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Busulfan, Fludarabine, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Stem Cell Transplant for Hematologic Cancer (Bu Flu TBI)

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: NCT00245037
Recruitment Status : Completed
First Posted : October 27, 2005
Results First Posted : July 2, 2017
Last Update Posted : September 27, 2017
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Richard Maziarz, OHSU Knight Cancer Institute

Brief Summary:

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor peripheral blood 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 system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects of giving busulfan and fludarabine together with total-body irradiation and to see how well they work in treating patients who are undergoing a donor stem cell transplant for hematologic cancer.

Condition or disease Intervention/treatment Phase
Chronic Myeloproliferative Disorders Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Neoplasms Precancerous Condition Biological: therapeutic allogeneic lymphocytes Drug: busulfan Drug: cyclosporine Drug: fludarabine phosphate Drug: mycophenolate mofetil Procedure: peripheral blood stem cell transplantation Radiation: Total Body Irradiation (TBI) Drug: Granulocyte colony-stimulating factor (G-CSF) Drug: Phenytoin Drug: Methotrexate Phase 1 Phase 2

Detailed Description:



  • To assess safety and toxicity of the addition of busulfan added to an established fludarabine and low-dose total-body irradiation (TBI) conditioning regimen for non-myeloablative allogeneic transplantation in patients with hematologic malignancies. (Phase I)
  • To assess the non-relapse mortality 1-year after conditioning with busulfan and fludarabine/TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease. (Phase II)


  • To assess overall survival 1-year survival. (Phase II)
  • To assess the incidence of graft rejection. (Phase II)
  • To assess the incidence of grade II-IV acute graft-vs-host disease (GVHD) and chronic extensive GVHD. (Phase II)
  • To assess rates of disease progression and/or relapse-related mortality. (Phase II)
  • To determine non-hematologic grade III-IV organ specific toxicity. (Phase II)


  • Nonmyeloablative-conditioning regimen: Patients receive busulfan IV on day -5 and fludarabine IV over 30 minutes on days -4 to -2. Patients undergo total body irradiation on day 0.
  • Allogeneic peripheral blood stem cell transplantation (PBSC): Patients undergo donor PBSC infusion on day 0.
  • Graft-versus-host disease prophylaxis: Patients receive oral cyclosporine twice daily on days -3 to 56 followed by a taper to day 180. Patients with a related stem cell donor receive oral mycophenolate mofetil twice daily on days 0-28. Patients with an unrelated stem cell donor receive oral mycophenolate mofetil 3 times daily on days 0-28 followed by a taper twice daily to day 56. Patients with evidence of relapse or persistent disease may also receive up to 3 donor lymphocyte infusions.

PROJECTED ACCRUAL: A total of 225 patients will be accrued for this study; 25 patients accrued into the Phase I and 200 patients into Phase II.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 147 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplant for the Treatment of Patients With Hematologic Malignancies Using Busulfan, Fludarabine and Total Body Irradiation
Study Start Date : June 2005
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

Arm Intervention/treatment
Experimental: Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
Biological: therapeutic allogeneic lymphocytes
A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species.

Drug: busulfan

Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative.

IV busulfan is available and diluted and administered per package insert guidelines.

Drug: cyclosporine

Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including Interleukin 2 (IL-2) and Interleukin 4 (IL-4).

- Starting on day -3, Cyclosporine (CSP) is given at a dose of 4.0 mg/kg p.o. b.i.d.

Drug: fludarabine phosphate

Fludarabine's active metabolite 2-fluoro-ara-A is an antimetabolite that inhibits DNA primase, DNA polymerase alpha and ribonucleotide nuclease.

  • Dosing: Days -4, -3 and -2: Fludarabine 30 mg/m2/day IV. Total dose equals 90 mg/m2.
  • Monitoring: Fludarabine level is not monitored.
  • Dose Adjustments: There are no provisions for fludarabine dose adjustments.

Drug: mycophenolate mofetil

Mycophenolate mofetil (MMF) is the morpholinyl ethyl ester of mycophenolic acid (MPA) and reversibly inhibits inosine monophosphate dehydrogenase, particularly the type II isoform that is more prominent in activated lymphocytes. As a result of the inhibition of de novo purine synthesis, proliferation of B- and T-lymphocytes is blocked and antibody production is inhibited.

  • Related Donors: MMF will be given daily at 15mg/kg q 12 hrs until day +28, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).
  • Unrelated Donors: MMF will be given daily at 15mg/kg q 8 hrs until day +28, then given daily at 15mg/kg q 12 hours until day +56, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).

