Venetoclax+Azacytidine+Modified BUCY Conditioning Regimen for Acute Lymphoblastic Leukemia 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 or relapsed/refractory acute lymphoblastic leukemia (ALL) 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 acute lymphoblastic leukemia. 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 ALL 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. Multiple case reports the efficacy of Venetoclax-based regimens in patients with ALL is encouraging. The objective of this study is to evaluate the feasibility, safety and efficacy of VEN-AZA bridging allogeneic hematopoietic stem cell transplantation in the treatment of high-risk ALL.

Official Title
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Venetoclax (VEN)+Azacytidine (AZA) Followed by Modified BUCY Conditioning Regimen for High Risk or Refractory/Relapsed Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT)

Conditions
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Allogeneic Hematopoietic Stem Cell Transplantation, Acute Lymphoblastic Leukemia

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 14 to 65 years; Diagnosis of high-risk or relapsed/refractory acute lymphoblastic leukemia at the time of transplant. 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 <14 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 regimen related toxicity as assessed by CTCAE v4.0 | 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 lymphoblastic leukemia