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

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ClinicalTrials.gov Identifier: NCT01339910
Recruitment Status : Terminated (Accrual terminated as recommended by the data and safety monitoring board.)
First Posted : April 21, 2011
Results First Posted : May 30, 2018
Last Update Posted : May 30, 2018
Sponsor:
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 Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition: Leukemia, Myelocytic, Acute
Interventions: Drug: Fludarabine and Busulfan
Drug: Fludarabine and Melphalan
Drug: Busulfan and Fludarabine
Drug: Busulfan and Cyclophosphamide
Drug: Cyclophosphamide and Total Body Irradiation

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were enrolled between June 2011 and April 2014 from 32 transplant centers

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
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.

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)

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)

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)
Reduced Intensity Conditioning (RIC)

One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan.

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

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

Participant Flow:   Overall Study
    Myeloablative Conditioning Regimen (MAC)   Reduced Intensity Conditioning (RIC)
STARTED   135   137 
COMPLETED   132   133 
NOT COMPLETED   3   4 
Withdrawal by Subject                1                0 
Physician Decision                1                0 
Disease relapse                1                4 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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.

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)

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)

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)
Reduced Intensity Conditioning (RIC)

One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan.

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

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
Total Total of all reporting groups

Baseline Measures
   Myeloablative Conditioning Regimen (MAC)   Reduced Intensity Conditioning (RIC)   Total 
Overall Participants Analyzed 
[Units: Participants]
 135   137   272 
Age 
[Units: Years]
Median (Full Range)
     
Participants Analyzed   135   137   272 
   54.8 
 (21.9 to 66.0) 
 54.8 
 (21.9 to 65.9) 
 54.8 
 (21.9 to 66.0) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Participants Analyzed   135   137   272 
Female      59  43.7%      70  51.1%      129  47.4% 
Male      76  56.3%      67  48.9%      143  52.6% 
Primary Disease 
[Units: Participants]
Count of Participants
     
Participants Analyzed   135   137   272 
Acute Myeloid Leukemia (AML)      108  80.0%      110  80.3%      218  80.1% 
Myelodysplastic Syndrome (MDS)      27  20.0%      27  19.7%      54  19.9% 
MDS WHO Classification [1] [2] 
[Units: Participants]
Count of Participants
     
Participants Analyzed   27   27   54 
RA/RARS/RCMD/RCMD-RS/Del-5q/MDS-U      16  59.3%      17  63.0%      33  61.1% 
RAEB-1      5  18.5%      5  18.5%      10  18.5% 
RAEB-2      6  22.2%      5  18.5%      11  20.4% 
[1]

Participants with MDS are categorized per 2008 WHO classification (Vardiman et al. 2009). Major features of each class are given below:

Refractory Anemia (RA): Anemia without marrow blasts or sideroblasts; Refractory Anemia with Ringed Sideroblasts (RARS): > 15% marrow sideroblasts; Refractory Cytopenias with Multilineage Dysplasia (RCMD): Dysplasia in >10% marrow cells; Isolated del(5q) (Del-5q): Isolated del(5q) in marrow; Unclassified (MDS-U) Refractory Anemia with Excess Blasts-1 (RAEB-1): 5-9% marrow blasts; Refractory Anemia with Excess Blasts-2 (RAEB-2): 10-19% marrow blasts;

[2] Participants with MDS
AML WHO Classification [1] [2] 
[Units: Participants]
Count of Participants
     
Participants Analyzed   108   110   218 
AML with recurrent genetic abnormalities      12  11.1%      20  18.2%      32  14.7% 
AML with multilineage dysplasia      8   7.4%      12  10.9%      20   9.2% 
AML and MDS, therapy related      2   1.9%      3   2.7%      5   2.3% 
AML, not otherwise specified      86  79.6%      75  68.2%      161  73.9% 
[1]

Participants with AML are categorized per 2008 WHO classification (Vardiman et al. 2009). Major features of each class are given below:

AML with recurrent genetic abnormalities: Presence of specific genetic abnormalities known to be prognostic; AML with multilineage dysplasia: > 50% of cells in at least 2 myeloid lineages are dysplastic; AML and MDS, therapy related: development of myeloid neoplasms in response to therapy that is diagnosed as either AML or MDS; AML not otherwise specified: AML that does not satisfy criteria for other classes

[2] Participants with AML
Disease Duration 
[Units: Months]
Median (Full Range)
     
Participants Analyzed   135   137   272 
   6 
 (2 to 86) 
 6 
 (2 to 130) 
 6 
 (2 to 130) 
Disease Risk Status [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed   135   137   272 
Standard      74  54.8%      71  51.8%      145  53.3% 
High      54  40.0%      61  44.5%      115  42.3% 
Unknown      7   5.2%      5   3.6%      12   4.4% 
[1] Disease risk status is defined according to cytogenetic and molecular abnormalities identified prior to transplantation and classified as standard or high risk. Among AML participants, high-risk disease is defined as the presence of cytogenetic abnormalities at 3q, 9q, 11q, 20q, 21q, or 17p; the presence of del(5q)/-5, -7/del(7q), t(6;9), or t(9;22); and/or FLT-3 internal tandem duplication mutation. Among MDS participants, high-risk disease is defined as the presence of > 10% blasts in bone marrow.
HCT-CI [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed   135   137   272 
    46  34.1%      40  29.2%      86  31.6% 
1-2      45  33.3%      52  38.0%      97  35.7% 
3 or more      42  31.1%      44  32.1%      86  31.6% 
Unknown      2   1.5%      1   0.7%      3   1.1% 
[1] The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (Sorror et al., 2005) summarizes relevant comorbidities present in participants prior to allogeneic transplant. Each comorbidity reported at the time of transplant is given a score of 0, 1, 2, or 3 and the overall HCT-CI score is the sum of the comorbidity scores, ranging from 0 - 26.
Conditioning Regimen [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed   135   137   272 
Flu/Bu4      87  64.4%      0   0.0%      87  32.0% 
Bu/Cy      40  29.6%      0   0.0%      40  14.7% 
Cy/TBI      8   5.9%      0   0.0%      8   2.9% 
Flu/Mel      0   0.0%      27  19.7%      27   9.9% 
Flu/Bu2      0   0.0%      110  80.3%      110  40.4% 
[1]

