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
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
• 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