Reduced Intensity Conditioning Regimens for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical trial is to compare outcomes of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan) in allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients. The main questions it aims to answer are: The safety of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan) in allogeneic hematopoietic stem cell transplantation for adult AML/MDS patients with HCT-CI≥3 or aged ≥55 years. The efficacy of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan) in allogeneic hematopoietic stem cell transplantation for adult AML/MDS patients with HCT-CI≥3 or aged ≥55 years. Participants will be randomized to one of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan)

Detailed Description
-----------------
Patients are randomized to one of two reduced intensity conditioning (RIC) regimens: the combination of fludarabine (30 mg/m^2/day, days -6 to days -2, the total dase is 150 mg/m^2) and busulfan (3.2 mg/kg/day, days -3 to days -2, the total dose is 6.4 mg/kg) (Flu/Bu) or fludarabine (30 mg/m^2/day, days -6 to days -2, the total dose is 150 mg/m^2) and melphalan (70 mg/m^2/day, days -3 to days -2, the total dose is 140 mg/m^2) (Flu/Mel). A total of 200 patients (100 to each arm) will be recruited in this study over a period of two years. Patients will be followed for up to 18 months from allogeneic hematopoietic stem cell transplantation.

Official Title
-----------------
Reduced Intensity Conditioning With Fludarabine and Busulfan Versus Fludarabine and Melphalan Before Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Randomised, Single-Center, Phase III Study

Conditions
-----------------
Acute Myeloid Leukemia, Adult, Myelodysplastic Syndrome(MDS), Allogeneic Hematopoietic Stem Cell Transplantation

Intervention / Treatment
-----------------
* Drug: Fludarabine and Busulfan
* Drug: Fludarabine and Melphalan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age equal or more than 18 years old. Patients diagnosed with AML or MDS. Patients who have related or unrelated bone marrow or peripheral blood donors and plan to undergo hematopoietic stem cell transplantation. Hct-specific complication index score (HCT-CI) more than or equal to 3 or the age of Patients ≥55 years. Sign the informed consent, promise to abide by the research procedures, and cooperate with the implementation of the whole process of the research. Exclusion Criteria: Patients with central nervous system involvement. Patients with HIV seropositive. Patients with other serious diseases and a life expectancy of less than six months Patients with severe mental or psychological disorders. Patients without written informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to one of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: fludarabine and busulfan<br>fludarabine (30 mg/m^2/day, days -6 to days -2, the total dase is 150 mg/m^2) and busulfan (3.2 mg/kg/day, days -3 to days -2, the total dose is 6.4 mg/kg) | Drug: Fludarabine and Busulfan<br>* Fludarabine with total dose of 150 mg/m^2 in combination with Busulfan with total dose of 6.4 mg/kg<br>* Other names: Fludara and Busulfex;|
| Experimental: fludarabine and melphalan<br>fludarabine (30 mg/m^2/day, days -6 to days -2, the total dose is 150 mg/m^2) and melphalan (70 mg/m^2/day, days -3 to days -2, the total dose is 140 mg/m^2) | Drug: Fludarabine and Melphalan<br>* Fludarabine with total dose of 150 mg/m^2 in combination with Melphalan with total dose of 140 mg/m^2<br>* Other names: Busulfex and Fludara;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Survival without relapse or progression of the primary disease. Kaplan-Meier (KM) method was used to estimate median PFS. | 18 months post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is defined as survival duration from the date of randomization to the date of death from any cause. Kaplan-Meier (KM) method was used to estimate median OS | 18 months post-randomization | 
| Non-Relapse Mortality (NRM) | Death not due to recurrence or progression of the primary disease. Recurrence was considered as a competing risk event, and the Gray test was used for statistical analysis. | 18 months post-randomization | 
| Disease Relapse | Relapse of the primary disease. Non-relapse mortality (TRM) was considered as a competing risk event, and Gray's test was used for statistical analysis. | 18 months post-randomization | 
| Percentage of Participants With Severe Acute Graft-versus-host Disease (GVHD) | Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash Rash <25% of body surface area Rash on 25-50% of body surface area Rash on > 50% of body surface area Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)*: 0: <2 mg/dL 2-3 mg/dL 3.01-6 mg/dL 6.01-15.0 mg/dL >15 mg/dL GI stage*: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus * If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4 | Day 100 post-transplant | 
| Percentage of Participants With Chronic GVHD | Chronic GVHD is classified as the occurrence of mild, moderate, or severe chronic GVHD per 2005 NIH Consensus Criteria (Filipovich et al. 2005) | 18 months post-transplant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hematopoietic stem cell transplantation (HSCT), reduced intensity conditioning (RIC), Acute Myeloid Leukemia(AML), Myelodysplastic Syndrome(MDS)