Reduced Intensity Regimen vs Myeloablative Regimen for Myeloid Leukemia or Myelodysplastic Syndrome (BMT CTN 0901)
- Conditions
- Leukemia, Myelocytic, Acute
- Interventions
- Registration Number
- NCT01339910
- Lead Sponsor
- Medical College of Wisconsin
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 272
- Age equal or less than 65 years old and equal to or greater than 18 years old.
- Patients with the diagnosis of MDS or AML with fewer than 5% myeloblasts in the bone marrow and no leukemic myeloblasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen enrollment.
- For patients receiving treatment of their MDS or AML prior to transplantation: a)Interval between the start of the most recent cycle of conventional cytotoxic chemotherapy and enrollment must be at least 30 days; b)Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and enrollment must be at least 10 days.
- Patients must have a related or unrelated bone marrow or peripheral blood donor who is human leukocyte antigen (HLA)-matched at 7 or 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing.
- HCT-Specific Comorbidity Index Score (HCT-CI) less than or equal to 4.
- Organ function: a) Cardiac function: Ejection fraction greater than or equal to 40%; b) Hepatic function: total bilirubin less than or equal to 2 times the upper limit of normal and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 times the upper limit of normal.; c)Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) greater than or equal to 40% and forced expiratory volume in one second (FEV1) greater than or equal to 50% (corrected for hemoglobin).
- Creatinine clearance greater than or equal to 50mL/min based on the Cockcroft-Gault formula.
- Signed informed consent.
- Prior allograft or prior autograft.
- Symptomatic coronary artery disease.
- Leukemia involvement in the central nervous system (CNS) within 4 weeks of enrollment for patients with a history of prior CNS leukemia involvement (i.e., leukemic blasts previously detected in the cerebral spinal fluid).
- Karnofsky Performance Score less than 70.
- Patients receiving supplemental oxygen.
- Planned use of donor lymphocyte infusion (DLI) therapy.
- Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms).
- Patients seropositive for the human immunodeficiency virus (HIV).
- Patients with prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent greater than 5 years previously. Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
- Females who are pregnant or breastfeeding.
- Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Reduced Intensity Conditioning (RIC) Fludarabine and Busulfan One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan. Myeloablative Conditioning Regimen (MAC) Busulfan and Fludarabine One of three different regimens in MAC will be administered; busulfan and fludarabine, busulfan and cyclophosphamide, or cyclophosphamide and total body irradiation. Myeloablative Conditioning Regimen (MAC) Busulfan and Cyclophosphamide One of three different regimens in MAC will be administered; busulfan and fludarabine, busulfan and cyclophosphamide, or cyclophosphamide and total body irradiation. Reduced Intensity Conditioning (RIC) Fludarabine and Melphalan One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan. Myeloablative Conditioning Regimen (MAC) Cyclophosphamide and Total Body Irradiation One of three different regimens in MAC will be administered; busulfan and fludarabine, busulfan and cyclophosphamide, or cyclophosphamide and total body irradiation.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Overall Survival (OS) 18 months post-randomization Overall survival is defined as survival of death from any cause.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Disease Relapse 18 months post-randomization Disease Relapse is defined as relapse of the primary disease.
Percentage of Participants With Relapse-Free Survival (RFS) 18 months post-randomization Relapse-free survival is defined as survival without relapse of the primary disease.
Percentage of Participants With Treatment-related Mortality 18 months post-randomization Treatment-related mortality is defined as death without a previous relapse of the primary disease.
Number of Participants With Donor Cell Engraftment Days 28 and 100 and 18 months post-transplant 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.
Percentage of Participants With Acute Graft Versus Host Disease (GVHD) Day 100 post-transplant 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 4Percentage of Participants With Neutrophil and Platelet Engraftment Days 28 and 60 post-transplant 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.
Percentage of Participants With Chronic GVHD 18 months post-transplant 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.
Number of Participants With Chronic GVHD Severity 18 months post-transplant Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.
Number of Participants With Primary Graft Failure 28 days post-transplant Primary graft failure is defined by lack of neutrophil engraftment.
Number of Participants With Secondary Graft Failure 18 months post-transplant 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.
Number of Participants With Maximum Grade 3-5 Toxicities 18 months 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 - fatalInfection Type 18 months post-transplant The number and types of infection events reported are tabulated.
Number of Participants With Infections 18 months post-transplant 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.Number of Participants With Cause of Death 18 months post-randomization 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.
Trial Locations
- Locations (32)
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Blood and Marrow Transplant Program at Northside Hospital
🇺🇸Atlanta, Georgia, United States
DFCI, Brigham & Women's Hospital
🇺🇸Boston, Massachusetts, United States
University of California, San Diego Medical Center
🇺🇸La Jolla, California, United States
University of Kansas
🇺🇸Kansas City, Kansas, United States
West Virginia University Hospital
🇺🇸Morgantown, West Virginia, United States
Mayo Clinic Phoenix
🇺🇸Phoenix, Arizona, 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
Mount Sinai Medical Center
🇺🇸New York, New York, United States
Washington University/Barnes Jewish Hospital
🇺🇸Saint Louis, Missouri, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
University Hospitals of Cleveland/Case Western
🇺🇸Cleveland, Ohio, United States
Baylor University Medical Center
🇺🇸Dallas, Texas, United States
University of Wisconsin Hospital & Clinics
🇺🇸Madison, Wisconsin, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
University of Pennsylvania Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Fred Hutchinson Cancer Research Center
🇺🇸Seattle, Washington, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
University of North Carolina Hospital at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Jewish Hospital BMT Program
🇺🇸Cincinnati, Ohio, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Texas Transplant Institute
🇺🇸San Antonio, Texas, United States
Utah BMT/University of Utah Medical School
🇺🇸Salt Lake City, Utah, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States