Flu/Bu4: busulfan (16 mg/kg oral or 12.8 mg/kg IV) and fludarabine (120-180 mg/m2); Bu/Cy: busulfan (16 mg/kg oral or 12.8 mg/kg IV) and cyclophosphamide (120 mg/kg) ; Cy/TBI: cyclophosphamide (120 mg/kg) and total body irradiation (1200-1420 cGy); Flu/Mel: fludarabine (120-180 mg/m2) and melphalan (≤ 150 mg/m2); Flu/Bu2: fludarabine (120-180 mg/m2) with busulfan (≤ 8 mg/kg oral or 6.4 mg/kg IV);

Flu/Bu4, Bu/Cy, and Cy/TBI are myeloablative conditioning regimens, while Flu/Mel and Flu/Bu2 are reduced intensity conditioning regimens.

GVHD Prophylaxis [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed   135   137   272 
Tacrolimus / Methotrexate      110  81.5%      112  81.8%      222  81.6% 
Cyclosporine / Methotrexate      3   2.2%      3   2.2%      6   2.2% 
TAC / Mycophenolate mofetil      8   5.9%      5   3.6%      13   4.8% 
Cyclosporine / Mycophenolate mofetil      1   0.7%      0   0.0%      1   0.4% 
Sirolimus / Tacrolimus      10   7.4%      12   8.8%      22   8.1% 
Other      3   2.2%      5   3.6%      8   2.9% 
[1] Prophylaxis for Graft Versus Host Disease
ATG Use [1] 
[Units: Participants]
Count of Participants
     
Participants Analyzed   135   137   272 
Yes      18  13.3%      22  16.1%      40  14.7% 
No      117  86.7%      115  83.9%      232  85.3% 
[1] Use of Anti-Thymocyte Globulin
Donor Type 
[Units: Participants]
Count of Participants
     
Participants Analyzed   135   137   272 
Matched Related      57  42.2%      58  42.3%      115  42.3% 
Mismatched Related      2   1.5%      5   3.6%      7   2.6% 
Matched Unrelated      66  48.9%      58  42.3%      124  45.6% 
Mismatched Unrelated      10   7.4%      16  11.7%      26   9.6% 
Donor Source 
[Units: Participants]
Count of Participants
     
Participants Analyzed   135   137   272 
Peripheral Blood      127  94.1%      123  89.8%      250  91.9% 
Bone Marrow      8   5.9%      14  10.2%      22   8.1% 


  Outcome Measures

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

2.  Secondary:   Percentage of Participants With Relapse-Free Survival (RFS)   [ Time Frame: 18 months post-randomization ]

3.  Secondary:   Percentage of Participants With Disease Relapse   [ Time Frame: 18 months post-randomization ]

4.  Secondary:   Percentage of Participants With Treatment-related Mortality   [ Time Frame: 18 months post-randomization ]

5.  Secondary:   Percentage of Participants With Neutrophil and Platelet Engraftment   [ Time Frame: Days 28 and 60 post-transplant ]

6.  Secondary:   Number of Participants With Donor Cell Engraftment   [ Time Frame: Days 28 and 100 and 18 months post-transplant ]

7.  Secondary:   Percentage of Participants With Acute Graft Versus Host Disease (GVHD)   [ Time Frame: Day 100 post-transplant ]

8.  Secondary:   Percentage of Participants With Chronic GVHD   [ Time Frame: 18 months post-transplant ]

9.  Secondary:   Number of Participants With Chronic GVHD Severity   [ Time Frame: 18 months post-transplant ]

10.  Secondary:   Number of Participants With Primary Graft Failure   [ Time Frame: 28 days post-transplant ]

11.  Secondary:   Number of Participants With Secondary Graft Failure   [ Time Frame: 18 months post-transplant ]

12.  Secondary:   Number of Participants With Maximum Grade 3-5 Toxicities   [ Time Frame: 18 months ]

13.  Secondary:   Infection Type   [ Time Frame: 18 months post-transplant ]

14.  Secondary:   Number of Participants With Infections   [ Time Frame: 18 months post-transplant ]

15.  Secondary:   Number of Participants With Cause of Death   [ Time Frame: 18 months post-randomization ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Adam Mendizabal, PhD
Organization: The Emmes Corporation
phone: 301-251-1161
e-mail: amendizabal@emmes.com


Publications of Results:
Other Publications:

Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT01339910     History of Changes
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 Submitted: April 20, 2011
First Posted: April 21, 2011
Results First Submitted: March 12, 2018
Results First Posted: May 30, 2018
Last Update Posted: May 30, 2018