Decitabine Plus mBU/CY for High Risk Acute Leukemia With MRD Pre-HSCT

Study Overview
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Brief Summary
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Allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains one of the currently available curative therapies for acute leukemia (AL). Leukemia relapse is one of the mainly causes of transplant failure. We reported previously that patients with high-risk molecular biomarkers who still have detectable minimal residual disease(MRD) pre-HSCT were at very high risk of relapse, with cumulative relapse rate of 50-80%. Decitabine has been demonstrated efficacy in the treatment of patients with recurrent or refractory leukemia and myelodysplastiv syndrome. It was reported that the combination of decitabine, with busufan and cyclophosphamide as a preparative regimen for allo-HSCT using HLA-matching donors was safe and effective. In this prospective, single-arm clinical trial, we aimed to examine the efficacy of combining decitabine with modified busulfan and cyclophosphamide (mBU/CY) as a preparative regimen for allo-HSCT in patients with very high-risk AL and detectable MRD pre-HSCT.

Detailed Description
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Patients enrolled in this study would receive decitabine 200mg·m-2·d-1 on day -12 and -11 pre-HSCT. The conditioning therapy for human leukocyte antigen (HLA)-mismatched HSCT patients was modified BU/CY plus ATG (thymoglobulin; Sang Stat, France) consisting of cytarabine (Ara-C 4 g·m-2·d-1) intravenously on days -10 to -9, busulfan (BU 3.2 mg·kg-1·d-1) intravenously on days -8 to -6, cyclophosphamide (CY 1.8 g·m-2·d-1), intravenously on days -5 to -4, semustine (Me-CCNU, 250 mg·m-2), orally once on day -3, and ATG (2.5 mg·kg-1·d-1) intravenously on days -5 to -2. In matched sibling transplantations, patients received hydroxycarbamide (80 mg·kg-1) orally on day -10 and a lower dose of Ara-C (2 g·m-2·d-1) on day -9, but otherwise an identical regimen to the HLA-mismatched patients without ATG. BM samples from patients were obtained to assess leukemia status after HSCT. The time points that we monitored BM samples included at time of allo-HSCT; 1 month, 2 months, 3 months, 4.5 months, 6 months, 9 months, and 12 months after allo-HSCT; and every 6 months thereafter to the defined endpoints or for at least until 5 years after transplantation.

Official Title
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Decitabine Plus mBU/CY for High Risk Acute Leukemia With Minimal Residual Disease Pre-HSCT

Conditions
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Stem Cell Transplant Complications, Leukemia, Myeloid, Acute, Leukemia Relapse

Intervention / Treatment
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* Drug: Decitabine
* Drug: mBU/CY and ATG
* Drug: mBU/CY


