RATIONALE: A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy, or that have become cancer. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclophosphamide and fludarabine together with total-body irradiation followed by cyclosporine and mycophenolate mofetil before the transplant may stop this from happening. PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with radiation therapy followed by cyclosporine and mycophenolate mofetil works in treating patients who are undergoing a donor stem cell transplant for hematologic cancer, metastatic breast cancer, or kidney cancer.
OBJECTIVES: * Determine if a nonmyeloablative regimen comprising cyclophosphamide, fludarabine, and radiotherapy followed by cyclosporine and mycophenolate mofetil provides a prompt and durable donor engraftment in patients with hematologic malignancies or kidney cancer who are undergoing allogeneic stem cell transplantation. * Determine the safety of this nonmyeloablative transplantation regimen in these patients. * Determine the risk of graft-versus-host-disease in patients treated with this regimen. * Determine the antineoplastic potency of nonmyeloablative stem cell transplantation in patients treated with this regimen. * Determine the effect of lower doses of daily fludarabine on treatment-related mortality (TRM) OUTLINE: Patients are stratified according to risk (standard vs high). * Preparative regimen\*: Patients receive cyclophosphamide intravenously (IV) over 2 hours on day -6 and fludarabine IV over 1 hour on days -6 to -2. Patients undergo total body irradiation on day -1. Some patients also receive anti-thymocyte globulin (ATG)\*\* IV every 12 hours on days -6 to -4. Patients who receive ATG\* include the following: * Related donor recipients who have not received combination chemotherapy within the past 6 months * Unrelated donor recipients who have not received combination chemotherapy within the past 3 months * Unrelated donor recipients who have received only 1 induction course for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or blastic phase chronic myelogenous leukemia (CML) NOTE: \*\*Patients who underwent prior autologous stem cell transplantation in the past year do not receive ATG. * Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0. * Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV over 2 hours beginning on day -3 and continuing until at least day 100. Patients also receive mycophenolate mofetil IV or orally twice daily on days -3 to 30. * Donor lymphocyte infusion (DLI): Patients without active GVHD but deteriorating donor chimerism may receive DLI IV over 2 hours. After completion of study treatment, patients are followed periodically for 2 years. PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
342
ATG dose is 15 mg/kg intravenous (IV) every 12 hours for 6 doses on days -6, -5, and -4. Those that should/will receive ATG in the preparative regimen: * Related donor recipients who have not had exposure to combination chemotherapy in the 6 months preceding transplant should * Unrelated donor recipients who have not had exposure to combination chemotherapy in the 3 months preceding transplant will * Unrelated donor recipients who have had only a single induction cycle for the treatment of ALL/AML or MDS or CML blast crisis should * Recipients with a prior autologous transplant in the year prior to second transplant do not require ATG.
Cyclophosphamide will be given in a two hour infusion, total dose 50 mg/kg on day -6.
Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a level of \>200. For adults the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. For children \< 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. Patients will receive CSA until day +100.
Fludarabine 30 mg/m\^2/day intravenous (IV) on day -6 through day -2., total dose 150 mg/m\^2 for 5 days.
Mycophenolate mofetil (MMF) 1.5 gram twice a day (BID) or if \< 50 kg will be given 15 mg/kg orally(po) BID,beginning on day -3, and discontinue at day +30 or 7 days after engraftment (3 consecutive days of absolute neutrophil count (ANC) \> 0.5 x 109 /L).
On day 0, if related donor, stem cells are infused via central line. If unrelated donor, marrow/PBSC is infused after arrival and processing on day 0.
The dose of TBI will be 200 cGy given in a single fraction on day -1.
Patients with white blood cell (WBC) counts \< 2500 any time after stem cell infusion will be started on G-CSF support at Day +5 at a dose of 5 mcg/kg intravenously or subcutaneously (IV/SQ) daily rounded to vial size until absolute neutrophil count (ANC) \> 2500 for 2 consecutive days.
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States
Neutrophil and Donor Cell Engraftment
Successful sustained engraftment is defined as primary neutrophil engraftment by day 42 and e90% donor cells at day 100, with or without DLI. Engraftment based on absolute neutrophil count of donor origin \> 0.5 x 10e9 /L for 3 days by day 42
Time frame: Day 42 and Day 100
Serious Adverse Events
Safety by development of severe adverse events within 100 days of transplant
Time frame: Day 100
Transplant Related Mortality
\> 30% transplant related mortality at 100 days (non-relapse).
Time frame: Day 100
Overall Survival
Time frame: 1 year
Acute Graft-Versus-Host Disease
Grade III-IV graft versus host disease
Time frame: Day 100
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