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Reduced-Intensity Busulfan and Fludarabine With or Without Antithymocyte Globulin Followed by Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Disease

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00448201
First Posted: March 16, 2007
Last Update Posted: May 30, 2017
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.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center
  Purpose

RATIONALE: Giving low doses of chemotherapy, such as busulfan and fludarabine, before a donor stem cell transplant helps stop the growth of cancer and abnormal cells. It also helps stop 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 or abnormal cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Immunosuppressive therapy may improve bone marrow function and may be an effective treatment for hematologic cancer or other disease.

PURPOSE: This clinical trial is studying the side effects and how well giving busulfan and fludarabine with or without antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer or other disease.


Condition Intervention Phase
Chronic Myeloproliferative Disorders Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes Biological: anti-thymocyte globulin Biological: sargramostim Biological: therapeutic allogeneic lymphocytes Drug: busulfan Drug: fludarabine phosphate Drug: methotrexate Drug: tacrolimus Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment With a More Intensive Therapeutic Regimen

Resource links provided by NLM:


Further study details as provided by UNC Lineberger Comprehensive Cancer Center:

Primary Outcome Measures:
  • Treatment-related Mortality [ Time Frame: 6 months ]
    Treatment related mortality for first 6 months. Defined as the number of treatment related deaths excluding deaths due to disease relapse.


Secondary Outcome Measures:
  • Complete Response at 6 and 12 Months Post-transplant [ Time Frame: 6 and 12 months ]
  • Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant [ Time Frame: Days 30, 60, and 90 ]

    Complete chimerism is defined as 100% donor cells detected, suggesting complete hematopoietic replacement. Mixed donor chimerism means host cells are detected in particular cells like lymphocytes. Five to 90% donor cells set the criteria for mixed chimerism (MC).

    Chimerism was not tabulated on day 30.


  • 5-year Disease-free Survival [ Time Frame: Year 5 ]
    The length of time post-transplant that the patient survives without any signs or symptoms of that cancer.

  • Graft-vs-host Disease at 6 Months Post-transplant [ Time Frame: 6 Months ]

    Graft-vs-host disease (GVHD) can be mild, moderate or severe depending on the differences in tissue type between patient and donor. Its symptoms can include:

    • Rashes, which include burning and redness, that erupt on the palms or soles and may spread to the trunk and eventually to the entire body
    • Blistering, causing the exposed skin surface to flake off in severe cases
    • Nausea, vomiting, abdominal cramps, diarrhea and loss of appetite, which can indicate that the gastrointestinal (digestive) tract is affected
    • Jaundice, or a yellowing of the skin, which can indicate liver damage
    • Excessive dryness of the mouth and throat, leading to ulcers
    • Dryness of the lungs, vagina and other surfaces

    Acute GVHD - Can occur soon after the transplanted cells begin to appear in the recipient. Acute GVHD ranges from mild, moderate or severe, and can be life-threatening if its effects are not controlled.

    Extensive chronic GVHD - Usually occurs at about three months post-transplant.



