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)

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 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.