average (all other patients).

Patients with standard risk–favorable disease, standard risk–average disease with undetectable immunoglobulin MRD via high throughput sequencing, and standard risk–high disease with MRD levels between 0.1% and 1% at the end of consolidation (EOC) were not eligible for randomization and therefore not included in the presented dataset.

“Our standard risk–favorable patients are known to have an excellent survival with standard chemotherapy alone, and thus they were nonrandomly assigned to standard treatment,” Rau added.

All other patients (those with standard risk–average disease with detectable immunoglobulin MRD levels per high throughput sequencing of approximately 80% and those with standard risk–high disease with MRD levels < 0.1% by EOC) were assigned to arms A/B or arms C/D, respectively.

“Our standard risk–average patients, all of whom had undetectable residual leukemia at the end of induction by an assay called flow cytometry–determined MRD, were further stratified on the basis of a more sensitive MRD assay called high throughput sequencing,” Rau added. “Approximately 20% of patients who are flow MRD negative are also negative by this more sensitive assay. That’s another group of patients with a known excellent expected survival with standard chemotherapy, and they too were nonrandomly assigned to standard treatment alone. All other standard risk–average patients were eligible for randomization.”

Patients classified as standard risk–high were further stratified according to MRD status at the end of the consolidation phase per flow cytometric analysis of bone marrow.

Rau noted that, “A small subset of [these] patients were still, at EOC, MRD positive, and those patients were nonrandomly assigned to receive chemotherapy plus blinatumomab because at the time of trial design, blinatumomab was already approved for patients with an MRD [level] above that threshold. All other standard risk–high patients were eligible for randomization.”

In AALL1731, arms A and C enrolled standard risk–average patients and standard risk–high patients, respectively, to receive standard consolidation chemotherapy followed by methotrexate (interim maintenance 1), delayed intensification, methotrexate (interim maintenance 2), and maintenance chemotherapy. Arms B and D enrolled standard risk–average patients and standard risk­–high patients, respectively, to receive standard consolidation chemotherapy followed by cycle 1 of blinatumomab, methotrexate (interim maintenance 1), blinatumomab cycle 2, delayed intensification, methotrexate (interim maintenance 2), and maintenance chemotherapy. Blinatumomab was administered at 15mcg/m² per day for 28-day cycles via continuous intravenous infusion.

Overall, clinical, demographic, and disease characteristics were balanced across the 2 risk categories. The median age of patients was 4.3 years (IQR, 2.8-6.4) and the majority of patients were boys (52.6%). Hispanic patients comprised 25.8% of the population, and 5.6% of patients were non-Hispanic Black.

The trial’s primary end point was DFS, as evaluated in a time-to-event analysis. Other key exploratory end points included the duration of overall survival, relapse, and safety. The data. cutoff for the current analysis was June 30, 2024.

Notably, in June 2024, the FDA approved blinatumomab for the treatment of adult and pediatric patients at least 1 month of age with CD19-positive, Ph-negative, B-ALL in the consolidation phase, regardless of MRD status.²

Additional Efficacy and Safety Findings

A post-hoc subset analysis in prognostically relevant patient subsets showed that the addition of blinatumomab significantly improved DFS outcomes vs chemotherapy alone regardless of patient sex (female, [HR, 0.27; 95% CI, 0.12-0.59]; male [HR, 0.52; 95% CI, 0.28-0.97]), most races/ethnicities (Hispanic, [HR, 0.29; 95% CI, 0.13-0.69], non-Hispanic Asian, [HR, 0.96; 95% CI, 0.06-15.3]; non-Hispanic White [HR, 0.52; 95% IC, 0.28-0.97]), cytogenetic risk (favorable, [HR, 0.29; 95% CI, 0.08-1.02]; neutral [HR, 0.41; 95% CI, 0.22-0.74]; unfavorable [HR, 0.40 ;95% CI, 0.14-1.14]), and EOI bone marrow MRD levels (< 0.01%, [HR, 0.36; 95% CI, 0.18-0.71]; ≥ 0.01%, [HR, 0.44; 95% CI, 0.22-0.86]).¹

“[These findings indicate] that, to an extent, blinatumomab neutralizes many of the known or prognostic features of B-ALL,” Rau explained.

Regarding safety, blinatumomab target toxicities reported in cycle 1 (n = 624) included cytokine release syndrome (CRS; grade ≥ 2, 2.9%; grade ≥ 3, 0.3%), seizure (1.4%; 0.8%), and encephalopathy (0.2%; 0.2%). Blinatumomab target toxicities reported in cycle 2 (n = 552) included CRS (grade ≥ 2, 1.6%; grade ≥ 3, 0.0%) and seizure (0.9%; 0.7%). No encephalopathy was reported in blinatumomab cycle 2.

In the standard risk–average population, higher rates of grade 3 or higher infectious toxicities were seen in the blinatumomab arm (n = 351) vs the chemotherapy alone arm (n = 376), including febrile neutropenia (47.0%; 39.6%; P = .05), sepsis and catheter-related infections (14.8%; 5.1%; P < .001), and other infections (32.8%; 26.3%; P = .06).

“Most of the differences in the rates [of sepsis and catheter-related infections] were attributable to increased events in the chemotherapy blocks that followed blinatumomab therapy,” Rau said.

In the standard risk–high population, higher rates of grade 3 or higher febrile neutropenia (57.1%; 50.5%; P = .12) and sepsis and catheter-related infections (20.9%; 17.0%; P = .28) were also seen in the blinatumomab arm (n = 273) vs the chemotherapy alone arm (n = 277); however, the rate of other infections was higher in the chemotherapy alone arm (37.9%) vs the blinatumomab arm (35.2%; P = .54). No differences in grade 4/5 adverse effects were observed between the randomized trial arms.

No deaths were reported during blinatumomab cycles, and no deaths were attributed to blinatumomab in randomly assigned patients.

“Overall, our results demonstrate that blinatumomab added to chemotherapy represents a new treatment standard for most patients with NCI standard-risk B-ALL,” Rau concluded.

References

1. Gupta S, Rau RE, Kairalla JA, et al. Blinatumomab added to chemotherapy improves disease-free survival in newly diagnosed NCI standard risk pediatric B-acute lymphoblastic leukemia: results from the randomized Children’s Oncology Group. N Engl J Med. Published online December 7, 2024. doi:10.1056/NEJMoa2411680
2. FDA approves Blincyto (blinatumomab) in CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) in the consolidation phase. News release. Amgen. June 14, 2024. Accessed December 5, 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