Abstract
COG study AALL1731 established that adding two cycles of the bispecific T-cell engager blinatumomab to risk-adapted chemotherapy (chemo) significantly improved 3-year disease-free survival (DFS) of children with National Cancer Institute (NCI) standard risk (SR) B-acute lymphoblastic leukemia (ALL) at average or higher risk of relapse (Gupta et al, NEJM 2025). Longer-term follow-up is critical to ensure the benefit persists. Further work is also needed to determine prognostic features in patients (pts) whose therapy now includes blinatumomab.
AALL1731 enrolled newly diagnosed NCI SR [age 1-<10 years with initial white blood cell count <50,000/µL] B-ALL pts, without BCR::ABL1 fusion, testicular or central nervous system (CNS)3 disease. After 3-drug induction, pts were risk stratified based on leukemia genetics, CNS status, day 8 blood flow cytometry-defined minimal residual disease (fcMRD), and end of induction (EOI) bone marrow (BM) fcMRD and EOI clonoSEQ assessment.
Pts at average risk of relapse (SR-Avg) with detectable or indeterminate EOI BM ClonoSEQ MRD were randomized to standard chemo (Arm A) or chemo plus 2 cycles of blinatumomab (Arm B). Pts at high risk of relapse (SR-High) with end of consolidation (EOC) BM mpFC MRD <0.1% were randomized to higher intensity chemo (Arm C) or chemo plus 2 cycles of blinatumomab (Arm D). Interim analyses (June 2024) showed that addition of blinatumomab was associated with improved DFS; enrollment was terminated and Arm A/C pts not yet in Maintenance offered crossover and blinatumomab. Using current data to 6/25, we compared DFS between Arms A/C and B/D, censoring pre-Maintenance pts when crossover was offered. We also determined the effect of blinatumomab on the impact of traditional prognosticators by comparing the associated risk within Arm A/C pts vs within Arm B/D pts.
Median follow-up was 3.5 years (IQR=2.5-4.3). Of 1,444 randomized pts, 133 were censored. In intent-to-treat analyses, 4-year DFS (± standard error) was 94.8±1.5% for pts randomized to blinatumomab arms (B/D) vs 86.9±2.2% control arms (A/C). Adding blinatumomab significantly improved DFS [Hazard Ratio (HR) 0.41, 95% confidence interval (CI) 0.27-0.62, 1-sided p<0.0001]. The 4-year cumulative incidence of relapse (CIR) for those randomized to blinatumomab vs control arms was 4.4±0.9% vs 12.6±1.5% (p<0.0001). While BM involved relapses were significantly reduced (4-year CIR 3.1±0.8% vs. 9.4±1.3%, p<0.0001), isolated CNS relapses were unchanged (1.4±0.5% vs 2.2±0.6%, p=0.41).
In Arms A/C (control) traditional variables used in COG retained adverse prognostic significance, in contrast to Arms B/D (blinatumomab). For example, in control arms, Hispanic ethnicity was associated with a two-fold increase in risk (HR 2.1, 95CI 1.3-3.4; p=0.004) while in blinatumomab arms the HR for Hispanic ethnicity was 1.3 (95CI 0.6-2.7; p=0.51). In control arm pts, EOI fcMRD≥0.01% had a 4-year DFS of 82.3±2.7% vs 89.7±1.7% for EOI fcMRD<0.01% (p=0.008). In blinatumomab arm pts however, EOI fcMRD≥0.01% 4-year DFS was 92.8±1.9% vs. 95.9±1.1% for MRD <0.01% (p=0.08). Notably, blinatumomab arm pts with EOI fcMRD ≥0.01% had superior outcomes to control arm pts with EOI fcMRD <0.01%.
Dramatic impact was seen in pts with EOC BM fcMRD 0.01%-<0.1% vs EOI MRD ≥0.01% but EOC fcMRD <0.01% (control:HR 5.9, 95CI 2.5-14.0; p<0.0001; blinatumomab:HR 2.6, 95CI 0.6-11.8; p=0.21). Indeed, EOC MRD 0.01%-<0.1% pts on Arm C experienced 4-year DFS of 30.8±16.8% (N=16) vs 81.8±11.6% (N=13) on Arm D. CNS2 pts, who in previous COG trials had inferior outcomes, had 4-year DFS of 96.8±2.3% on blinatumomab arms.
Unfavorable genetics [iAMP21, KMT2A rearrangement, t(17;19), hypodiploidy] retained adverse impact (Arm C: HR 3.5 vs favorable, 95CI 1.6-7.6; p=0.002; Arm D: HR 4.1, 95CI 1.1-15.2; p=0.04). However, addition of blinatumomab was still associated with improved outcomes in pts with unfavorable genetics (4-year DFS Arm C 77.1±5.9% vs Arm D 91.7±3.6%).The benefit associated with adding blinatumomab to the treatment of NCI SR B-ALL is maintained with further follow-up. While some adverse prognosticators retain significance in the context of blinatumomab-containing backbones, the addition of blinatumomab is of benefit for all examined subgroups, with most prognosticators losing significance. These results confirm this new standard therapy and have important implications for which subgroups could be considered for a reduction in traditional chemo in the future.