Enrollment: 71
Actual Study Start Date: January 7, 2011
Study Completion Date: May 23, 2012
Primary Completion Date: January 11, 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Methotrexate Only Arm
GVHD Prophylaxis with Methotrexate
Biological: sargramostim
GM-CSF 500 ug everyday (QD) subcutaneously will be given to recipients who remain with an Absolute neutrophil count (ANC) < 1000/microliter (uL) past day 20
Biological: therapeutic allogeneic lymphocytes
A minimum total cluster of differentiation 34 (CD34)+ cell dose of 3 x 10^6 cells/kg and a maximum 8 x 10^6 cells/kg will be infused on day 0
Drug: busulfan
6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
Drug: fludarabine phosphate
fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3
Drug: methotrexate
Methotrexate 5 mg/m^2 per day on days +1, +3 and +6
Drug: tacrolimus
Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
Procedure: peripheral blood stem cell transplantation
Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
Active Comparator: 2 Doses ATG + Methotrexate
GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
Biological: anti-thymocyte globulin
0.5 mg/kg on day -3, 2.5 mg/kg on day -2 (groups 2, 3 and 4) and 3 mg/kg on day -1 (group 4 only)
Biological: sargramostim
GM-CSF 500 ug everyday (QD) subcutaneously will be given to recipients who remain with an Absolute neutrophil count (ANC) < 1000/microliter (uL) past day 20
Biological: therapeutic allogeneic lymphocytes
A minimum total cluster of differentiation 34 (CD34)+ cell dose of 3 x 10^6 cells/kg and a maximum 8 x 10^6 cells/kg will be infused on day 0
Drug: busulfan
6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
Drug: fludarabine phosphate
fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3
Drug: methotrexate
Methotrexate 5 mg/m^2 per day on days +1, +3 and +6
Drug: tacrolimus
Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
Procedure: peripheral blood stem cell transplantation
Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
Active Comparator: 2 Doses ATG
GVHD prophylaxis with 2 doses ATG
Biological: anti-thymocyte globulin
0.5 mg/kg on day -3, 2.5 mg/kg on day -2 (groups 2, 3 and 4) and 3 mg/kg on day -1 (group 4 only)
Biological: sargramostim
GM-CSF 500 ug everyday (QD) subcutaneously will be given to recipients who remain with an Absolute neutrophil count (ANC) < 1000/microliter (uL) past day 20
Biological: therapeutic allogeneic lymphocytes
A minimum total cluster of differentiation 34 (CD34)+ cell dose of 3 x 10^6 cells/kg and a maximum 8 x 10^6 cells/kg will be infused on day 0
Drug: busulfan
6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
Drug: fludarabine phosphate
fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3
Drug: tacrolimus
Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
Procedure: peripheral blood stem cell transplantation
Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
Active Comparator: 3 Doses ATG
GVHD prophylaxis with 3 doses ATG
Biological: anti-thymocyte globulin
0.5 mg/kg on day -3, 2.5 mg/kg on day -2 (groups 2, 3 and 4) and 3 mg/kg on day -1 (group 4 only)
Biological: sargramostim
GM-CSF 500 ug everyday (QD) subcutaneously will be given to recipients who remain with an Absolute neutrophil count (ANC) < 1000/microliter (uL) past day 20
Biological: therapeutic allogeneic lymphocytes
A minimum total cluster of differentiation 34 (CD34)+ cell dose of 3 x 10^6 cells/kg and a maximum 8 x 10^6 cells/kg will be infused on day 0
Drug: busulfan
6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
Drug: fludarabine phosphate
fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3
Drug: tacrolimus
Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
Procedure: peripheral blood stem cell transplantation
Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed diagnosis of 1 of the following:

    • Chronic lymphocytic leukemia (CLL), meeting the following criteria:

      • Absolute lymphocyte count > 5,000/mm³
      • Lymphocytes must appear morphologically mature with < 55% prolymphocytes
      • Lymphocyte phenotype with expression of CD19 and cluster of differentiation 5 (CD5)
    • Prolymphocytic leukemia (PLL), meeting the following criteria:

      • Absolute lymphocyte count > 5,000/mm³
      • More than 55% prolymphocytes
      • Morphologically diagnosed
    • Chronic myelogenous leukemia (CML), meeting the following criteria:

      • Diagnosis of CML or similar myeloproliferative disorders based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated white blood cell (WBC) counts in peripheral blood or bone marrow
      • In first chronic phase CML and a candidate for treatment with reduced-dose busulfan
      • Patients with other cytogenetic abnormalities, such as t(9;12), that are associated with an aggressive clinical course are eligible
    • Non-Hodgkin's lymphoma (NHL), meeting the following criteria:

      • Any World Health Organization (WHO) class histologic subtype allowed
      • Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping
      • Bone marrow biopsies as sole means of diagnosis are not allowed for follicular lymphoma
    • Hodgkin's lymphoma, meeting the following criteria:

