Reduced Intensity Regimen vs Myeloablative Regimen for Myeloid Leukemia or Myelodysplastic Syndrome (BMT CTN 0901)

A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation Comparing Regimen Intensity in Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia (BMT CTN #0901)

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.

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.