Procedure: peripheral blood stem cell transplantation

Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. There are three types of transplants:

  • In autologous transplants, patients receive their own stem cells.
  • In syngeneic transplants, patients receive stem cells from their identical twin.
  • In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.

Radiation: Total Body Irradiation (TBI)

TBI is a form of radiotherapy used primarily as part of the preparative regimen for haematopoietic stem cell (or bone marrow) transplantation. As the name implies, TBI involves irradiation of the entire body, though in modern practice the lungs are often partially shielded to lower the risk of radiation-induced lung injury.

  • Toxicities: At the dosage used, side effects are not expected. Nevertheless, there may be fever, alopecia, parotitis, diarrhea, reversible skin pigmentation, mucositis and late effects including cataract formation, pulmonary damage, carcinogenesis, and sterilization.
  • Dosing: TBI will be given in one 200 cGy fraction from linear accelerator at a rate of 15-19 cGy/min.

Drug: Granulocyte colony-stimulating factor (G-CSF)

Granulocyte colony-stimulating factor (G-CSF or GCSF) is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 (CSF 3).

It is a glycoprotein, growth factor and cytokine produced by a number of different tissues to stimulate the bone marrow to produce granulocytes and stem cells. G-CSF then stimulates the bone marrow to release them into the blood.

  • Toxicities: At the dosage used, the most common side effect will be medullary bone pain.
  • Dosing: 5 mcg/kg/day given per institutional standards (on approximately days 10-15 or not at all).

Drug: Phenytoin
This drug is used to prevent seizures while on chemotherapy.

Drug: Methotrexate
Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments.

Primary Outcome Measures :
  1. Regimen-Related Toxicities [ Time Frame: 5 years post-transplant ]
    Non-hematologic toxicities and adverse experiences ≥ Grade 3 occurrences measured up to day +100 using the NCI Common Toxicity Criteria for Adverse Events v3.0 (CTCAE). Infections and GVHD will be assessed up to 5 years post transplant. The following data represents the number of regimen-related, grade 3 and 4 toxicities that occurred in each category.

  2. Non-relapse Mortality [ Time Frame: Two years post-transplant ]
    Percent of subjects with non-relapse mortality two years after conditioning with busulfan with fludarabine/200 cGy TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease.

Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: Years 1, 2, 3 and 5 ]
    The percentage of overall patient survival (out of 147 participants) for Years 1, 2, 3 and 5.

  2. Progression-Free Survival [ Time Frame: Years 1, 2, 3, and 5 ]

    The percentage of progression-free patients (out of 147 participants) at Years 1, 2, 3, and 5.

    Definition of Disease Progression:

    MM/Plasma Cell: Increasing bone pain or increase in serum/urine monoclonal protein by 25%.

    CLL/NHL/HD: New sites of lymphadenopathy; ≥ 25% increase in lymph node size; Blood or bone marrow involvement with clonal B-cells; Increase of ≥ 25% bone marrow involvement; ≥ 25% increase in blood involvement with clonal B-cells.

    AML/ALL: Any incidence of relapse (>5% blasts) by evaluation of the bone marrow aspirate.

    CML: Inability to control platelet or granulocyte counts; Increase in baseline number of metaphases demonstrating the Ph+ chromosome by >25%; Any other new cytogenetic abnormality; Transformation to accelerated phase or blast crisis.

    MDS/MPD: Any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of new blasts (>5%) or worsening cytopenia or cytogenetic evidence of recurrence.

  3. Relapse Mortality [ Time Frame: Years 1 and 2 ]
    The percentage of patients (out of 147 participants) who relapsed at Years 1 and 2. Relapse is defined as the presence of >5% blasts by morphology on a post-transplant bone marrow aspirate.

  4. Acute Graft-Versus-Host Disease (aGVHD) Outcome [ Time Frame: Day 100, Month 6 ]

    Grading of Acute GVHD:

    Severity of Individual Organ Involvement:


    • 1 a maculopapular eruption involving less than 25% of the body surface
    • 2 a maculopapular eruption involving 25-50% of the body surface
    • 3 generalized erythroderma
    • 4 generalized erythroderma with bullous formation and/or with desquamation Liver
    • 1 bilirubin 2.0-3.0mg/100mL
    • 2 bilirubin 3-5.9mg/100mL
    • 3 bilirubin 6-14.9mg/100mL
    • 4 bilirubin >15mg/100mL Gut Diarrhea is graded +1 to +4 in severity. Nausea/vomiting and/or anorexia caused by GVHD is assigned as +1 in severity Diarrhea
    • 1 <1000mL of liquid stool/day
    • 2 >1,000mL of stool/day
    • 3 >1,500mL of stool/day
    • 4 2,000mL of stool/day, severe abdominal pain, with or without ileus

