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
Year: 2025
Type: conference-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.
Source: Blood
Authors: Takahiro Shima, Koji Nagafuji, Toshihiro Miyamoto, Shuichi Ota, Yuna Katsuoka, Satoshi Yoshihara, Naoyuki Uchida, Senji Kasahara, Hiroki Hosoi, Mitsumasa Watanabe, Hitoji Uchiyama, Junya Kanda, Takeru Asano, Yuichiro Nawa, Ken Takase, Atsushi Satake, Junya Kuroda, Tetsuya Eto, Yutaka Imamura, Yasuhiko Miyazaki, Akio Mori, Satoshi Yamamoto, Takahiro Nagashima, Shinichi Masuda, Yoshiki Nakae, Hitoshi Minamiguchi, Yuta Katayama, Tatsunori Ishikawa, Shiro Fujii, Tomoaki Fujisaki, Katsuto Takenaka, Goichi Yoshimoto, Ilseung Choi, Masao Ogata, Koji Kato, Naoki Harada, Mika Kuroiwa, Masahiro Onozawa, Hisashi Yamamoto, Junichi Kitagawa, Taku Tsukamoto, Noboru Asada, Ryota Imanaka, Kazushi Tanimoto, Shuro Yoshida, Yuichiro Semba, Yoshikane Kikushige, Yoshikiyo Ito, Takahiro Maeda, Koichi Akashi
Institutions: Kyushu University, Kurume University, Kanazawa University, Sapporo Hokuyu Hospital, Sendai Medical Center, Hyogo Medical University, Toranomon Hospital, Federation of National Public Service Personnel Mutual Aid Associations, Gifu Municipal Hospital, Wakayama Medical University, Wakayama University, Hyogo Prefectural Amagasaki General Medical Center, Kyoto first Red Cross hospital, Kyoto University, Himeji Red Cross Hospital, Ehime Prefectural Central Hospital, National Kyushu Medical Center, Kansai Medical University, Kyoto Prefectural University of Medicine, Hamanomachi Hospital, St Mary's Hospital, Oita Prefectural Hospital, Sapporo City General Hospital, Japanese Red Cross Kitami Hospital, Japanese Red Cross Narita Hospital, Nippon Life Hospital, Shiga University of Medical Science, Shiga University of Medical Science Hospital, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Chugoku Central Hospital, Tokushima University Hospital, Matsuyama Red Cross Hospital, Ehime University, Saga-Ken Medical Centre Koseikan, National Hospital Organization Kyushu Cancer Center, Oita University, Oita University Hospital, Chihaya Hospital, Fukuoka Higashi Medical Center, Hokkaido University, Hokkaido University Hospital, University Hospital Kyoto Prefectural University of Medicine, Okayama University, Okayama University Hospital, Ehime University Hospital, Imamura Hospital
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7108634708