Blinatumomab versus high-dose chemotherapy in the first-line therapy of high-risk childhood B-cell acute lymphoblastic leukemia: The results of a Phase 3 trial of the cALL-pol consortium in Poland

Abstract The Childhood Acute Lymphoblastic Leukemia in Poland (cALL-POL) consortium links all pediatric oncology centers in the country and gives an opportunity to perform nation-wide clinical trials. Since there is limited data on safety and efficacy of chemotherapy replacement with blinatumomab among pediatric patients we conducted a phase 3 trial (AIEOP-BFM 2017 Poland, EudraCT # 2020-005017-41) involving children with newly diagnosed B-cell precursor ALL (BCP-ALL) who had high risk (HR) of relapse according to AIEOP-BFM criteria. Patients were randomly assigned to receive three HR blocks of chemotherapy or three sequential 28-day cycles of blinatumomab in post induction phase. The primary end points were toxicity (AESI – adverse event of special interest, AE/SAE – adverse event/serious adverse event grade ≥4) and measurable residual disease (MRD, centralized assessment by the TCR/Ig genes rearrangements) after the first and third cycle of randomization regimen. Additionally, exploratory analysis of event-free survival was performed with an event defined as a treatment resistance, relapse or death. Between June 25, 2021 and November 19, 2024, N=827 children were diagnosed with ALL in Poland. Among them N=727 (87.9%) entered the AEIOP-BFM ALL 2017 Polandclinical trial including N=638 (87.7%) with BCP-ALL. Subsequently, N=87 (female 45.6%, age at diagnosis 7.3+/-5.2 years, median follow-up 22.17 months) of BCP-ALL patients were classified as HR at the end of consolidation phase and subjected for 1:1 randomization. Among patients who completed randomized phase of trial, treatment with blinatumomab significantly reduced the risk of developing at least one clinically-relevant adverse event (AESI or AE/SAE grade ≥4)32.4% vs. 81.1%; RR(95%CI)=0.40 (0.24-0.65), p<0.0001. Moreover, the treatment with blinatumomab was superior to HR chemotherapy blocks in achieving negative MRD (97.3% vs. 56.8%; p=0.0033 RR(95%CI)=0.10(0.01-0.74) and 97.3% vs. 64.9%; p=0.053 RR(95%CI)=0.17(0.02-1.32) after the first and third block of therapy during randomization phase, respectively. Considering exploratory analysis, the MRD status after the first and third of cycle of high-risk chemotherapy or blinatumomab was a significant prognostic factor in univariate Cox regression analysis on event-free survival with HR(95%CI)=3.40(1.02-11.40) p=0.0472 and HR(95%CI)=9.90(2.85-34.33) p=0.0003, respectively. Replacing chemotherapy with blinatumomab among patients with newly diagnosed HR childhood BCP-ALL improved toxicity profile and was significantly better in reduction of MRD levels. Despite short follow-up time this resulted in improved probability of event free survival. The study was funded by the Medical Research Agency (MRA) of Poland (the cALL-POL project, ABM/2019/1).