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: acute leukemia patients with MLL-r,TLS-ERG,or SIL-TAL1,whose minimal residual disease were detectable pre-HSCT Exclusion Criteria: pregnancy women uncontrolled severe infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Patients enrolled in this study would receive decitabine 200mg·m-2·d-1 on day -12 and -11 pre-HSCT. The conditioning therapy for human leukocyte antigen (HLA)-mismatched HSCT patients was modified BU/CY plus ATG. In matched sibling transplantations, patients received hydroxycarbamide (80 mg·kg-1) orally on day -10 and a lower dose of Ara-C (2 g·m-2·d-1) on day -9, but otherwise an identical regimen to the HLA-mismatched patients without ATG.BM samples from patients would be obtained to assess leukemia status after HSCT. The time points that we monitored BM samples included at time of allo-HSCT; 1 month, 2 months, 3 months, 4.5 months, 6 months, 9 months, and 12 months after allo-HSCT; and every 6 months thereafter to the defined endpoints or for at least until 5 year after transplantation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Decitabine plus mBU/CY for HLA-mismatched HSCT<br>Decitabine plus mBU/CY as precondition regimen for High Risk Acute Leukemia With MRD at the time of HLA-mismatched HSCT. Details: The conditioning therapy for human eukocyte antigen (HLA)-mismatched HSCT patients was decitabine plus modified BU/CY and ATG,consisting of decitabine 100mg·m-2·d-1 q12h on days-12 and -11,cytarabine (Ara-C 4 g·m-2·d-1) intravenously on days -10 to -9, busulfan (BU 3.2 mg·kg-1·d-1) intravenously on days -8 to -6, cyclophosphamide (CY 1.8 g·m-2·d-1), intravenously on days -5 to -4, simustine (Me-CCNU, 250 mg/m2), orally once on day -3, and ATG (2.5 mg·kg-1·d-1) intravenously on days -5 to -2. | Drug: Decitabine<br>* Decitabine 200mg.m-2.d-1 intervanously on days -12 and -11<br>Drug: mBU/CY and ATG<br>* Ara-C 4 g·m-2·d-1 intravenously on days -10 to -9 Busulfan (BU 3.2 mg·kg-1·d-1) intravenously on days -8 to -6, Cyclophosphamide (CY 1.8 g·m-2·d-1) intravenously on days -5 to -4 Simustine (Me-CCNU, 250 mg·m-2) orally once on day -3 ATG (2.5 mg·kg-1·d-1) intravenously on days -5 to -2<br>|
| Experimental: Decitabine plus mBU/CY for matched sibling transplant<br>Decitabine plus mBU/CY as precondition regimen for High Risk Acute Leukemia With MRD at the time of matched sibling transplant. Details: In matched sibling transplantations, patients received decitabine 100mg·m-2·d-1 q12h on days-12 and -11,hydroxycarbamide (80 mg/kg) orally on day -10 and a lower dose of Ara-C (2 g·m-2·d-1) on day -9, busulfan (BU 3.2 mg·kg-1·d-1) intravenously on days -8 to -6, cyclophosphamide (CY 1.8 g·m-2·d-1), intravenously on days -5 to -4, simustine (Me-CCNU, 250 mg/m2), orally once on day -3. | Drug: Decitabine<br>* Decitabine 200mg.m-2.d-1 intervanously on days -12 and -11<br>Drug: mBU/CY<br>* hydroxycarbamide (80 mg·kg-1) orally on day -10 Ara-C (2 g·m-2·d-1) on day -9 Busulfan (BU 3.2 mg·kg-1·d-1) intravenously on days -8 to -6, Cyclophosphamide (CY 1.8 g·m-2·d-1) intravenously on days -5 to -4 Simustine (Me-CCNU, 250 mg·m-2) orally once on day -3<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1 year cumulative incidence of relapse | The cumulative incidence of relapse at 1 year post allo-HSCT | 1 year post allo-HSCT | 
| 2 year cumulative incidence of relapse | The cumulative incidence of relapse at 2 years post allo-HSCT | 2 years post allo-HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-relapse mortality | The cumulative incidence of non-relapse mortality at 1 year post allo-HSCT | 1 year post allo-HSCT | 
| 1 year overall survival | The overall survival at 1 year post allo-HSCT | 1 year post allo-HSCT | 
| 5 years overall survival | The overall survival at 5 years post allo-HSCT | 5 years post allo-HSCT | 
| 1 year leukemia free survival | The leukemia free survival at 1 years post allo-HSCT | 1 year post allo-HSCT | 
| 5 years leukemia free survival | The leukemia free survival at 5 years post allo-HSCT | 5 years post allo-HSCT | 
| engraftment | The total neutrophil and platelet engraftment rate | 100 days post allo-HSCT | 
| Acute graft versus host disease | The cumulative incidence of grade II-IV acute graft versus host disease | 100 days post allo-HSCT | 
| Chronic graft versus host disease | The cumulative incidence of intermediate to severe chronic graft versus host disease | 1 years post allo-HSCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high risk acute myeloid leukemia, hematopoietic stem cell transplantation, leukemia relapse, preparation regimen, decitabine