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

• ClinicalTrials.gov Identifier: NCT01339910
• Recruitment Status: Terminated
• First Posted: April 21, 2011
• Results First Posted: May 30, 2018
• Last Update Posted: January 4, 2023
• Sponsor: Medical College of Wisconsin
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Cancer Institute (NCI); Blood and Marrow Transplant Clinical Trials Network; National Marrow Donor Program
• Information provided by (Responsible Party): Medical College of Wisconsin

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Leukemia, Myelocytic, Acute	Drug: Fludarabine and Busulfan; Drug: Fludarabine and Melphalan; Drug: Busulfan and Fludarabine; Drug: Busulfan and Cyclophosphamide; Drug: Cyclophosphamide and Total Body Irradiation	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 272 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: June 2011
• Actual Primary Completion Date: January 16, 2017
• Actual Study Completion Date: October 16, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Reduced Intensity Conditioning (RIC); One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan.	Drug: Fludarabine and Busulfan; (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; Other Name: Fludara and Busulfex; Drug: Fludarabine and Melphalan; (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; Other Name: Fludara and Alkeran
Active Comparator: Myeloablative Conditioning Regimen (MAC); 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; (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); Other Name: Busulfex and Fludara; Drug: Busulfan and Cyclophosphamide; (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); Other Name: Busulfex and Cytoxan; Drug: Cyclophosphamide and Total Body Irradiation; (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); Other Name: Cytoxan and radiation

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Overall Survival (OS) [ Time Frame: 18 months post-randomization ]
   Overall survival is defined as survival of death from any cause.

Secondary Outcome Measures :

1. Percentage of Participants With Relapse-Free Survival (RFS) [ Time Frame: 18 months post-randomization ]
   Relapse-free survival is defined as survival without relapse of the primary disease.
2. Percentage of Participants With Disease Relapse [ Time Frame: 18 months post-randomization ]
   Disease Relapse is defined as relapse of the primary disease.
3. Percentage of Participants With Treatment-related Mortality [ Time Frame: 18 months post-randomization ]
   Treatment-related mortality is defined as death without a previous relapse of the primary disease.
4. Percentage of Participants With Neutrophil and Platelet Engraftment [ Time Frame: 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.
5. Number of Participants With Donor Cell Engraftment [ Time Frame: 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.
6. Percentage of Participants With Acute Graft Versus Host Disease (GVHD) [ Time Frame: 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 4

7. Percentage of Participants With Chronic GVHD [ Time Frame: 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.
8. Number of Participants With Chronic GVHD Severity [ Time Frame: 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.
9. Number of Participants With Primary Graft Failure [ Time Frame: 28 days post-transplant ]
   Primary graft failure is defined by lack of neutrophil engraftment.
10. Number of Participants With Secondary Graft Failure [ Time Frame: 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.
11. Number of Participants With Maximum Grade 3-5 Toxicities [ Time Frame: 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 - fatal

12. Infection Type [ Time Frame: 18 months post-transplant ]
    The number and types of infection events reported are tabulated.
13. Number of Participants With Infections [ Time Frame: 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.

14. Number of Participants With Cause of Death [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic Phoenix

Phoenix, Arizona, United States, 85054

United States, California

University of California, San Diego Medical Center

La Jolla, California, United States, 92093

United States, Florida

University of Florida College of Medicine

Gainesville, Florida, United States, 32610-0277

Florida Hospital Cancer Institute

Orlando, Florida, United States, 32804

H. Lee Moffitt Cancer Center

Tampa, Florida, United States, 33624

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

Blood and Marrow Transplant Program at Northside Hospital

Atlanta, Georgia, United States, 30342

United States, Kansas

University of Kansas

Kansas City, Kansas, United States, 66160

United States, Kentucky

University of Kentucky

Lexington, Kentucky, United States, 40536

United States, Massachusetts

DFCI, Brigham & Women's Hospital

Boston, Massachusetts, United States, 02114

United States, Michigan

Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

Mayo Clinic Rochester

Rochester, Minnesota, United States, 55095

United States, Missouri

Washington University/Barnes Jewish Hospital

Saint Louis, Missouri, United States, 63110

United States, Nebraska

University of Nebraska Medical Center

Omaha, Nebraska, United States, 68198

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

Mount Sinai Medical Center

New York, New York, United States, 10029

University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, North Carolina

University of North Carolina Hospital at Chapel Hill

Chapel Hill, North Carolina, United States, 27599

Duke University Medical Center

Durham, North Carolina, United States, 27705

United States, Ohio

Jewish Hospital BMT Program

Cincinnati, Ohio, United States, 45236

University Hospitals of Cleveland/Case Western

Cleveland, Ohio, United States, 44106-5061

Cleveland Clinic Foundation

Cleveland, Ohio, United States, 44195

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239-3098

United States, Pennsylvania

University of Pennsylvania Cancer Center

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Baylor University Medical Center

Dallas, Texas, United States, 75246

Texas Transplant Institute

San Antonio, Texas, United States, 78229

United States, Utah

Utah BMT/University of Utah Medical School

Salt Lake City, Utah, United States, 84132

United States, Washington

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States, 98109

United States, West Virginia

West Virginia University Hospital

Morgantown, West Virginia, United States, 26506

United States, Wisconsin

University of Wisconsin Hospital & Clinics

Madison, Wisconsin, United States, 53792-5156

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53211

Sponsors and Collaborators

Medical College of Wisconsin

National Heart, Lung, and Blood Institute (NHLBI)

National Cancer Institute (NCI)

Blood and Marrow Transplant Clinical Trials Network

National Marrow Donor Program

Investigators

• Study Director: Mary Horowitz, MD; Center for International Blood and Marrow Transplant Research

  Study Documents (Full-Text)

Documents provided by Medical College of Wisconsin:

Study Protocol and Informed Consent Form  [PDF] March 3, 2014

Statistical Analysis Plan  [PDF] May 11, 2015

More Information

Additional Information:

National Marrow Donor Program 

Publications of Results:

Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. doi: 10.1200/JCO.2016.70.7091. Epub 2017 Feb 13.

Other Publications:

Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009 Jul 30;114(5):937-51. doi: 10.1182/blood-2009-03-209262. Epub 2009 Apr 8.

Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005 Oct 15;106(8):2912-9. doi: 10.1182/blood-2005-05-2004. Epub 2005 Jun 30.

Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.

Copelan E, Casper JT, Carter SL, van Burik JA, Hurd D, Mendizabal AM, Wagner JE, Yanovich S, Kernan NA. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007 Dec;13(12):1469-76. doi: 10.1016/j.bbmt.2007.08.047.

• Responsible Party: Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT01339910
• Other Study ID Numbers: BMTCTN0901; U01HL069294 ( U.S. NIH Grant/Contract ); U01HL069294-05 ( U.S. NIH Grant/Contract ); BMT CTN 0901 ( Other Identifier: Blood and Marrow Transplant Clinical Trial Network ); 5U24CA076518 ( U.S. NIH Grant/Contract )
• First Posted: April 21, 2011
• Results First Posted: May 30, 2018
• Last Update Posted: January 4, 2023
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Findings will be published in a manuscript
• Time Frame: Within 6 months of official study closure at participating sites.
• Access Criteria: Available to the public.
• URL: https://biolincc.nhlbi.nih.gov/home/

Keywords provided by Medical College of Wisconsin:

Acute Myelogenous Leukemia; Myelodysplastic Syndrome

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Preleukemia; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Bone Marrow Diseases; Precancerous Conditions; Vidarabine; Cyclophosphamide; Melphalan; Busulfan; Fludarabine; Fludarabine phosphate; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Anti-Infective Agents