Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01168219
Recruitment Status : Active, not recruiting
First Posted : July 23, 2010
Results First Posted : April 3, 2018
Last Update Posted : July 10, 2018
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and anti-thymocyte globulin followed by donor stem cell transplant and azacitidine works in treating patients with high-risk myelodysplastic syndrome and older patients with acute myeloid leukemia. Giving low doses of chemotherapy, such as busulfan and fludarabine phosphate, before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-vs-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before transplant and giving azacitidine, tacrolimus, and methotrexate after the transplant may stop this from happening.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Adult Acute Megakaryoblastic Leukemia Adult Acute Monoblastic Leukemia Adult Acute Monocytic Leukemia Adult Acute Myeloid Leukemia in Remission Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With Maturation Adult Acute Myeloid Leukemia With Minimal Differentiation Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1 Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A Adult Acute Myeloid Leukemia Without Maturation Adult Acute Myelomonocytic Leukemia Adult Erythroleukemia Adult Pure Erythroid Leukemia Alkylating Agent-Related Acute Myeloid Leukemia de Novo Myelodysplastic Syndrome Myelodysplastic Syndrome Myelodysplastic Syndrome With Excess Blasts Previously Treated Myelodysplastic Syndrome Recurrent Adult Acute Myeloid Leukemia Secondary Myelodysplastic Syndrome Untreated Adult Acute Myeloid Leukemia Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Biological: Anti-Thymocyte Globulin Drug: Azacitidine Drug: Busulfan Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Drug: Methotrexate Other: Pharmacological Study Drug: Tacrolimus Phase 2

Detailed Description:


I. To determine if this treatment can improve 2-year progression-free survival (PFS) in patients with high risk myelodysplastic syndrome (MDS) and in patients with acute myeloid leukemia (AML) >= 60 yrs age


I. To determine the safety and feasibility of using post-transplantation azacitidine.

II. To determine the ability to use pharmacokinetic-directed busulfan to achieve area under the curve (AUC) within 20% of target AUC in > 80% of patients.

III. To determine the rate of grade II-IV and III-IV acute graft-vs-host disease (GVHD).

IV. To determine the incidence of extensive chronic GVHD. V. To determine treatment-related mortality at 100 days and at 1 year. VI. To determine 5-year overall survival.


REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).

CONSOLIDATION: Beginning on day 42, patients receive azacitidine subcutaneously (SC) or IV on days 1-5.

Treatment repeats every 4 weeks for 6 courses. Blood and bone marrow samples may be collected periodically for correlative and pharmacokinetic studies.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 68 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of the Addition of Azacitidine (NSC#102816) to Reduced-Intensity Conditioning Allogeneic Transplantation for Myelodysplasia (MDS) and Older Patients With AML
Study Start Date : July 15, 2010
Actual Primary Completion Date : November 15, 2015
Estimated Study Completion Date : November 15, 2018

Arm Intervention/treatment
Experimental: Treatment (chemotherapy and transplant)

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).

CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplantation
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • allogeneic stem cell transplantation
  • HSC
  • HSCT

Biological: Anti-Thymocyte Globulin
Given IV
Other Names:
  • antithymocyte globulin
  • Antithymocyte Serum
  • ATG
  • ATS
  • Thymoglobulin

Drug: Azacitidine
Given SC or IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Drug: Busulfan
Given IV
Other Names:
  • 1, 4-Bis[methanesulfonoxy]butane
  • BUS
  • Bussulfam
  • Busulfanum
  • Busulfex
  • Busulphan
  • CB 2041
  • CB-2041
  • Glyzophrol
  • GT 41
  • GT-41
  • Joacamine
  • Methanesulfonic Acid Tetramethylene Ester
  • Methanesulfonic acid, tetramethylene ester
  • Mielucin
  • Misulban
  • Misulfan
  • Mitosan
  • Myeleukon
  • Myeloleukon
  • Myelosan
  • Mylecytan
  • Myleran
  • Sulfabutin
  • Tetramethylene Bis(methanesulfonate)
  • Tetramethylene bis[methanesulfonate]
  • WR-19508

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Methotrexate
Given IV
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • CL 14377
  • CL-14377
  • Emtexate
  • Emthexat
  • Emthexate
  • Farmitrexat
  • Fauldexato
  • Folex
  • Folex PFS
  • Lantarel
  • Ledertrexate
  • Lumexon
  • Maxtrex
  • Medsatrexate
  • Metex
  • Methoblastin
  • Methotrexate LPF
  • Methotrexate Methylaminopterin
  • Methotrexatum
  • Metotrexato
  • Metrotex
  • Mexate
  • Mexate-AQ
  • MTX
  • Novatrex
  • Rheumatrex
  • Texate
  • Tremetex
  • Trexeron
  • Trixilem
  • WR-19039

Other: Pharmacological Study
Correlative studies

Drug: Tacrolimus
Given PO or IV
Other Names:
  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic

Primary Outcome Measures :
  1. Progression-free Survival [ Time Frame: At 2 years ]

    Number of patients who were alive and progression-free at 2 years. >


    AML progression is defined as:

    • Reappearance of leukemia blast cells in peripheral blood and > 5% blasts in marrow
    • If no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow >= 1 week later with > 5% blasts
    • Development of extramedullary leukemia

    MDS progression is defined as

    • For patients with <5% bone marrow blasts: ≥50% increase in blasts to >5% blasts
    • For patients with 5-10% bone marrow blasts: ≥50% increase to >10% blasts
    • Any of the following: Reappearance of prior documented characteristic cytogenetic abnormality or refractory cytopenias with unequivocal evidence of dysplasia on bone marrow biopsy/aspirate

Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Up to 5 years ]
    Estimated using the Kaplan-Meier product limit estimator.

