Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children

Abstract

Background: B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes.

Methods: We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or higher risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival.

Results: The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±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 disease-free survival 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 higher 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.

Conclusions: Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or higher risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).

Figure 1:. CONSORT flow diagram.

Status of all National Cancer Institute (NCI) standard risk (SR) B-lymphoblastic leukemia (B-ALL) patients enrolled on AALL1731 (N=4264) throughout the course of the trial is shown. At the end of Induction therapy patients were risk stratified as Down syndromeS-High, SR-Favorable (SR-Fav), SR-Average (SR-Avg) and SR-High (N=916). Down Syndrome-High and SR-Fav were not eligible for randomization. Consent for randomization was obtained at EOI after risk stratification, while randomization did not occur until Consolidation therapy had been completed or was near completion. The number of and reasons for SR-Avg and SR-High patients not being randomized and for randomized patients not receiving randomized therapy are shown.

Figure 2:. Outcomes according to randomization.

Panel A shows the comparison of 3-year disease-free survival (DFS) (top row), overall survival (OS) (middle row) and cumulative incidence of relapse (CIR) (bottom row) for the overall randomized cohort (left column), randomized SR-Avg patients (middle column) and randomized SR-High patients (right column). Panel B shows the comparison of the 3-year DFS, OS, total CIR and CIR by relapse site among the overall randomized cohort, SR-Avg group, and SR-High group. Note that OS and CIR were not protocol-specified formal endpoints. Widths of intervals were not adjusted for multiplicity and thus for non-primary analyses should not be used in place of hypothesis testing.

Figure 3:. Disease-free survival among various patient subgroups using restricted mean survival time estimates.

Risk Group was a stratification factor, all other subgroup analyses were post-hoc. The lines indicate the 95% confidence intervals, and arrows represent confidence intervals that exceed the graph parameters. Widths of intervals were not adjusted for multiplicity and thus for non-primary analyses should not be used in place of hypothesis testing. HTS, High-throughput sequencing; MRD, Minimal residual disease; N, Number; SR, Standard risk. *Day 29 HTS MRD subgroup analysis includes only SR-Average patients with detectable HTS measured MRD. Patients with undetectable HTS MRD were not eligible for randomization. Patients with unavailable HTS MRD or indeterminate HTS MRD were eligible for randomization and are included in the overall outcomes.