      • Any WHO class histologic subtype allowed
      • Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping
    • Multiple myeloma, meeting the following criteria:

      • Active disease requiring treatment (Durie-Salmon stages I, II, or III)
    • Acute myeloid leukemia with documented control, defined as < 10% bone marrow blasts and no circulating blasts
    • Acute lymphoblastic leukemia, meeting the following criteria:

      • In early first relapse or beyond OR in first complete remission and has 1 of the following high-risk features:

        • t(9;22) or t(4;11)
        • WBC count > 30,000/mm³ at presentation
        • Non-T-cell phenotype
        • More than 30 years of age
    • Agnogenic myeloid metaplasia/myelofibrosis

      • Patients who are transfusion dependent or who have evolving myelodysplastic or leukemic features or high-risk cytogenetic abnormalities are eligible
    • Myelodysplastic syndromes (MDS) as defined by WHO criteria
  • Meets 1 of the following criteria:

    • Over 55 years of age
    • Ineligible for busulfan-based therapy based on diminished organ function or poor performance status
    • Indolent and chemotherapy-responsive CLL, low-grade NHL, small lymphocytic lymphoma, or PLL
  • Patients who have undergone prior autologous stem cell transplantation are preferentially enrolled on clinical trial CALGB-100002, if available and patient is eligible
  • HLA-matched or mismatched related donor or HLA-matched unrelated donor available

    • HLA-identical sibling (6/6 or 9/10) (minimal serologic typing required for class I [A, B]; molecular typing required for class II (DRB1))
    • 9/10 matched unrelated donor (MUD) (molecular analysis at HLA A, B, C, DRB1, and DQB1 by high resolution typing required)
    • 5/6 MUD (molecular analysis at HLA A, B, and DRB1 required)
    • No syngeneic donors

PATIENT CHARACTERISTICS:

  • Creatinine clearance ≥ 40 mL/min
  • Bilirubin ≤ 3 times upper limit of normal (ULN)
  • aspartate aminotransferase (AST) ≤ 3 times ULN
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease
  • Left ventricular ejection fraction (LVEF) ≥ 30% by multigated acquisition scan (MUGA)
  • No uncontrolled diabetes mellitus or active serious infection
  • No known hypersensitivity to Escherichia coli-derived products
  • No HIV infection
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • More than 4 weeks since prior chemotherapy, radiotherapy (except prophylactic cranial x-ray therapy), or surgery
  Contacts and Locations
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 ClinicalTrials.gov identifier (NCT number): NCT00448201


Locations
United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States, 27599-7295
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Thomas C. Shea, MD UNC Lineberger Comprehensive Cancer Center
  More Information

Additional Information:
Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00448201     History of Changes
Other Study ID Numbers: LCCC 0306
P30CA016086 ( U.S. NIH Grant/Contract )
First Submitted: March 14, 2007
First Posted: March 16, 2007
Results First Submitted: April 17, 2017
Results First Posted: May 30, 2017
Last Update Posted: May 30, 2017
Last Verified: May 2017

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
prolymphocytic leukemia
accelerated phase chronic myelogenous leukemia
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
blastic phase chronic myelogenous leukemia
childhood acute lymphoblastic leukemia in remission
childhood acute myeloid leukemia in remission
childhood chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
de novo myelodysplastic syndromes
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
noncontiguous stage II adult Burkitt lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II grade 1 follicular lymphoma
noncontiguous stage II grade 2 follicular lymphoma
noncontiguous stage II grade 3 follicular lymphoma
noncontiguous stage II mantle cell lymphoma
noncontiguous stage II marginal zone lymphoma
noncontiguous stage II small lymphocytic lymphoma
previously treated myelodysplastic syndromes

Additional relevant MeSH terms:
Lymphoma
Syndrome
Leukemia
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Plasmacytoma
Myeloproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease
Pathologic Processes
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Precancerous Conditions
Methotrexate
Fludarabine phosphate
Tacrolimus
Busulfan