    Severity of GVHD:

    Grade 1 +1 to +2 skin rash; No gut or liver involvement Grade 2 +1 to +3 skin rash;+1 GI involvement and/or +1 liver

  5. Chronic Graft-Versus-Host Disease (cGVHD) Outcome [ Time Frame: Years 1, 2 and 3 ]

    Grading of Chronic GVHD:

    Limited: Localized skin involvement and/or hepatic dysfunction due to chronic GVHD


    One or more of the following:

    Generalized skin involvement Liver histology showing chronic aggressive hepatitis, bridging necrosis or cirrhosis Involvement of the eye: Schirmer's test with <5 mm wetting Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy Involvement of any other target organ

    Chronic GVHD Severity:

    Mild: Signs and symptoms of cGVHD do not interfere substantially with function and do not progress once appropriately treated with local therapy or standard systemic therapy.

    Moderate: Signs and symptoms of cGVHD interfere somewhat with function despite appropriate therapy or are progressive through first line systemic therapy.

    Severe: Signs and symptoms of cGVHD limit function substantially despite appropriate therapy or are progressive through second line systemic therapy

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Diagnosis of a hematologic malignancy of 1 of the following high-risk types:

    • Acute lymphoblastic leukemia
    • Acute myeloid leukemia
    • Chronic myelogenous leukemia
    • Chronic lymphocytic leukemia
    • Myelodysplastic syndromes
    • Myeloproliferative disorder
    • Multiple myeloma
    • Plasma cell dyscrasias
    • Non-Hodgkin lymphoma
    • Hodgkin disease


Performance status

  • Karnofsky 50-100%

Life expectancy

  • Not specified


  • Not specified


  • No liver failure
  • No cirrhosis with evidence of portal hypertension
  • No alcoholic hepatitis
  • No esophageal varices
  • No chronic hepatitis
  • No other liver disease


  • Not specified


  • Left Ventricular Ejection Fraction (LVEF) > 35%
  • No symptomatic coronary artery disease or cardiac failure requiring therapy


  • Diffusing capacity of lung for carbon monoxide (DLCO) > 30%
  • Total lung capacity > 30%
  • Forced expiratory volume in 1 second (FEV_1) > 30%
  • No supplementary continuous oxygen


  • HIV negative
  • No active nonhematologic malignancy except localized skin cancer
  • No overt organ dysfunction


  • Not specified

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): NCT00245037

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United States, Oregon
Knight Cancer Institute at Oregon Health and Science University
Portland, Oregon, United States, 97239-3098
Sponsors and Collaborators
OHSU Knight Cancer Institute
National Cancer Institute (NCI)
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Study Chair: Richard Maziarz, MD OHSU Knight Cancer Institute

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Responsible Party: Richard Maziarz, Principal Investigator, OHSU Knight Cancer Institute Identifier: NCT00245037     History of Changes
Other Study ID Numbers: IRB00000210
P30CA016058 ( U.S. NIH Grant/Contract )
OHSU-HEM-05011-L ( Other Identifier: OHSU Knight Cancer Institute )
OHSU-210 ( Other Identifier: OHSU IRB )
First Posted: October 27, 2005    Key Record Dates
Results First Posted: July 2, 2017
Last Update Posted: September 27, 2017
Last Verified: September 2017
Keywords provided by Richard Maziarz, OHSU Knight Cancer Institute:
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
atypical chronic myeloid leukemia, breakpoint cluster region-Abelson (BCR-ABL) negative
refractory chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
stage II multiple myeloma
stage III multiple myeloma
primary systemic amyloidosis
refractory multiple myeloma
myelodysplastic/myeloproliferative neoplasm, unclassifiable
chronic eosinophilic leukemia
primary myelofibrosis
chronic neutrophilic leukemia
essential thrombocythemia
polycythemia vera
chronic myelomonocytic leukemia
acute undifferentiated leukemia
extramedullary plasmacytoma
isolated plasmacytoma of bone
monoclonal gammopathy of undetermined significance
stage I multiple myeloma
secondary acute myeloid leukemia
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Precancerous Conditions
Myelodysplastic Syndromes
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pathologic Processes
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Mycophenolic Acid