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Patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine phosphate, mycophenolate mofetil, filgrastim, cyclophosphamide, cyclosporine and fractionated total-body irradiation.

All patients will receive G-CSF 5 mcg/kg/day intravenously(IV) (dose rounded to vial size) based on the actual body weight IV beginning on day +1 after umbilical cord blood (UCB) infusion. G-CSF will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10\^9/L for three consecutive days.

filgrastim

Cyclophosphamide to be administered with high volume fluid flush and mesna (MT(S) 9006) at 10:00am, or per institutional routine, on days-7 and -6 after fludarabine. Cyclophosphamide 60mg/kg/day intravenous (IV) x 2 days, total dose 120 mg/kg (days -7 and -6) Dosing is calculated based on Actual BodyWeight (ABW) unless ABW \> 30 kg above Ideal BodyWeight (IBW), in which case the dose should be computed using adjusted body weight.

cyclophosphamide

Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of \> 200 ng/mL. For adults the initial dose will be 2.5 mg/kg intravenously (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.

cyclosporine

Fludarabine 25 mg/m2/day intravenously (IV) x 3 days, total dose 75 mg/m2 (days -8 to -6);

fludarabine phosphate

All patients will begin mycophenolate mofetil (MMF) on day -3. Patients ≥ 40 kilograms will receive MMF at the dose of 3 grams/day divided into 2 or 3 doses (every 12 or 8 hours).

Pediatric patient (\<40 kilograms) will receive MMF at the dose of 15 mg/kg three times a day.

mycophenolate mofetil

The product is infused via intravenous (IV) drip directly into the central line without a needle, pump or filter.

umbilical cord blood transplantation

The recommended TBI is 165 cGy given twice daily for a total dose of 1320 cGy (days -4 to -1).

total-body irradiation

Claudio G. Brunstein, MD, PhD

RATIONALE: Giving chemotherapy drugs, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of cancer cells and prepares the patient's bone marrow for the stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation works in treating patients who are undergoing an umbilical cord blood transplant for hematologic cancer.

OBJECTIVES:

Primary

* Determine the 1-year survival of patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine, cyclophosphamide, and fractionated total-body irradiation.

Secondary

* Determine the incidence of transplant-related mortality at 6 months after UCBT.
* Evaluate the pattern of chimerism after double UCBT.
* Determine the incidence of neutrophil engraftment at day 42 after UCBT.
* Determine the incidence of platelet engraftment at 6 months after UCBT.
* Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 after UCBT.
* Determine the incidence of chronic GVHD at 1 year after UCBT.
* Determine the disease-free survival at 1 and 2 years after UCBT.
* Determine the incidence of relapse at 1 year after UCBT.

OUTLINE: This is a nonrandomized, open-label, multicenter study.

* Preparative Regimen: Patients receive fludarabine IV over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients also undergo total-body irradiation twice daily on days -4 to -1.
* Umbilical Cord Blood Transplantation (UCBT): Patients undergo 1 or 2 units of UCBT on day 0. Patients receive filgrastim (G-CSF) IV once daily beginning on day 1 and continuing until blood counts recover.
* Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours 2 or 3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. Patients also receive mycophenolate mofetil IV or orally 2 or 3 times a day beginning on day -3 and continuing until day 30 or 7 days after engraftment in the absence of acute GVHD.

After completion of study treatment, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: A total of 150 patients will be accrued for this study.

Myeloablative Umbilical Cord Blood Transplantation in Hematological Diseases

Transplantation of Unrelated Umbilical Cord Blood for Patients With Hematological Diseases With Cyclophosphamide/Fludarabine/Total Body Irradiation Myeloablative Preparative Regimen

Number of patients alive at 1 year after transplant.

Determine the incidence of transplant-related mortality at 6 months after UCBT

Determine the incidence of platelet engraftment (platelet recovery \>50,000/uL) at 6 months after UCBT.

Determine the incidence of neutrophil engraftment at day 42 after UCBT Patients diagnosed with graft failure (failure of absolute neutrophil count ANC \> 5 x 10\^8/L of donor origin by day +42)

Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 after UCBT. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria following Przepiorka et al, 1995, Consensus Clinical Stage and Grade of Acute GVHD.

Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level.

Determine the incidence of chronic GVHD at 1 year after UCBT. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria.

Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level.

Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.

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