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Fludarabine Phosphate, Low-Dose Total-Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine, Mycophenolate Mofetil, Donor Lymphocyte Infusion in Treating Patients With Hematopoietic Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00006251
First Posted: June 9, 2004
Last Update Posted: August 10, 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):
Fred Hutchinson Cancer Research Center
  Purpose
This clinical trial studies fludarabine phosphate, low-dose total-body irradiation, and donor stem cell transplant followed by cyclosporine, mycophenolate mofetil, and donor lymphocyte infusion in treating patients with hematopoietic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, and total body irradiation (TBI) before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also keep the patient's immune response 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-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.

Condition Intervention Phase
Acute Undifferentiated Leukemia Adult Nasal Type Extranodal NK/T-cell Lymphoma Anaplastic Large Cell Lymphoma Angioimmunoblastic T-cell Lymphoma Childhood Burkitt Lymphoma Childhood Diffuse Large Cell Lymphoma Childhood Grade III Lymphomatoid Granulomatosis Childhood Immunoblastic Large Cell Lymphoma Childhood Myelodysplastic Syndromes Childhood Nasal Type Extranodal NK/T-cell Lymphoma Chronic Myelomonocytic Leukemia Cutaneous B-cell Non-Hodgkin Lymphoma de Novo Myelodysplastic Syndromes Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue Hepatosplenic T-cell Lymphoma Intraocular Lymphoma Juvenile Myelomonocytic Leukemia Mast Cell Leukemia Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable Myeloid/NK-cell Acute Leukemia Nodal Marginal Zone B-cell Lymphoma Noncutaneous Extranodal Lymphoma Peripheral T-cell Lymphoma Post-transplant Lymphoproliferative Disorder Previously Treated Myelodysplastic Syndromes Primary Systemic Amyloidosis Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Adult Burkitt Lymphoma Recurrent Adult Diffuse Large Cell Lymphoma Recurrent Adult Diffuse Mixed Cell Lymphoma Recurrent Adult Diffuse Small Cleaved Cell Lymphoma Recurrent Adult Grade III Lymphomatoid Granulomatosis Recurrent Adult Hodgkin Lymphoma Recurrent Adult Immunoblastic Large Cell Lymphoma Recurrent Adult Lymphoblastic Lymphoma Recurrent Adult T-cell Leukemia/Lymphoma Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Myeloid Leukemia Recurrent Childhood Anaplastic Large Cell Lymphoma Recurrent Childhood Grade III Lymphomatoid Granulomatosis Recurrent Childhood Large Cell Lymphoma Recurrent Childhood Lymphoblastic Lymphoma Recurrent Childhood Small Noncleaved Cell Lymphoma Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Mycosis Fungoides/Sezary Syndrome Recurrent Renal Cell Cancer Recurrent Small Lymphocytic Lymphoma Recurrent/Refractory Childhood Hodgkin Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Hairy Cell Leukemia Refractory Multiple Myeloma Small Intestine Lymphoma Splenic Marginal Zone Lymphoma Stage II Multiple Myeloma Stage III Multiple Myeloma T-cell Large Granular Lymphocyte Leukemia Testicular Lymphoma Waldenström Macroglobulinemia Radiation: total-body irradiation Drug: fludarabine phosphate Drug: cyclosporine Drug: mycophenolate mofetil Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation Biological: donor lymphocytes Procedure: peripheral blood stem cell transplantation Other: laboratory biomarker analysis Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Induction of Mixed Hematopoietic Chimerism in Patients Using Fludarabine, Low Dose TBI, PBSC Infusion and Post-Transplant Immunosuppression With Cyclosporine and Mycophenolate Mofetil

Resource links provided by NLM:

