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519 A Nationwide Clinical Trial ALL-B12: An Optimized Therapy for Pediatric B-Precursor Acute Lymphoblastic Leukemia with Excellent Overall Survival and Minimal Non-Relapse Mortality: A Report from the Japan Children’s Cancer GroupClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Progress Through Collaboration: Impactful Cooperative Efforts to Optimize Care for ALL
Hematology Disease Topics & Pathways:
ALL, Lymphoid Leukemias, clinical trials, Research, Clinical Research, Diseases, Lymphoid Malignancies
Sunday, December 10, 2023: 12:30 PM

Motohiro Kato, MD1, Yasuhiro Okamoto, MD, PhD2, Toshihiko Imamura, MD, PhD3, Akiko Kada, PhD4*, Akiko M Saito, MD, PhD4*, Yuka Iijima-Yamashita5*, Takao Deguchi, MD, PhD6, Kentaro Oki, MD, PhD7*, Takashi Fukushima8*, Ken-ichi Anami, MT9*, Masashi Sanada, MD10, Tomohiko Taki11*, Yoshiko Hashii, MD12, Nobutaka Kiyokawa, MD, PhD13*, Yoshiyuki Kosaka, M.D, Ph.D14*, NAO Yoshida, MD15*, Yuki Yuza, MD, PhD16*, Masakatsu Yanagimachi17*, Kenichiro Watanabe, MD, PhD18*, Atsushi Sato, MD, PhD19*, Chihaya Imai, MD, PhD20, Takashi Taga, MD, PhD21*, Souichi Adachi, MD, PhD22*, Keizo Horibe, MD, PhD23*, Atsushi Manabe, MD, PhD24 and Katsuyoshi Koh, MD, PhD25*

1Department of Pediatrics, The University of Tokyo, Tokyo, Japan
2Kagoshima University, Kagoshima, JPN
3Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, JPN
4Clinical Research Center, NHO Nagoya Medical Center, Nagoya, JPN
5Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, JPN
6Division of Cancer Immunodiagnostics, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, JPN
7Department of Pediatric Hematology and Oncology Research,, National Research Institute for Child Health and Development, Tokyo, JPN
8Department of Child Health, Institute of Medicine,, University of Tsukuba, Tsukuba, Japan
9Department of Medical Oncology, Hematology, and Infectious Diseases, Faculty of Medicine,, Fukuoka University, Fukuoka, JPN
10Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, JPN
11Kyorin University Faculty of Health Sciences, Tokyo, JPN
12Osaka University, Suita, JPN
13Department of Pediatric Hematology and Oncology Research, National Research Institute For Child Health and Development, Tokyo, JPN
14Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan
15Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, JPN
16Department of Hematology and Oncology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
17Kanagawa Children's Medical Center, Yokohama, Japan
18Department of Hematology and Oncology, Shizuoka Children's Hospital, Shizuoka, SHZ, JPN
19Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai, Japan
20Niigata Univ. Grad. School of Med. & Dental Sci., Niigata, JPN
21Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
22Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
23NHO Nagoya Medical Center, Nagoya, JPN
24Hokkaido University Graduate School of Medicine, Sapporo, HOK, JPN
25Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan


Advancements in treatment have significantly improved therapeutic outcomes for pediatric acute lymphoblastic leukemia (ALL) and relapsed ALL. However, there remains a need for therapies that minimize relapse in high-risk groups and avoid long-term complications. To address this gap. we conducted the nationwide clinical trial ALL-B12, aimed at newly diagnosed B-precursor ALL aged 1-18 years.


ALL-B12 enrolled participants from November 2012 to November 2017. Patients were stratified based on the NCI classification (age and WBC count at diagnosis). Those with NCI-SR and NCI-HR were assigned to the standard risk group (SR) and the intermediate group (IR), respectively. Poor steroid responders and those with high-risk genomic abnormalities were assigned to the high risk group (HR). A treatment regimen, including 4-drug remission induction, early consolidation, HD-MTX-containing intensification, re-induction, and maintenance, was implemented. Anthracycline dose in the induction therapy was reduced in SR patients. In contrast, early consolidation was intensified with L-ASP for a part (randomized) of the IR and the entire HR. Patients classified as CNS3 were treated as high risk, receiving 12 Gy cranial irradiation; prophylactic cranial irradiation was avoided in non-CNS3 groups. Allogeneic hematopoietic cell transplantation (allo-HCT) during the first remission was restricted to those in the very high-risk group with specific genomic abnormalities (e.g., hypodiploid <44 and TCF3-HLF) and residual MRD above 10^-3 at the end of early consolidation. A randomized comparison was carried out within each risk group to identify the optimal treatment. We assessed the effectiveness of intensification with VCR/DEX pulses for the SR, the impact of L-ASP intensification for the IR, and compared block-type treatment and HD-MTX intensified with VCR and L-ASP (HD-MTX/VL) for the HR. The primary outcome measure was the 5-year event-free survival (EFS) rate.


In total, 1,936 patients were enrolled, with 1,804 patients receiving protocol treatment after excluding ineligible patients such as those with BCR-ABL1 positivity. The percentage of patients achieving remission at the end of early consolidation was 98.9%. The overall 5-year EFS and OS probability were 85.2% (95%CI 83.5-86.8%) and 94.3% (95%CI 93.1-95.3%), respectively. Only 1.7% of patients underwent allo-HCT during the first remission. The mortality rate during induction was just 0.6%, with non-relapse mortality (NRM) after remission at 0.6%. The overall relapse incidence was 13.2%, and the overall CNS relapse rate was 1.9%. Among patients assigned to risk groups, 1,107 (62.7%) were assigned to the SR, 459 (26.0%) to the IR, and 200 (11.3%) to the HR. The 5yEFS for the SR was 89.9%. The post-randomization EFS rates for those with and without VCR/DEX intensification were 90.7% and 90.1%, respectively, indicating nearly identical survival curves (p = 0.73). The EFS for the IR was 79.7%, but L-ASP intensification was expected to be effective, the EFS for groups with and without ASP intensification was 82.1% and 77.9%, respectively, failing to reach statistical significance (p = 0.31). The EFS for the HR was 75.5%, with overlapping survival curves for block treatment (75.7%) and HD-MTX/VL (74.2%) (p = 0.92). MRD dynamics were associated with prognosis, and early consolidation therapy enhanced by ASP resulted in better MRD clearance. MRD of 10^-4 was associated with poor prognosis at both the end of induction and the end of early consolidation.


In our multi-center clinical trial, we observed excellent outcomes in a diverse group of patients nationwide. Using the NCI criteria for stratification, a significant number of patients were categorized into the SR. Additionally, introducing L-ASP during early consolidation decreased the number of MRD-positive patients, which subsequently reduced the subset needing allo-HCT. This strategic adjustment in treatment intensity resulted in both high EFS rates and low NRM. Given the rise of immunotherapy and its promising results for recovery even post-relapse, there's a pressing need to enhance overall outcomes while minimizing non-relapse mortality. We anticipate refining our stratification further and integrating immunotherapy and other innovative treatments into our approach.

Disclosures: Kato: Chugai: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Sato: Chugai: Honoraria. Imai: Juno Therapeutics: Patents & Royalties; CURED Inc: Consultancy, Patents & Royalties, Research Funding. Horibe: Kyowa Kirin: Consultancy; Amgen: Consultancy, Speakers Bureau; NIPPON SHINYAKU: Consultancy; Pfizer Japan: Consultancy; Astellas Pharma: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Novartis Pharma: Speakers Bureau.

*signifies non-member of ASH