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.

Study Overview

• Status: Terminated
• Conditions: Leukemia, Myelocytic, Acute
• Intervention / Treatment: Drug: Fludarabine and Busulfan; Drug: Fludarabine and Melphalan; Drug: Busulfan and Fludarabine; Drug: Busulfan and Cyclophosphamide; Drug: Cyclophosphamide and Total Body Irradiation

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 Type: Interventional
• Enrollment (Actual): 272
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Phoenix
  • California
    • La Jolla, California, United States, 92093
      • University of California, San Diego Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610-0277
      • University of Florida College of Medicine
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute
    • Tampa, Florida, United States, 33624
      • H. Lee Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Atlanta, Georgia, United States, 30342
      • Blood and Marrow Transplant Program at Northside Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • DFCI, Brigham & Women's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Rochester, Minnesota, United States, 55095
      • Mayo Clinic Rochester
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University/Barnes Jewish Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospital at Chapel Hill
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • Jewish Hospital BMT Program
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106-5061
      • University Hospitals of Cleveland/Case Western
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Cancer Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Utah BMT/University of Utah Medical School
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-5156
      • University of Wisconsin Hospital & Clinics
    • Milwaukee, Wisconsin, United States, 53211
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Cytoxan and radiation

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); National Marrow Donor Program; Blood and Marrow Transplant Clinical Trials Network

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• National Marrow Donor Program
• Blood and Marrow Transplant Clinical Trials Network

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2011
• Primary Completion (Actual): January 16, 2017
• Study Completion (Actual): October 16, 2017

Study Registration Dates

• First Submitted: April 20, 2011
• First Submitted That Met QC Criteria: April 20, 2011
• First Posted (Estimate): April 21, 2011

Study Record Updates

• Last Update Posted (Actual): January 4, 2023
• Last Update Submitted That Met QC Criteria: December 6, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Myelodysplastic Syndrome; Acute Myelogenous Leukemia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Melphalan; Fludarabine; Fludarabine phosphate; Busulfan; Vidarabine
• Other Study ID Numbers: BMTCTN0901; U01HL069294 (U.S. NIH Grant/Contract); 5U24CA076518 (U.S. NIH Grant/Contract); U01HL069294-05 (NIH); BMT CTN 0901 (Other Identifier: Blood and Marrow Transplant Clinical Trial Network)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Findings will be published in a manuscript
• IPD Sharing Time Frame: Within 6 months of official study closure at participating sites.
• IPD Sharing Access Criteria: Available to the public.