  2. Treatment Related Mortality (TRM) [ Time Frame: Up to 6 months post-treatment ]
    TRM is defined as death within the first six months after transplant not secondary to relapse.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Meets one of the following sets of criteria:

    • Myelodysplastic syndromes (MDS):

      • Disease with high-risk features (found either at diagnosis or before initiation of cytotoxic therapy), defined as one of the following:

        • International prognostic scoring system (IPSS) risk >= intermediate-2
        • Refractory anemia with excess blasts by French-American-British (FAB) classification
        • High-risk cytogenetics (either complex or -7)
      • Less than 10% bone marrow blasts as determined by bone marrow biopsy within the past 4 weeks (reduction in marrow blast percentage may be achieved with chemotherapy or other therapy)
      • Less than 75 years old
    • Acute myeloid leukemia (AML):

      • No FAB M3
      • No acute leukemia following blast transformation of prior chronic myelogenous leukemia or other myeloproliferative disease
      • Patients with preceding MDS or treatment-related AML are eligible
      • Prior central nervous system (CNS) involvement is allowed provided the disease is in remission at transplantation
      • Morphologic complete remission (leukemia-free state) is defined as meeting all of the following criteria:

        • Bone marrow blasts < 5% (as determined by bone marrow within the past 4 weeks), but without requirement for normal peripheral blood counts
        • No extramedullary leukemia
        • No blasts in peripheral blood
      • Achieved complete remission (CR) after no more than 2 courses of induction chemotherapy

        • Patients treated with azacitidine or decitabine who achieve a leukemia-free state are eligible (may have required up to 4 courses of therapy to reach this status)
      • Age 60 to 74 years
  • Donors must meet the following criteria:

    • One of the following:

      • HLA-identical sibling (6/6) by serologic typing for class (A, B) and low-resolution molecular typing for class II (DRB1)
      • Matched unrelated donor (8/8) by high-resolution molecular typing at HLA-A, -B, -C, and DRB1
    • No syngeneic donors
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Calculated creatinine clearance ≥ 40 mL/min
  • Bilirubin < 2 mg/dL OR bilirubin 2-3 mg/dL provided direct bilirubin is normal
  • Aspartate aminotransferase (AST) < 3 times upper limit of normal
  • Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease
  • Left ventricle ejection fraction (LVEF) >= 30% by echocardiogram (ECHO) or multigated acquisition (MUGA)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No uncontrolled diabetes mellitus or active serious infections
  • No known hypersensitivity to E. coli-derived products, azacitidine, or mannitol
  • No human immunodeficiency virus (HIV) infection or active hepatitis B or C
  • Prior azacitidine or decitabine allowed

    • No patients who progressed from MDS to AML during treatment with azacitidine or decitabine
  • At least 4 weeks since prior deoxyribonucleic acid (DNA)-hypomethylating chemotherapy, radiotherapy, and/or surgery
  • No more than 2 courses of consolidation therapy before transplantation (for patients with AML)

    • Any consolidation regimen that does not require transplantation can be used
    • No more than 6 months from documentation of morphologic CR to transplantation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01168219

United States, Delaware
Beebe Medical Center
Lewes, Delaware, United States, 19958
Christiana Care Health System-Christiana Hospital
Newark, Delaware, United States, 19718
United States, Florida
Florida Hospital Orlando
Orlando, Florida, United States, 32803
United States, Iowa
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, United States, 52242
United States, Maryland
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, United States, 21201
Union Hospital of Cecil County
Elkton, Maryland, United States, 21921
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New Hampshire
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, New Jersey
Cooper Hospital University Medical Center
Camden, New Jersey, United States, 08103
United States, New York
Northwell Health NCORP
Lake Success, New York, United States, 11042
Mount Sinai Hospital
New York, New York, United States, 10029
Weill Medical College of Cornell University
New York, New York, United States, 10065
United States, North Carolina
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States, 27599
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Ravi Vij Alliance for Clinical Trials in Oncology

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01168219     History of Changes
Other Study ID Numbers: NCI-2011-02053
NCI-2011-02053 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CALGB 100801 ( Other Identifier: Alliance for Clinical Trials in Oncology )
CALGB-100801 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
U10CA031946 ( U.S. NIH Grant/Contract )
First Posted: July 23, 2010    Key Record Dates
Results First Posted: April 3, 2018
Last Update Posted: July 10, 2018
Last Verified: June 2018

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Leukemia, Monocytic, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Erythroblastic, Acute
Anemia, Refractory, with Excess of Blasts
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myeloproliferative Disorders
Anemia, Refractory
Fludarabine phosphate
Antilymphocyte Serum