Efficacy and safety of risk-stratified chemotherapy with azacitidine for children with myeloid leukaemia with Down syndrome: protocol for a multicentre phase II trial (JCCG AML-D24)
23 affiliations
- 1Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- 2Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japan
- 3Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Otsu, Japan
- 4Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
- 5Department of Hematology and Oncology, Children’s Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, Japan
- 6Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan
- 7Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- 8Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan
- 9Department of Pediatrics, Ehime Prefectural Central Hospital, Matsuyama, Japan
- 10Department of Pediatrics, Oita University Faculty Of Medicine, Oita, Japan
- 11Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- 12Division of Cancer Immunodiagnostics, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan
- 13Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
- 14Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- 15Department of Pediatrics, Kindai University Faculty of Medicine, Sakai, Japan
- 16Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- 17Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan
- 18Division of Fetal Development, National Research Institute for Child Health and Development, Tokyo, Japan
- 19Clinical Research Center, NHO Nagoya Medical Center, Nagoya, Japan
- 20Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
- 21Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan
- 22Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- 23Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan
Abstract
Introduction: The prognosis of myeloid leukaemia associated with Down syndrome (ML-DS) is excellent with reduced-intensity chemotherapy; however, that of refractory or relapsed ML-DS remains dismal. These contrasting outcomes highlight the importance of risk-stratified therapy, based on reliable prognostic factors, to prevent treatment-related mortality and relapse. In addition, novel therapeutic strategies capable of overcoming the poor prognosis of high-risk patients are eagerly anticipated. Based on the results of molecular analyses, in vitro functional assays and anecdotal case reports, azacitidine (AZA), a hypomethylating agent, is a promising candidate for novel therapeutic strategies for high-risk ML-DS.
Methods and analysis: In this multicentre, single-arm phase II clinical trial, the Japan Children’s Cancer Group AML-D24, we will stratify patients with newly diagnosed ML-DS according to age at diagnosis, GATA1 mutation status and treatment response. Patients <24 months of age at the diagnosis with a GATA1 mutation who achieve morphological complete remission and are negative for flow cytometric measurable residual disease at the end of induction will be classified as the low-risk (LR) group and receive less intensive chemotherapy. The other participants, stratified into the non-LR group, will be treated with AZA-combined chemotherapy. The objective of this trial is to evaluate the efficacy and safety of AZA-combined chemotherapy in children with non-LR ML-DS. The primary endpoint is the 3-year event-free survival in the non-LR group. The planned enrolment is 145 patients, including 47 non-LR patients. The study period consists of a 7-year accrual period (including an enrolment suspension period for interim analysis) followed by a 3-year follow-up period for a total duration of 10 years.
Ethics and dissemination: This study was approved by the National Hospital Organization Review Board for Clinical Trials (Nagoya, Japan) on 12 May 2025 and was registered in the Japan Registry of Clinical Trials ( https://jrct.mhlw.go.jp/latest-detail/jRCTs041250031 ). Written informed consent will be obtained from all patients and/or their guardians. The results of this study will be disseminated through publication in peer-reviewed journals and presentation at national and international scientific conferences.
Trial registration number: jRCTs041250031.
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BibTeX
@article{nakashima2026efficacy,
title = {{Efficacy and safety of risk-stratified chemotherapy with azacitidine for children with myeloid leukaemia with Down syndrome: protocol for a multicentre phase II trial (JCCG AML-D24)}},
author = {Kentaro Nakashima and Daisuke Hasegawa and Jun Matsubayashi and Shiro Tanaka and Asahito Hama and Genki Yamato and Shota Kato and Mamoru Honda and Kozo Nagai and Hironori Goto and Shin-Ichi Tsujimoto and Takao Deguchi and Kaori Niwa and Hidefumi Hiramatsu and Kiminori Terui and Tsutomu Toki and Kenichi Yoshida and Tomoko Kawai and Akiko M Saito and Hiroshi Moritake and Takashi Taga and Yasuhiro Okamoto and Katsuyoshi Koh and Daisuke Tomizawa},
journal = {BMJ Open},
year = {2026},
month = sep,
doi = {10.1136/bmjopen-2025-115972},
url = {https://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2025-115972},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Efficacy and safety of risk-stratified chemotherapy with azacitidine for children with myeloid leukaemia with Down syndrome: protocol for a multicentre phase II trial (JCCG AML-D24)
AU - Kentaro Nakashima
AU - Daisuke Hasegawa
AU - Jun Matsubayashi
AU - Shiro Tanaka
AU - Asahito Hama
AU - Genki Yamato
AU - Shota Kato
AU - Mamoru Honda
AU - Kozo Nagai
AU - Hironori Goto
AU - Shin-Ichi Tsujimoto
AU - Takao Deguchi
AU - Kaori Niwa
AU - Hidefumi Hiramatsu
AU - Kiminori Terui
AU - Tsutomu Toki
AU - Kenichi Yoshida
AU - Tomoko Kawai
AU - Akiko M Saito
AU - Hiroshi Moritake
AU - Takashi Taga
AU - Yasuhiro Okamoto
AU - Katsuyoshi Koh
AU - Daisuke Tomizawa
PY - 2026
DA - 2026/09/30
JO - BMJ Open
DO - 10.1136/bmjopen-2025-115972
UR - https://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2025-115972
AB - Introduction: The prognosis of myeloid leukaemia associated with Down syndrome (ML-DS) is excellent with reduced-intensity chemotherapy; however, that of refractory or relapsed ML-DS remains dismal. These contrasting outcomes highlight the importance of risk-stratified therapy, based on reliable prognostic factors, to prevent treatment-related mortality and relapse. In addition, novel therapeutic strategies capable of overcoming the poor prognosis of high-risk patients are eagerly anticipated. Based on the results of molecular analyses, in vitro functional assays and anecdotal case reports, azacitidine (AZA), a hypomethylating agent, is a promising candidate for novel therapeutic strategies for high-risk ML-DS. Methods and analysis: In this multicentre, single-arm phase II clinical trial, the Japan Children’s Cancer Group AML-D24, we will stratify patients with newly diagnosed ML-DS according to age at diagnosis, GATA1 mutation status and treatment response. Patients <24 months of age at the diagnosis with a GATA1 mutation who achieve morphological complete remission and are negative for flow cytometric measurable residual disease at the end of induction will be classified as the low-risk (LR) group and receive less intensive chemotherapy. The other participants, stratified into the non-LR group, will be treated with AZA-combined chemotherapy. The objective of this trial is to evaluate the efficacy and safety of AZA-combined chemotherapy in children with non-LR ML-DS. The primary endpoint is the 3-year event-free survival in the non-LR group. The planned enrolment is 145 patients, including 47 non-LR patients. The study period consists of a 7-year accrual period (including an enrolment suspension period for interim analysis) followed by a 3-year follow-up period for a total duration of 10 years. Ethics and dissemination: This study was approved by the National Hospital Organization Review Board for Clinical Trials (Nagoya, Japan) on 12 May 2025 and was registered in the Japan Registry of Clinical Trials ( https://jrct.mhlw.go.jp/latest-detail/jRCTs041250031 ). Written informed consent will be obtained from all patients and/or their guardians. The results of this study will be disseminated through publication in peer-reviewed journals and presentation at national and international scientific conferences. Trial registration number: jRCTs041250031.
SN - 2044-6055
SN - 2044-6055
ER -