Decitabine Plus mBU/CY Preconditioning for Relapse/Refractory Acute Leukemia

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 relapse or refractory AL were at very high risk of relapse post allo-HSCT, with cumulative relapse rate of 50-80%. Decitabine has been demonstrated efficacy in the treatment of patients with recurrent or refractory leukemia and myelodysplastic syndrome. It was reported that the combination of decitabine, with busulfan 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 recurrent and refractory AL patients.

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(bone marrow) 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 Preconditioning for Relapse/Refractory Acute Leukemia Patients Undergoing HSCT

Conditions
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Stem Cell Transplant Complications, Relapse Leukemia, Refractory Leukemia

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: patients with relapsed acute leukemia patients with acute leukemia in the third（or more）complete remission (CR3) status 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 recurrent and refractory acute leukemia at the time of HLA-mismatched HSCT Details: The conditioning therapy for human leukocyte 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, semustine (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 intravenously 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 Semustine (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 (minimal residual disease) 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, semustine (Me-CCNU, 250 mg/m2), orally once on day -3. | Drug: Decitabine<br>* Decitabine 200mg.m-2.d-1 intravenously 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 Semustine (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 | 
| 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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recurrent acute leukemia, refractory acute leukemia, preconditioning regimen, allogeneic stem cell transplantation