Venetoclax+Azacytidine+Modified BUCY Conditioning Regimen for Acute Myeloid Leukemia and Myelodysplastic Syndromes Undergoing Allo-HSCT

Study Overview
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Brief Summary
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The purpose of this prospective, open-label, single-center study is to evaluate the efficacy and safety of VEN-AZA (venetoclax and azacytidine) followed by modified BUCY (busulfan and cyclophosphamide) as conditioning regimen for high-risk myelodysplastic syndrome (MDS) and high-risk or relapsed/refractory acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Detailed Description
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Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only potentially curative therapy for patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, relapse remains a leading cause for treatment failure after hematopoietic cell transplantation (HCT) in patients, optimization of conditioning regimen can improve prognosis and decrease relapse. Abnormal gene methylation is common in AML and MDS patients. Azacytidine is a DNA methylation transferase inhibitor that can re-express tumor suppressor genes in leukemia cells. Venetoclax is a selective BCL-2 inhibitor, which has antitumor activity against a variety of hematological malignancies. The combination of the two drugs show a synergistic anti-tumor effect. The objective of this study is to evaluate the safety and efficacy of VEN-AZA regimen followed by Allo-HSCT in the treatment of high-risk MDS and high-risk or relapsed/refractory AML.

Official Title
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Venetoclax + Azacytidine Followed by Modified BUCY Conditioning Regimen for High-risk Myelodysplastic Syndromes (MDS) and High-risk or Relapsed/Refractory Acute Myeloid Leukemia (AML) Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT)

Conditions
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Allogeneic Hematopoietic Stem Cell Transplantation, Acute Myeloid Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: VEN+AZA+Modified BUCY


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 8 to 65 years; Diseases must be MDS and AML; high-risk MDS: int-2 risk, high risk by the IPSS; IPSS-R int-risk (> 3.5 points), high risk, very high risk; high risk,very high risk by the WPSS; high-risk or relapsed/refractory AML: (1) age≥60 years; (2) High white blood cell count at first diagnosis (WBC≥100*10^9/L); (3) secondary AML (previous history of MDS, myeloproliferative disease, or treatment-related AML, etc.); (4) Complicated with extramedullary leukemia, such as central nervous system leukemia, granulocytic sarcoma, hepatosenomegaly; （5）high risk factors and relapsed/refractory AML（reference 2022-AML-ELN guideline）（6）not in remission or ≥CR2 before transplantation; Must need a bone marrow transplant; Must have the ability to observe the efficacy and events; Patient must have ability to understand and willingness to provide written informed consent prior to participation in the study and any related procedures being performed. Exclusion Criteria: Age <8 or >65 years; Uncontrolled bacterial, viral, fungal, or other infection before conditioning regimen; Pregnant or lactating females; Current participation in another clinical trial; Contra-indication to one of the drug of the regimen; Any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver or other organ system that may place the patient at undue risk to undergo the agents included in the conditioning regimen.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VEN+AZA+Modified BUCY<br> | Drug: VEN+AZA+Modified BUCY<br>* Venetoclax: 200mg/day*7days（It should be combined with triazole antifungal drugs). Azacytidine: 75mg/ m²/day*7days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| disease-free survival (DFS) | It is measured from the time from randomization to the first of relapse or death. | 3 years after transplantation | 
| overall survival (OS) | It is measured from the time of entry into this trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive. | 3 years after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| veno-occlusive disease (VOD) | incidence of veno-occlusive disease (VOD) events (refer to modified Seattle Criteria of VOD) | 3 years after transplantation | 
| graft-versus-host disease (GvHD) | incidence and severity of acute (aGvHD) and chronic graft-versus-host disease (cGvHD) (aGvHD refer to Glucksberg Criteria and cGvHD refer to the National Institutes of Health Consensus) | 3 years after transplantation | 
| transplant related mortality (TRM) | cumulative incidence of transplant related mortality | 3 years after transplantation | 
| Regimen related toxicity | Number of participants with conditioning regimen related toxicity | 3 years after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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venetoclax, azacytidine, hematopoietic stem cell transplantation, acute myeloid leukemia, myelodysplastic syndrome