Genetic and Rare Diseases Information Center resources: Lymphosarcoma B-cell Lymphoma Multiple Myeloma Chronic Lymphocytic Leukemia Leukemia, B-cell, Chronic Hodgkin Lymphoma Renal Cell Carcinoma Follicular Lymphoma Diffuse Large B-Cell Lymphoma Cutaneous T-cell Lymphoma Acute Lymphoblastic Leukemia Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Myelodysplastic Syndromes Waldenstrom Macroglobulinemia Chronic Myelomonocytic Leukemia Chronic Myeloproliferative Disorders Lymphoblastic Lymphoma Childhood Acute Lymphoblastic Leukemia Mantle Cell Lymphoma Marginal Zone Lymphoma Peripheral T-cell Lymphoma Burkitt Lymphoma AL Amyloidosis Juvenile Myelomonocytic Leukemia Myelodysplastic/myeloproliferative Disease Mycosis Fungoides Angioimmunoblastic T-cell Lymphoma Angioimmunoblastic Lymphadenopathy With Dysproteinemia Leukemia, T-cell, Chronic Adult T-cell Leukemia/lymphoma Extranodal Nasal NK/T Cell Lymphoma Large Granular Lymphocyte Leukemia Aggressive NK Cell Leukemia Hodgkin Lymphoma, Childhood Lymphoma, Large-cell Anaplastic Large Cell Lymphoma Sezary Syndrome Lymphomatoid Granulomatosis Plasmablastic Lymphoma Lymphoma, Large-cell, Immunoblastic Hairy Cell Leukemia Mastocytosis
U.S. FDA Resources

Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Risk of graft rejection defined as the absence of detectable peripheral blood donor T cells with the addition of fludarabine phosphate [ Time Frame: Up to day 56 ]
  • Incidence of acute grade II/IV GVHD [ Time Frame: Up to day 90 after the last DLI ]
  • Incidence of chronic GVHD [ Time Frame: Up to 24 months ]

Secondary Outcome Measures:
  • Incidence of myelosuppression (ANC < 500/ul for > 2 days, platelets < 20,000/ul for > 2 days) after initial PBSC infusion [ Time Frame: Up to day 56 ]
  • Response of malignancy to DLI [ Time Frame: Up to 24 months ]
  • Incidence of aplasia after DLI [ Time Frame: Up to 24 months ]
  • Dose of CD3+ cells required to convert mixed to full lymphoid chimeras [ Time Frame: Up to 24 months ]
  • Incidence of non-relapse mortality [ Time Frame: Up to 24 months ]

Enrollment: 21
Study Start Date: May 2000
Primary Completion Date: September 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (fludarabine phosphate, TBI, PBSC transplant, DLI)

CONDITIONING REGIMEN : Patients receive fludarabine phosphate IV on days - 4 to -2 and undergo low-dose TBI on day 0. (Note: Patients who have had an autologous transplant within 90 days prior to day 0 will not receive fludarabine phosphate.)

PBSC INFUSION: Patients undergo allogeneic PBSC transplant on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 35 with a taper to day 56. Patients receive mycophenolate mofetil PO BID on days 0-27.

POST TRANSPLANT DLI: Patients with stable mixed chimerism on day 56, and without evidence of GVHD, undergo DLI IV over 30 minutes on day 65. Patients without a complete response, full donor chimerism, and GVHD after 2 months undergo further DLI at higher cell numbers. Up to 6 DLIs may be given 65 days apart.

Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclosporine
Given PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic PBSC transplant
Biological: donor lymphocytes
Undergo DLI
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic PBSC transplant
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the risk of graft rejection associated with the addition of fludarabine (fludarabine phosphate) to a non-myeloablative conditioning regimen for patients with malignant diseases treatable by allogeneic stem cell transplantation and compare this rate to that observed among patients previously treated without fludarabine.

II. To estimate the rate of grade acute II/IV graft-vs-host disease (GVHD) and chronic GVHD in patients treated with low-dose total-body irradiation (TBI), fludarabine, peripheral blood stem cell (PBSC) infusion and immunosuppression with cyclosporine and mycophenolate mofetil.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days - 4 to -2 and undergo low-dose TBI on day 0. (Note: Patients who have had an autologous transplant within 90 days prior to day 0 will not receive fludarabine phosphate.)

PBSC INFUSION: Patients undergo allogeneic PBSC transplant on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 35 with a taper to day 56. Patients receive mycophenolate mofetil PO BID on days 0-27.

