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

Tracking Information

• First Submitted Date: April 20, 2011
• First Posted Date: April 21, 2011
• Results First Submitted Date: March 12, 2018
• Results First Posted Date: May 30, 2018
• Last Update Posted Date: January 4, 2023
• Actual Study Start Date: June 2011
• Actual Primary Completion Date: January 16, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 1, 2018)

Percentage of Participants With Overall Survival (OS) [ Time Frame: 18 months post-randomization ]

Overall survival is defined as survival of death from any cause.

Original Primary Outcome Measures (submitted: April 20, 2011)

Overall Survival [ Time Frame: 18 months ]

The primary objective of the trial is to compare 18 month overall survival rates of the two groups of patients starting from the time of randomization to the RIC or MAC arms.

Current Secondary Outcome Measures (submitted: May 1, 2018)

• 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.
• Percentage of Participants With Disease Relapse [ Time Frame: 18 months post-randomization ]
  Disease Relapse is defined as relapse of the primary disease.
• 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.
• 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.
• 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.
• 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
• 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.
• 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.
• Number of Participants With Primary Graft Failure [ Time Frame: 28 days post-transplant ]
  Primary graft failure is defined by lack of neutrophil engraftment.
• 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.
• 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
• Infection Type [ Time Frame: 18 months post-transplant ]
  The number and types of infection events reported are tabulated.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: April 20, 2011)

• Disease-Free Survival [ Time Frame: time from randomization to relapse, death, initiation of non-protocol AML or MDS therapy, loss to follow up or end of study whichever comes first ]
  Disease-free survival will be at different time points. Patients are considered a failure if they die or suffer from disease relapse.
• Treatment-related Mortality [ Time Frame: 18 months ]
  Treatment-related mortality (TRM) is defined as death occurring in a patient from causes other than disease relapse. Individuals who relapse are censored for the event of TRM.
• Neutrophil and Platelet Engraftment [ Time Frame: 100 days ]
  Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500 µL 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 and 50,000/µL 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.
• Donor Cell Engraftment [ Time Frame: Day 100 and 18 months post transplantation ]
  Donor cell engraftment will be assessed by donor recipient chimerism studies. For this protocol, mixed chimerism will be defined as the presence of donor cells, as a proportion of the total population of less than 95% in the peripheral blood or bone marrow. Full donor chimerism is defined as greater than 95% donor donor cells. Mixed or full donor chimerism will be evidence of donor engraftment. For this protocol, graft rejection is defined as the inability to detect or loss of detection of greater than 5% donor cells as a proportion of the total population.
• Acute GVHD of Grades II-IV and III-IV [ Time Frame: 100 days ]
  The first day of acute GVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade (e.g., if the onset of grade I acute GVHD is on Day 19 post-transplant and onset of grade III is on Day 70 post-transplant, time to grade III is Day 70). This endpoint will be evaluated through 100 days and compared between treatment arms.
• Chronic GVHD [ Time Frame: 18 months ]
  The first day of chronic GVHD onset will be used to calculate cumulative incidence curves. Rates and severity of cGVHD will be compared between treatment arms.
• Incidence of Primary Graft Failure [ Time Frame: 28 days ]
  This is defined by lack of neutrophil engraftment by 28 days. Rates of primary graft failure will be compared between treatment arms.
• Incidence of Secondary Graft Failure [ Time Frame: 18 months ]
  This is defined by initial neutrophil engraftment followed by subsequent decline in neutrophil counts less than 500/µL unresponsive to growth factor therapy. Rates of secondary graft failure will be compared between treatment arms.
• Incidence of Toxicities Greater Than Grade 3 [ Time Frame: 18 months ]
  All toxicities greater than or equal to Grade 3 will be tabulated by grade for each treatment arm, by type of toxicity as well as the peak grade overall. Toxicity frequencies will be described for each time interval as well as cumulative over time.
• Incidence of Infections [ Time Frame: 6, 12, and 18 months post transplant or until death ]
  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.
• Immune Reconstitution [ Time Frame: Baseline, 100 days, 12 months and 18 months post transplant ]
  Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19 and CD56 positive lymphocytes will be done through flow cytometric analysis at baseline , 100 days, 12 months and 18 months post transplantation. Results will be tabulated according to time from transplant.
• Quality of Life [ Time Frame: Prior to transplant, 100 days, 12 and 18 months or until death ]
  HQL will be described and compared between the two treatment arms over time. The self report questionnaires will be completed prior to transplantation and subsequently at 100 days, 12, and 18 months from randomization or until death. HQL include: FACT-BMT, SF-36, MDASI and EQ-5D.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Reduced Intensity Regimen vs Myeloablative Regimen for Myeloid Leukemia or Myelodysplastic Syndrome (BMT CTN 0901)
• 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)
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Leukemia, Myelocytic, Acute

Intervention

• 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
• 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

Study Arms

• Experimental: Reduced Intensity Conditioning (RIC)
  One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan.
  Interventions:

  • Drug: Fludarabine and Busulfan
  • Drug: Fludarabine and Melphalan
• 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.
  Interventions:

  • Drug: Busulfan and Fludarabine
  • Drug: Busulfan and Cyclophosphamide
  • Drug: Cyclophosphamide and Total Body Irradiation

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.
• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 24, 2014): 272
• Original Estimated Enrollment (submitted: April 20, 2011): 356
• Actual Study Completion Date: October 16, 2017
• Actual Primary Completion Date: January 16, 2017 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: 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 )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

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/

• Current Responsible Party: Medical College of Wisconsin
• Original Responsible Party: Shelly Carter, ScD, The EMMES Corporation
• Current Study Sponsor: Medical College of Wisconsin
• Original Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Collaborators

• 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

• PRS Account: Medical College of Wisconsin
• Verification Date: December 2022