Venetoclax-Enhanced BUCY vs. Standard BUCY Conditioning in High-Risk AML and MDS Patients Undergoing Allo-HSCT (Ven-BUCY Study)

Summary

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.

Eligibility

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)

Conditions5

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