The study is designed as a Phase III, multicenter trial comparing outcomes after allogeneic hematopoietic stem cell transplantation (HCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) between patients receiving myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) regimens.
Patients randomized to RIC will receive one of two regimen types: the combination of fludarabine (120-180 mg/m\^2) and busulfan (less than or equal to 8 mg/kg or IV equivalent) (Flu/Bu) or fludarabine (120-180 mg/m\^2) and melphalan (less than 150 mg/m\^2) (Flu/Mel). Patient randomized to MAC will receive one of three regimens: busulfan (16 mg/kg oral or 12.8 mg/kg IV equivalent) and cyclophosphamide (120 mg/kg) (Bu/Cy); or, busulfan (16 mg/kg PO or 12.8 mg/kg IV) and fludarabine (120-180 mg/m\^2) (Bu/Flu); or, cyclophosphamide (120 mg/kg) and total body irradiation (greater than 1200-1420cGy) (CyTBI). A total of 356 patients (178 to each arm) will be accrued on this study over a period of four years. Patients will be followed for up to 18 months from transplantation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
272
(Flu/Bu) * Fludarabine: 30 mg/m\^2/day on Days -6 to -2 (total dose of 150 mg/m\^2) * Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day (total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4
(Flu/Mel) * Fludarabine: 30 mg/m\^2/day on Days -5 to -2 (total dose of 120 mg/m\^2) * Melphalan: 140 mg/m\^2 on Day -2
(Bu/Flu) * Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m\^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m\^2, respectively) on Days -5 to -2 * Fludarabine: 30 mg/m\^2/day on Days -5 to -2: Flu (total dose of 120 mg/m\^2)
Percentage of Participants With Overall Survival (OS)
Overall survival is defined as survival of death from any cause.
Time frame: 18 months post-randomization
Percentage of Participants With Relapse-Free Survival (RFS)
Relapse-free survival is defined as survival without relapse of the primary disease.
Time frame: 18 months post-randomization
Percentage of Participants With Disease Relapse
Disease Relapse is defined as relapse of the primary disease.
Time frame: 18 months post-randomization
Percentage of Participants With Treatment-related Mortality
Treatment-related mortality is defined as death without a previous relapse of the primary disease.
Time frame: 18 months post-randomization
Percentage of Participants With Neutrophil and Platelet Engraftment
Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500x10\^6/liter for 3 consecutive measurements on different days. The first of the 3 days will be designated the day of neutrophil engraftment. Platelet engraftment is defined as achieving platelet counts greater than 20,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions. The first of the 7 days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 7 days.
Time frame: Days 28 and 60 post-transplant
Number of Participants With Donor Cell Engraftment
Donor cell engraftment will be assessed by donor-recipient chimerism assays. Full donor chimerism is defined as the presence of at least 95% donor cells as a proportion of the total population in the peripheral blood or bone marrow. Graft rejection is defined as the presence of no more than 5% donor cells as a proportion of the total population. Mixed chimerism is defined as the presence of between 5% and 95% donor cells. Mixed or full donor chimerism will be considered evidence of donor engraftment.
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(Bu/Cy) * Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m\^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m\^2, respectively) on Days -7 to -4 * Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)
(Cy/TBI) * TBI: 1200-1420 cGy on Days -7 to -4 * Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)
Mayo Clinic Phoenix
Phoenix, Arizona, United States
University of California, San Diego Medical Center
La Jolla, California, United States
University of Florida College of Medicine
Gainesville, Florida, United States
Florida Hospital Cancer Institute
Orlando, Florida, United States
H. Lee Moffitt Cancer Center
Tampa, Florida, United States
Emory University
Atlanta, Georgia, United States
Blood and Marrow Transplant Program at Northside Hospital
Atlanta, Georgia, United States
University of Kansas
Kansas City, Kansas, United States
University of Kentucky
Lexington, Kentucky, United States
DFCI, Brigham & Women's Hospital
Boston, Massachusetts, United States
...and 22 more locations
Time frame: Days 28 and 100 and 18 months post-transplant
Percentage of Participants With 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 1. Rash \<25% of body surface area 2. Rash on 25-50% of body surface area 3. Rash on \> 50% of body surface area 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL 1. 2-3 mg/dL 2. 3.01-6 mg/dL 3. 6.01-15.0 mg/dL 4. \>15 mg/dL GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. 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
Time frame: Day 100 post-transplant
Percentage of Participants With Chronic GVHD
Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification.
Time frame: 18 months post-transplant
Number of Participants With Chronic GVHD Severity
Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.
Time frame: 18 months post-transplant
Number of Participants With Primary Graft Failure
Primary graft failure is defined by lack of neutrophil engraftment.
Time frame: 28 days post-transplant
Number of Participants With Secondary Graft Failure
Secondary graft failure is defined by initial neutrophil engraftment followed by subsequent decline in neutrophil counts to less than 500x10\^6/liter that is unresponsive to growth factor therapy.
Time frame: 18 months post-transplant
Number of Participants With Maximum Grade 3-5 Toxicities
The maximum grade of toxicities reported by participants over the study duration are tabulated. Per the CTCAE criteria, toxicities are graded on a scale of 0-5, with higher numbers indicating greater severity. The categories correspond as follows: 3 - severe; 4 - life-threatening; 5 - fatal
Time frame: 18 months
Infection Type
The number and types of infection events reported are tabulated.
Time frame: 18 months post-transplant
Number of Participants With Infections
The maximum severity of infections reported by participants are tabulated. The number of infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after transplant. The cumulative incidence of severe, life-threatening, or fatal infections will be compared between the two treatment arms at 6, 12, and 18 months from transplant or until death.
Time frame: 18 months post-transplant
Number of Participants With Cause of Death
Primary cause of death was adjudicated using previously described criteria (Copelan et al. 2007). When relapse occurred, it was considered the primary cause of death regardless of other events.
Time frame: 18 months post-randomization