POST TRANSPLANT DONOR LYMPHOCYTE INFUSION (DLI): Patients with stable mixed chimerism on day 56, and without evidence of GVHD, undergo DLI IV over 30 minutes on day 65. Patients without a complete response, full donor chimerism, and GVHD after 2 months undergo further DLI at higher cell numbers. Up to 6 DLIs may be given 65 days apart.

After completion of study treatment, patients are followed up at 4, 6, 12, 18 and 24 months and then annually thereafter.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   up to 74 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients aged > 49 years and < 75 years with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma who are not eligible for a curative autologous transplantation or who have failed prior autologous transplantation; patients with NHL and CLL must have failed prior therapy with an alkylating agent and/or fludarabine, or be at high risk of relapse; patients with multiple myeloma must have stage II or III disease and received prior chemotherapy
  • Patients < 50 years of age with NHL, CLL or multiple myeloma at high risk of regimen related toxicity through prior autologous transplant or through pre-existing medical conditions
  • Patients < 75 years of age with other malignant diseases treatable by allogeneic bone marrow transplant (BMT) whom through pre-existing chronic disease affecting kidneys, liver, lungs, and heart are considered to be at high risk for regimen related toxicity using standard high dose regimens; the following diseases are the likely candidates:

    • Myelodysplastic syndromes
    • Myeloproliferative syndromes
    • Acute Leukemia with < 10% blasts
    • Amyloidosis
    • Hodgkin's disease
    • Renal cell carcinoma
  • Patients with other malignancies declining standard allografts may be approved for transplant following presentation and approval by the Fred Hutchinson Cancer Research Center (FHCRC) chimerism group
  • DONOR:

    • Human leukocyte antigen (HLA) genotypically or phenotypically identical related donor
    • Donor must consent to granulocyte colony-stimulating factor (G-CSF) administration and leukopheresis
    • Donor must have adequate veins for leukopheresis or agree to placement of central venous catheter (femoral, subclavian)
    • Age < 75 years

Exclusion Criteria:

  • Eligible for a high-priority curative autologous transplant
  • Patients with rapidly progressive aggressive NHL unless in minimal disease state
  • Active central nervous system (CNS) involvement with disease
  • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
  • Females who are pregnant
  • Patients who are human immunodeficiency virus (HIV) positive
  • Cardiac ejection fraction < 40%
  • Severe defects in pulmonary function testing (defects are currently categorized as mild, moderate and severe) as defined by the pulmonary consultant, or receiving supplementary continuous oxygen
  • Total bilirubin > 2 x the upper limit of normal
  • Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) 4 x the upper limit of normal
  • Karnofsky score < 50
  • Patients with poorly controlled hypertension
  • Patients with renal failure are eligible, however patients with renal compromise (serum creatinine greater than 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum cyclosporine levels
  • DONOR:

    • Identical twin
    • Age less than 12 years
    • Pregnancy
    • Infection with HIV
    • Inability to achieve adequate venous access
    • Known allergy to G-CSF
    • Current serious systemic illness
  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): NCT00006251


Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Italy
University of Torino
Torino, Italy, 10126
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: David Maloney Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00006251     History of Changes
Other Study ID Numbers: 1533.00
NCI-2013-01634 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
1533.00 ( Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium )
P01CA078902 ( U.S. NIH Grant/Contract )
P30CA015704 ( U.S. NIH Grant/Contract )
First Submitted: September 11, 2000
First Posted: June 9, 2004
Last Update Posted: August 10, 2017
Last Verified: August 2017

Additional relevant MeSH terms:
Lymphoma
Syndrome
Leukemia
Leukemia, Myeloid
Multiple Myeloma
Neoplasms, Plasma Cell
Leukemia, Myeloid, Acute
Lymphoma, Follicular
Myelodysplastic Syndromes
Preleukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Hodgkin Disease
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Large B-Cell, Diffuse
Burkitt Lymphoma
Lymphoma, T-Cell
Lymphoma, Large-Cell, Immunoblastic
Plasmablastic Lymphoma
Mycoses
Carcinoma, Renal Cell
Mycosis Fungoides
Sezary Syndrome
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Lymphoma, T-Cell, Cutaneous