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.

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.

Patients will be followed weekly during the first month post-transplant, monthly for 6 months, and every 3 months thereafter until 3 years post-enrollment. The primary endpoint is 2-year relapse-free survival (RFS). Secondary endpoints include overall survival (OS), non-relapse mortality (NRM), relapse rate, MRD clearance, and adverse events graded by CTCAE v5.0.

This study seeks to determine whether adding venetoclax to a standard myeloablative regimen can enhance anti-leukemic efficacy and improve long-term outcomes without increasing transplant-related toxicity.

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)