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:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00006251
First received: September 11, 2000
Last updated: August 1, 2014
Last verified: August 2014
  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: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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: Myelodysplastic Syndromes Leukemia, Myeloid Multiple Myeloma Lymphosarcoma Mantle Cell Lymphoma B-cell Lymphomas Burkitt Lymphoma Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma Acute Lymphoblastic Leukemia, Childhood Kidney Cancer Renal Cancer Acute Myelocytic Leukemia Acute Non Lymphoblastic Leukemia Follicular Lymphoma Lymphoma, Large-cell Acute Myeloid Leukemia, Adult Lymphoma, Small Cleaved-cell, Diffuse Chronic Lymphocytic Leukemia Leukemia, B-cell, Chronic Hodgkin Lymphoma Lymphoma, Large-cell, Immunoblastic Plasmablastic Lymphoma Mycosis Fungoides Sezary Syndrome Cutaneous T-cell Lymphoma Leukemia, T-cell, Chronic Acute Myeloid Leukemia, Childhood Waldenstrom Macroglobulinemia Anaplastic Large Cell Lymphoma Small Non-cleaved Cell Lymphoma Hodgkin Lymphoma, Childhood Chronic Myelomonocytic Leukemia Hairy Cell Leukemia Lymphomatoid Granulomatosis Angioimmunoblastic T-cell Lymphoma Angioimmunoblastic Lymphadenopathy With Dysproteinemia Chronic Myeloproliferative Disorders Peripheral T-cell Lymphoma Myelodysplastic/myeloproliferative Disease Large Granular Lymphocyte Leukemia Juvenile Myelomonocytic Leukemia AL Amyloidosis Systemic Mastocytosis 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 ] [ Designated as safety issue: No ]
  • Incidence of acute grade II/IV GVHD [ Time Frame: Up to day 90 after the last DLI ] [ Designated as safety issue: No ]
  • Incidence of chronic GVHD [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]

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 ] [ Designated as safety issue: No ]
  • Response of malignancy to DLI [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
  • Incidence of aplasia after DLI [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
  • Dose of CD3+ cells required to convert mixed to full lymphoid chimeras [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
  • Incidence of non-relapse mortality [ Time Frame: Up to 24 months ] [ Designated as safety issue: Yes ]

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

Ages Eligible for Study:   up to 74 Years
Genders Eligible for Study:   Both
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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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
Investigators
Principal Investigator: David Maloney Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00006251     History of Changes
Other Study ID Numbers: 1533.00, NCI-2013-01634, 1533.00, P01CA078902, P30CA015704
Study First Received: September 11, 2000
Last Updated: August 1, 2014
Health Authority: United States: Federal Government

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

ClinicalTrials.gov processed this record on September 18, 2014