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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Leukemia, Myelocytic, Acute

Intervention / Treatment
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* Drug: Fludarabine and Busulfan
* Drug: Fludarabine and Melphalan
* Drug: Busulfan and Fludarabine
* Drug: Busulfan and Cyclophosphamide
* Drug: Cyclophosphamide and Total Body Irradiation


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reduced Intensity Conditioning (RIC)<br>One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan. | Drug: Fludarabine and Busulfan<br>* (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<br>* Other names: Fludara and Busulfex;Drug: Fludarabine and Melphalan<br>* (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<br>* Other names: Fludara and Alkeran;|
| Active Comparator: Myeloablative Conditioning Regimen (MAC)<br>One of three different regimens in MAC will be administered; busulfan and fludarabine, busulfan and cyclophosphamide, or cyclophosphamide and total body irradiation. | Drug: Busulfan and Fludarabine<br>* (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)<br>* Other names: Busulfex and Fludara;Drug: Busulfan and Cyclophosphamide<br>* (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)<br>* Other names: Busulfex and Cytoxan;Drug: Cyclophosphamide and Total Body Irradiation<br>* (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)<br>* Other names: Cytoxan and radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Survival (OS) | Overall survival is defined as survival of death from any cause. | 18 months post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Relapse-Free Survival (RFS) | Relapse-free survival is defined as survival without relapse of the primary disease. | 18 months post-randomization | 
| Percentage of Participants With Disease Relapse | Disease Relapse is defined as relapse of the primary disease. | 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. | 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. | 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. | 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 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 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. | 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. | 18 months post-transplant | 
| Number of Participants With Primary Graft Failure | Primary graft failure is defined by lack of neutrophil engraftment. | 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. | 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 | 18 months | 
| Infection Type | The number and types of infection events reported are tabulated. | 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. | 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. | 18 months post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myelogenous Leukemia, Myelodysplastic Syndrome