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

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Childhood Burkitt Lymphoma

Cutaneous B-cell Non-Hodgkin Lymphoma

T-cell Large Granular Lymphocyte Leukemia

Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue

Splenic Marginal Zone Lymphoma

Recurrent Adult Diffuse Small Cleaved Cell Lymphoma

Recurrent Grade 3 Follicular Lymphoma

Recurrent Marginal Zone Lymphoma

Childhood Myelodysplastic Syndromes

Recurrent Adult Grade III Lymphomatoid Granulomatosis

Post-transplant Lymphoproliferative Disorder

Small Intestine Lymphoma

Recurrent Grade 1 Follicular Lymphoma

Recurrent Mantle Cell Lymphoma

Angioimmunoblastic T-cell Lymphoma

Recurrent/Refractory Childhood Hodgkin Lymphoma

Primary Systemic Amyloidosis

Chronic Myelomonocytic Leukemia

Waldenström Macroglobulinemia

Recurrent Small Lymphocytic Lymphoma

Recurrent Grade 2 Follicular Lymphoma

Juvenile Myelomonocytic Leukemia

Nodal Marginal Zone B-cell Lymphoma

Recurrent Adult Burkitt Lymphoma

Stage III Multiple Myeloma

Recurrent Childhood Anaplastic Large Cell Lymphoma

Recurrent Mycosis Fungoides/Sezary Syndrome

Hepatosplenic T-cell Lymphoma

Adult Nasal Type Extranodal NK/T-cell Lymphoma

Refractory Hairy Cell Leukemia

Recurrent Childhood Small Noncleaved Cell Lymphoma

Recurrent Childhood Grade III Lymphomatoid Granulomatosis

Childhood Immunoblastic Large Cell Lymphoma

Recurrent Adult Hodgkin Lymphoma

Refractory Multiple Myeloma

Recurrent Childhood Acute Lymphoblastic Leukemia

Previously Treated Myelodysplastic Syndromes

Anaplastic Large Cell Lymphoma

Childhood Grade III Lymphomatoid Granulomatosis

Recurrent Adult Diffuse Mixed Cell Lymphoma

Testicular Lymphoma

Recurrent Renal Cell Cancer

Recurrent Childhood Acute Myeloid Leukemia

Refractory Chronic Lymphocytic Leukemia

Recurrent Adult Immunoblastic Large Cell Lymphoma

Recurrent Adult Acute Lymphoblastic Leukemia

Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma

Recurrent Adult Lymphoblastic Lymphoma

Noncutaneous Extranodal Lymphoma

Intraocular Lymphoma

Childhood Nasal Type Extranodal NK/T-cell Lymphoma

de Novo Myelodysplastic Syndromes

Recurrent Adult Diffuse Large Cell Lymphoma

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

Myeloid/NK-cell Acute Leukemia

Recurrent Childhood Lymphoblastic Lymphoma

Childhood Diffuse Large Cell Lymphoma

Mast Cell Leukemia

Recurrent Childhood Large Cell Lymphoma

Recurrent Adult Acute Myeloid Leukemia

Acute Undifferentiated Leukemia

Recurrent Adult T-cell Leukemia/Lymphoma

Peripheral T-cell Lymphoma

Stage II Multiple Myeloma

Treatments

Other: laboratory biomarker analysis

Biological: donor lymphocytes

Procedure: peripheral blood stem cell transplantation

Drug: mycophenolate mofetil

Drug: cyclosporine

Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation

Drug: fludarabine phosphate

Radiation: total-body irradiation

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00006251

P01CA078902 (U.S. NIH Grant/Contract)

1533.00 (Other Identifier)

P30CA015704 (U.S. NIH Grant/Contract)

NCI-2013-01634 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

21 patients

Sex

All

Ages

Under 74 years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

21 participants in 1 patient group

Treatment (fludarabine phosphate, TBI, PBSC transplant, DLI)

Experimental group

Description:

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.

Treatment: