A Prospective, Multicenter, Randomized Controlled Study Comparing Venetoclax-Enhanced BUCY With Standard BUCY Conditioning in High-Risk AML and MDS Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 138
- 试验地点
- 2
- 主要终点
- Relapse-Free Survival (RFS)
研究概览
简要总结
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.
详细描述
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, post-transplant relapse remains the leading cause of treatment failure, especially among patients receiving matched sibling or unrelated donor transplants. While myeloablative conditioning (MAC) regimens like BUCY (busulfan + cyclophosphamide) offer stronger anti-leukemic effects compared to reduced-intensity regimens, the relapse rate in high-risk myeloid neoplasms remains unacceptably high, partly due to residual leukemia stem cells (LSCs).
Venetoclax, a selective BCL-2 inhibitor, has shown synergistic effects when combined with hypomethylating agents or intensive chemotherapy. It improves remission depth and targets chemotherapy-resistant LSCs. Emerging data suggest that venetoclax may also enhance graft-versus-leukemia (GVL) effects without significantly increasing the risk of graft-versus-host disease (GVHD).
This investigator-initiated, open-label, two-arm, randomized controlled trial will enroll 138 patients aged 12-60 years with high-risk AML or MDS across six transplant centers in China. Patients will be stratified by disease (AML vs. MDS) and randomized (1:1) to receive either:
Standard BUCY regimen: Busulfan (0.8 mg/kg q6h on day -7 to -4), Cyclophosphamide (60 mg/kg/day on day -3 and -2), and MeCCNU (250 mg/m² on day -1), with optional ATG for donors/recipients >40 years.
Ven-BUCY regimen: Venetoclax (400 mg/day or 360 mg/m²/day from day -14 to -8) in addition to the standard BUCY components, with similar ATG guidance. Antifungal prophylaxis and venetoclax dose adjustment (e.g., to 100 mg with posaconazole) will follow local guidelines.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) according to 2022 WHO classification
- •Age between 12 and 60 years
- •High-risk MDS as defined by at least one of the following:
- •IPSS intermediate-2/high risk or IPSS-R intermediate/high/very high risk
- •TP53 mutation
- •RAS pathway mutation (e.g., NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, KIT)
- •Therapy-related MDS
- •High-risk AML as defined by at least one of the following:
- •TP53, RUNX1, or ASXL1 mutation
- •t(6;9)(p23;q34.1)/DEK-NUP214
- •KMT2A rearrangement
- •BCR-ABL1 fusion
- •inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)
- •-5/del(5q), -7, -17/abn(17p)
- •Complex or monosomal karyotype
- •FLT3-ITD high with wild-type NPM1
- •Initial WBC ≥ 10×10^9/L
- •Secondary AML with history of MDS/MPN or therapy-related AML
- •AML with specific mutations (SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, STAG2)
- •MRD positive before transplantation
- •For AML: must have achieved CR or CRi prior to transplantation; for MDS: bone marrow blasts < 20%
- •Availability of a matched related or unrelated donor (10/10 or 9/10 HLA match)
- •ECOG performance status 0-2
- •Creatinine clearance ≥ 60 mL/min (Cockcroft-Gault)
- •AST/ALT ≤ 3 × ULN and total bilirubin ≤ 2 × ULN
- •LVEF ≥ 50% by echocardiogram
- •Life expectancy > 8 weeks
- •Willingness to use effective contraception methods during and for a specified period after the study
- •Signed informed consent
排除标准
- •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
- •More than one prior hematopoietic stem cell transplantation
- •Inability to understand the study protocol or provide informed consent
- •History of grade ≥ 3 non-hematologic adverse reaction to prior venetoclax therapy
- •Receipt of chemotherapy (except hydroxyurea/dexamethasone) or radiotherapy within 14 days before study treatment
- •Ongoing use of BCR-ABL1, IDH, or FLT3 inhibitors without proper washout (≥ 7 days)
研究组 & 干预措施
Vene-BUCY
Participants in this arm will receive a venetoclax-enhanced BUCY conditioning regimen before undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT).
- Venetoclax is administered from day -14 to -8 (400 mg/day for patients ≥14 years; 360 mg/m²/day for patients aged 12-14 years).
- Busulfan (0.8 mg/kg every 6 hours, days -7 to -4).
- Cyclophosphamide (60 mg/kg/day, days -3 and -2).
- MeCCNU (250 mg/m² on day -1). Antithymocyte globulin (ATG) may be added for donor or recipient age >40 years. Venetoclax dose is reduced if co-administered with strong CYP3A4 inhibitors such as posaconazole.
干预措施: Venetoclax (Drug)
BUCY
Participants in this arm will receive the standard BUCY myeloablative conditioning regimen prior to allo-HSCT.
- Busulfan (0.8 mg/kg every 6 hours, days -7 to -4).
- Cyclophosphamide (60 mg/kg/day, days -3 and -2).
- MeCCNU (250 mg/m² on day -1). ATG may be included in cases where the donor or recipient is over 40 years old. No venetoclax is used in this arm.
干预措施: None-placebo (Other)
Vene-BUCY
Participants in this arm will receive a venetoclax-enhanced BUCY conditioning regimen before undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT).
- Venetoclax is administered from day -14 to -8 (400 mg/day for patients ≥14 years; 360 mg/m²/day for patients aged 12-14 years).
- Busulfan (0.8 mg/kg every 6 hours, days -7 to -4).
- Cyclophosphamide (60 mg/kg/day, days -3 and -2).
- MeCCNU (250 mg/m² on day -1). Antithymocyte globulin (ATG) may be added for donor or recipient age >40 years. Venetoclax dose is reduced if co-administered with strong CYP3A4 inhibitors such as posaconazole.
干预措施: Busulfan (BU) (Drug)
BUCY
Participants in this arm will receive the standard BUCY myeloablative conditioning regimen prior to allo-HSCT.
- Busulfan (0.8 mg/kg every 6 hours, days -7 to -4).
- Cyclophosphamide (60 mg/kg/day, days -3 and -2).
- MeCCNU (250 mg/m² on day -1). ATG may be included in cases where the donor or recipient is over 40 years old. No venetoclax is used in this arm.
干预措施: Busulfan (BU) (Drug)
结局指标
主要结局
Relapse-Free Survival (RFS)
时间窗: From the date of transplantation until relapse or death from any cause, assessed up to 24 months
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.
次要结局
- Treatment-Related Adverse Events(From start of conditioning until 28 days after transplantation, and during follow-up up to 3 months)
- Incidence of Acute Graft-versus-Host Disease (aGVHD)(From day of stem cell infusion to day 100 post-transplantation)
- Overall Survival (OS)(Up to 36 months post-transplantation)
- Non-Relapse Mortality (NRM)(Up to 36 months post-transplantation)
- Relapse Rate(Up to 36 months post-transplantation)
- Measurable Residual Disease (MRD) Status(Assessed monthly during the first 6 months, and then every 3 months until 24 months post-transplantation)
- Incidence of Chronic Graft-versus-Host Disease (cGVHD)(From day 100 post-transplantation to 36 months)
研究者
Yanmin Zhao
Dr
First Affiliated Hospital of Zhejiang University