Efficacy of upfront blinatumomab combined with reduced-intensity chemotherapy for newly diagnosed adult Philadelphia chromosome–negative B-lineage acute lymphoblastic leukemia: Interim analysis of two prospective studies of JSCT ALL/MRD2023 and ALL/MRD2019 in Japan

Abstract

Abstract Background In adult patients with Philadelphia chromosome–negative B-cell acute lymphoblastic leukemia (Ph– B-ALL), treatment strategies must balance long-term survival with the mitigation of therapy-related toxicity. The introduction of the bispecific T-cell engager blinatumomab (Blina) has emerged as a promising approach, particularly for measurable residual disease (MRD)-positive patients. However, the optimal timing of Blina administration and its role in modulating chemotherapy intensity remain to be fully elucidated. We conducted a comparative analysis of two prospective clinical trials: ALL/MRD2019, which added Blina only for patients with post-intensive chemotherapy MRD positivity, and ALL/MRD2023, which implemented upfront Blina in all patients following early consolidation with reduced-intensity chemotherapy. Methods Both protocols consisted of induction therapy (Treatment A) followed by consolidation using cytarabine (Treatment B) and methotrexate (Treatment C). MRD was evaluated by allele-specific oligonucleotide quantitative PCR targeting rearranged TCR and IG genes. In the ALL/MRD2019 protocol, patients who were MRD-negative after Treatment C-1 received additional cycles of A, B, and C, followed by maintenance. MRD-positive patients received one additional A course, omitted additional B and C, and received 4 cycles of Blina. In the ALL/MRD2023 protocol, all patients received 4 cycles of Blina after Treatment C-1, regardless of MRD status. In both protocols, patients with MRD positivity after C-1 or with relapse during therapy were recommended for allogeneic stem cell transplantation if feasible; non-transplant candidates received 2 years of maintenance. ALL/MRD2023 omitted Treatment B-2 and C-2 (thus reducing chemotherapy intensity) but increased intrathecal prophylaxis from 7 to 12 doses. As both studies are ongoing, the primary endpoints of this interim analysis were 2-year overall survival (OS) and leukemia-free survival (LFS). Results As of June 2025, 137 patients had been enrolled in the ALL/MRD2023 study and 121 in the ALL/MRD2019 study (total 258 patients). The MRD negativity rate after induction (Treatment A-1) was 53.3% in ALL/MRD2023 vs 45.5% in ALL/MRD2019 (p=0.21). In the ALL/MRD2019 cohort, 26.4% were MRD-positive after Treatment C-1 and received Blina accordingly. The 2-year OS and LFS were 98.9% (95%CI: 92.5 to 99.8) and 85.6% (95%CI: 71.9 to 92.9) in ALL/MRD2023, compared to 89.6% (95%CI: 82.0 to 94.1) and 74.1% (95%CI: 64.7 to 81.3) in ALL/MRD2019, respectively (OS: p=0.07, LFS: p=0.69). Age-stratified analyses showed consistently superior 2-year OS and LFS in ALL/MRD2023 across all age groups (16–35, 36–55, 56–65 years), with OS: 100% (95%CI: not reached to not reached) vs 91.4% (95%CI: 78.7 to 96.7), 97.3% (95%CI: 82.3 to 99.6) vs 88.5% (95%CI: 72.2 to 85.5), and 100% (95%CI: not reached to not reached) vs 87.5% (95%CI: 65.8 to 95.9); and LFS: 87.3% (95%CI: 71.9 to 94.6) vs 71.3% (95%CI: 56.3 to 81.9), 90.9% (95%CI: 77.4 to 96.5) vs 73.6% (95%CI: 55.4 to 85.3), and 93.3% (95%CI: 61.3 to 99.0) vs 80.3% (95%CI: 58.8 to 91.4), respectively. Among MRD-negative patients after Treatment C-1, 2-year OS and LFS were 98.6% (95%CI: 90.4 to 99.8) and 92.0% (95%CI: 82.7 to 96.4) in ALL/MRD2023 vs 91.1% (95%CI: 82.3 to 95.7) and 76.8% (95%CI: 65.6 to 84.7) in ALL/MRD2019 (OS: p=0.13, LFS: p=0.57). Among MRD-positive patients after Treatment C-1, ALL/MRD2023 showed 2-year OS and LFS of 100% (95%CI: not reached to not reached) and 72.2% (95%CI: 41.6 to 88.6) compared to ALL/MRD2019 [85.3% (95%CI: 65.4 to 19.9) and 67.2% (95%CI: 65.4 to 94.2)] (OS: p=0.22, LFS: p=0.93). Conclusion Although the follow-up period remains relatively short and statistical significance has not yet been demonstrated, preliminary data suggest that the ALL/MRD2023 protocol with upfront blinatumomab administration and reduced-intensity chemotherapy may offer improved OS and LFS compared to the conventional intensive chemotherapy approach of ALL/MRD2019. Given the numerically superior outcomes observed across multiple age groups and MRD strata, the ALL/MRD2023 regimen represents a promising treatment strategy that warrants further validation through longer follow-up and mature outcome analyses. These findings support the potential of upfront Blina to enhance survival while minimizing chemotherapy-related toxicity in adult Ph– B-ALL.