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

Chronic Myelomonocytic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00006251
• Other study ID #: 1533.00
• Secondary ID: NCI-2013-0163415
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 2000

Study information

• Verified date: January 2020
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. primary completion date: September 2005
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 74 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Undifferentiated Leukemia
• Adult Nasal Type Extranodal NK/T-cell Lymphoma
• Amyloidosis
• Anaplastic Large Cell Lymphoma
• Angioimmunoblastic T-cell Lymphoma
• Burkitt Lymphoma
• Carcinoma, Renal Cell
• 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
• Hodgkin Disease
• Immunoglobulin Light-chain Amyloidosis
• Intraocular Lymphoma
• Juvenile Myelomonocytic Leukemia
• Leukemia
• Leukemia, Hairy Cell
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Leukemia, Mast-Cell
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Leukemia, T-Cell
• Leukemia-Lymphoma, Adult T-Cell
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, B-Cell, Marginal Zone
• Lymphoma, Extranodal NK-T-Cell
• Lymphoma, Follicular
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Large-Cell, Anaplastic
• Lymphoma, Large-Cell, Immunoblastic
• Lymphoma, Mantle-Cell
• Lymphoma, Non-Hodgkin
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Cutaneous
• Lymphoma, T-Cell, Peripheral
• Lymphomatoid Granulomatosis
• Lymphoproliferative Disorders
• Mast Cell Leukemia
• Multiple Myeloma
• Mycoses
• Mycosis Fungoides
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
• Myeloid/NK-cell Acute Leukemia
• Myeloproliferative Disorders
• Neoplasms, Plasma Cell
• Nodal Marginal Zone B-cell Lymphoma
• Noncutaneous Extranodal Lymphoma
• Peripheral T-cell Lymphoma
• Plasmablastic Lymphoma
• Post-transplant Lymphoproliferative Disorder
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia
• 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
• Sezary Syndrome
• Small Intestine Lymphoma
• Splenic Marginal Zone Lymphoma
• Stage II Multiple Myeloma
• Stage III Multiple Myeloma
• Syndrome
• T-cell Large Granular Lymphocyte Leukemia
• Testicular Lymphoma
• Waldenstrom Macroglobulinemia
• Waldenström Macroglobulinemia

Intervention

Radiation:
• total-body irradiation
Undergo TBI

Drug:
• fludarabine phosphate
Given IV
• cyclosporine
Given PO
• mycophenolate mofetil
Given PO

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:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
Italy	University of Torino	Torino
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Risk of graft rejection defined as the absence of detectable peripheral blood donor T cells with the addition of fludarabine phosphate		Up to day 56
Primary	Incidence of acute grade II/IV GVHD		Up to day 90 after the last DLI
Primary	Incidence of chronic GVHD		Up to 24 months
Secondary	Incidence of myelosuppression (ANC < 500/ul for > 2 days, platelets < 20,000/ul for > 2 days) after initial PBSC infusion		Up to day 56
Secondary	Response of malignancy to DLI		Up to 24 months
Secondary	Incidence of aplasia after DLI		Up to 24 months
Secondary	Dose of CD3+ cells required to convert mixed to full lymphoid chimeras		Up to 24 months
Secondary	Incidence of non-relapse mortality		Up to 24 months