This is a prospective, multicenter, randomized controlled trial designed to evaluate the efficacy and safety of venetoclax-enhanced BUCY (Ven-BUCY) conditioning compared to the standard BUCY regimen in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Eligible participants aged 12 to 60 years will be randomized 1:1 to receive either Ven-BUCY or standard BUCY conditioning. The primary endpoint is relapse-free survival (RFS) at two years post-transplant. Secondary outcomes include overall survival, relapse rate, non-relapse mortality, measurable residual disease (MRD), and treatment-related adverse events. The study aims to improve post-transplant outcomes by deepening disease remission through the addition of venetoclax, a BCL-2 inhibitor known to target leukemia stem cells and enhance chemotherapy sensitivity.
Diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) according to 2022 WHO classification
Age between 12 and 60 years
IPSS intermediate-2/high risk or IPSS-R intermediate/high/very high risk
TP53 mutation
Uncontrolled cardiovascular disease or New York Heart Association class III/IV heart failure
Other severe comorbid conditions that may interfere with study participation
Known HIV infection or uncontrolled active hepatitis B or C
Pregnant or breastfeeding women
Parallel
Venetoclax
DrugVenetoclax is administered orally at 400 mg/day for participants ≥14 years or 360 mg/m²/day for those aged 12-14 years, from day -14 to -8 before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dose is adjusted to 100 mg/day (or 90 mg/m²/day for pediatric patients) if used with strong CYP3A4 inhibitors such as posaconazole.
None-placebo
Other interventionParticipants in this arm will not receive venetoclax as part of their conditioning regimen. They will undergo standard myeloablative conditioning with BUCY (busulfan, cyclophosphamide, and MeCCNU), prior to allogeneic hematopoietic stem cell transplantation. This arm serves as the active comparator to evaluate the addition of venetoclax in the experimental arm.
Busulfan (BU)
DrugBUCY group (Control group): Busulfan (BU 0.8 mg/kg/q6h, days -7 to -4), Cyclophosphamide (CTX 60 mg/kg/day, days -3 to -2), and MeCCNU (250 mg/m²/day, day -1). For recipients or donors over 40 years of age, ATG (Thymoglobulin, total dose 2.5-4.5 mg/kg, divided over days -3 to -1) may be added.
Relapse-Free Survival (RFS)
Relapse-Free Survival (RFS) is defined as the time from the date of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to the first documented relapse of the primary disease or death from any cause, whichever occurs first. Participants who remain alive and relapse-free will be censored at the time of last follow-up.
Overall Survival (OS)
Overall survival (OS) is defined as the time from the date of transplantation to death from any cause. Patients who are alive at the last follow-up will be censored. Survival curves will be estimated using the Kaplan-Meier method.
Non-Relapse Mortality (NRM)
Non-relapse mortality (NRM) is defined as death from any cause other than disease relapse after transplantation. Competing risk analysis will be used to assess NRM incidence between groups.
Relapse Rate
Relapse rate refers to the cumulative incidence of disease recurrence post-transplantation, assessed through bone marrow evaluation, flow cytometry, and molecular markers. Competing risk models will be applied for statistical analysis.
Measurable Residual Disease (MRD) Status
MRD will be assessed by multiparameter flow cytometry and/or molecular techniques at scheduled timepoints after transplantation to evaluate minimal residual leukemia. MRD positivity and conversion dynamics will be compared between groups.
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First Affiliated Hospital of Zhejiang University
Lead sponsor
The First Affiliated Hospital of Zhengzhou University
Collaborator
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Collaborator
Tongji Hospital
Collaborator
The Children's Hospital of Zhejiang University School of Medicine
Collaborator
Ruijin Hospital
Collaborator
