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

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.

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