{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:27:53Z","timestamp":1792787273359,"version":"4.5.0"},"reference-count":18,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"unspecified","delay-in-days":29,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Japan Agency for Medical Research and Development","award":["25ck0106043h0001"],"award-info":[{"award-number":["25ck0106043h0001"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2026,9,7]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"\n Introduction<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Methods and analysis<\/jats:title>\n \n In this multicentre, single-arm phase II clinical trial, the Japan Children\u2019s Cancer Group AML-D24, we will stratify patients with newly diagnosed ML-DS according to age at diagnosis,\n GATA1<\/jats:italic>\n mutation status and treatment response. Patients <24\u2009months of age at the diagnosis with a\n GATA1<\/jats:italic>\n 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\u2009patients, 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.\n <\/jats:p>\n <\/jats:sec>\n \n Ethics and dissemination<\/jats:title>\n \n 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 (\n https:\/\/jrct.mhlw.go.jp\/latest-detail\/jRCTs041250031<\/jats:ext-link>\n ). 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.\n <\/jats:p>\n <\/jats:sec>\n \n Trial registration number<\/jats:title>\n jRCTs041250031.<\/jats:p>\n <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-115972","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:36:19Z","timestamp":1790775379000},"page":"e115972","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"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)"],"prefix":"10.1136","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4633-110X","authenticated-orcid":false,"given":"Kentaro","family":"Nakashima","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, St. Luke\u2019s International Hospital, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4104-6833","authenticated-orcid":false,"given":"Jun","family":"Matsubayashi","sequence":"additional","affiliation":[{"name":"Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiro","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asahito","family":"Hama","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Children\u2019s Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genki","family":"Yamato","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3656-2665","authenticated-orcid":false,"given":"Shota","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamoru","family":"Honda","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology, Saitama Children\u2019s Medical Center, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kozo","family":"Nagai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ehime Prefectural Central Hospital, Matsuyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Oita University Faculty Of Medicine, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Ichi","family":"Tsujimoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Deguchi","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunodiagnostics, Children\u2019s Cancer Center, National Center for Child Health and Development, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Niwa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidefumi","family":"Hiramatsu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan"},{"name":"Department of Pediatrics, Kindai University Faculty of Medicine, Sakai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiminori","family":"Terui","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Toki","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Kawai","sequence":"additional","affiliation":[{"name":"Division of Fetal Development, National Research Institute for Child Health and Development, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko M","family":"Saito","sequence":"additional","affiliation":[{"name":"Clinical Research Center, NHO Nagoya Medical Center, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Moritake","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Taga","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuyoshi","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology, Saitama Children\u2019s Medical Center, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Tomizawa","sequence":"additional","affiliation":[{"name":"Division of Leukemia and Lymphoma, Children\u2019s Cancer Center, National Center for Child Health and Development, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"2026093006351374000_16.9.e115972.1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-01-764324"},{"key":"2026093006351374000_16.9.e115972.2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-01-765057"},{"key":"2026093006351374000_16.9.e115972.3","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1038\/s41375-021-01157-w","article-title":"Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome","volume":"35","author":"Taga","year":"2021","journal-title":"Leukemia"},{"key":"2026093006351374000_16.9.e115972.4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-03-414755"},{"key":"2026093006351374000_16.9.e115972.5","doi-asserted-by":"crossref","first-page":"6532","DOI":"10.1182\/bloodadvances.2022009381","article-title":"Survival outcomes of children with relapsed or refractory myeloid leukemia associated with Down syndrome","volume":"7","author":"Raghuram","year":"2023","journal-title":"Blood Adv"},{"key":"2026093006351374000_16.9.e115972.6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.12.3687"},{"key":"2026093006351374000_16.9.e115972.7","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.27484"},{"key":"2026093006351374000_16.9.e115972.8","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.089425"},{"key":"2026093006351374000_16.9.e115972.9","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1182\/blood.2021012206","article-title":"High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial","volume":"138","author":"Hitzler","year":"2021","journal-title":"Blood"},{"key":"2026093006351374000_16.9.e115972.10","article-title":"Prognostic factors for myeloid leukemia in Down syndrome: Results from the Japan Children\u2019s Cancer Group studies AML-D05 and AML-D11","volume":"71","author":"Hasegawa","year":"2024","journal-title":"Pediatr Blood Cancer"},{"key":"2026093006351374000_16.9.e115972.11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.13.2209"},{"key":"2026093006351374000_16.9.e115972.12","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1038\/s41375-021-01414-y","article-title":"Clinical and biological aspects of myeloid leukemia in Down syndrome","volume":"35","author":"Boucher","year":"2021","journal-title":"Leukemia"},{"key":"2026093006351374000_16.9.e115972.13","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2759"},{"key":"2026093006351374000_16.9.e115972.14","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023022247"},{"key":"2026093006351374000_16.9.e115972.15","doi-asserted-by":"crossref","first-page":"104179","DOI":"10.1016\/j.exphem.2024.104179","article-title":"Antileukemic effect of azacitidine, a DNA methyltransferase inhibitor, on cell lines of myeloid leukemia associated with Down syndrome","volume":"132","author":"Tanaka","year":"2024","journal-title":"Exp Hematol"},{"key":"2026093006351374000_16.9.e115972.16","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.27414","article-title":"Effective response to azacitidine in a child with a second relapse of myeloid leukemia associated with Down syndrome after bone marrow transplantation","volume":"65","author":"Uemura","year":"2018","journal-title":"Pediatr Blood Cancer"},{"key":"2026093006351374000_16.9.e115972.17","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.31244","article-title":"Azacitidine treatment for myeloid leukemia associated with Down syndrome: A nationwide retrospective study in Japan","volume":"71","author":"Kato","year":"2024","journal-title":"Pediatr Blood Cancer"},{"key":"2026093006351374000_16.9.e115972.18","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/pst.2090","article-title":"Sample size calculations for single-arm survival studies using transformations of the Kaplan-Meier estimator","volume":"20","author":"Nagashima","year":"2021","journal-title":"Pharm Stat"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2025-115972","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:36:21Z","timestamp":1790775381000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2025-115972"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":18,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,30]]},"published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1136\/bmjopen-2025-115972"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2025-115972","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]}}}