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Patients receive preparative therapy with Fludarabine, cyclophosphamide, total body irradiation and Treg infusion followed by umbilical cord blood transplantation.

Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush and mesna (MT(S)9006) on day -8 and -7 one hour after fludarabine infusion.

cyclophosphamide

Will be administered beginning on day -3 and adjusted to maintain a level of \>200. For adults the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours.

cyclosporine

Fludarabine 25 mg/m\^2/day will be administered as a 1 hour intravenous infusion on days -9 through -7.

fludarabine phosphate

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

mycophenolate mofetil

On day -1 prior to UCB transplantation, Treg cells will be infused IV without in-line filtration. A semi-log dose escalation of CD4+CD25+ Treg cells is scheduled with 3 patients at each step. Doses will be 0.1 x 10\^6/kg, 0.3 x 10\^6/kg, 1 x 10\^6/kg and 3 x 10\^6/kg weight (determined on the day prior to administration of the preparative therapy).

Treg cell infusion

Following the administration of the preparative therapy, all subjects will undergo UCB transplantation. The UCB will be administrated by IV infusion without in-line filtration.

umbilical cord blood transplantation

Radiotherapy: 165 cGy will be administered on day -5 through -2 two fractions each day.

total-body irradiation

Claudio G. Brunstein, MD, PhD

RATIONALE: Giving chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of cancer or abnormal 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. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer or abnormal cells (graft-versus-tumor effect). Giving an infusion of the donor's T-regulatory cells before the transplant may help increase this effect. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase I trial is studying the side effects and best dose of umbilical cord blood T-regulatory cell infusion followed by donor umbilical cord blood transplant in treating patients with high-risk leukemia or other hematologic diseases.

OBJECTIVES:

Primary

* Determine the maximum tolerated dose of umbilical cord blood (UCB)-derived CD4- and CD25-positive T-regulatory (Treg) cell infusion followed by double unrelated donor UCB transplantation in patients with high-risk leukemia or other hematologic diseases.

Secondary

* Determine the speed of neutrophil and platelet recovery at day 42 in these patients.
* Determine the incidence of "double chimerism" (e.g., engraftment of both UCB units) at day 21 in these patients.
* Determine the risk of severe grade III-IV acute graft-versus-host disease (GVHD) at day 100 in these patients.
* Determine the risk of chronic GVHD at 1 year post transplantation in these patients.
* Determine the probability of survival at 100 days and 1 year post transplantation in these patients.

OUTLINE: This is an open-label, dose-escalation study of CD4- and CD25-positive umbilical cord blood (UCB)-derived T-regulatory cells (Treg).

* Preparative therapy: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -9 to -7 and cyclophosphamide IV over 2 hours on days -8 and -7 (1 hour after fludarabine infusion). Patients then undergo total-body irradiation (TBI) twice daily on days -5 to -2.
* UCB-derived Treg infusion: Patients receive UCB-derived Treg cells IV on day -1.
* Double unrelated donor UCB transplantation: Patients undergo double unrelated donor UCB transplantation by IV infusion on day 0.
* Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours or orally 2 or 3 times daily beginning on day -3 and continuing until day 100, followed by a taper to day 180, in the absence of GVHD. Patients also receive mycophenolate mofetil (MMF) orally or IV twice daily on days -3 to 30 or 7 days after engraftment, whichever is later, in the absence of acute GVHD\*. If no donor engraftment occurs, MMF may be continued at the discretion of the attending physician.

NOTE: \*If the patient has acute GVHD requiring systemic therapy, MMF may be stopped 7 days after GVHD is controlled (e.g., resolution of skin rash, vomiting, and diarrhea).

Cohorts of 3-6 patients receive escalating doses of UCB-derived Treg cells until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience nonhematologic dose-limiting toxicity within 48 hours of Treg cell infusion. At least 6 patients are treated at the MTD.

Umbilical Cord Blood T-Regulatory Cell Infusion Followed by Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Leukemia or Other Hematologic Diseases

Umbilical Cord Blood Transplant With Co-Infusion of T Regulatory Cells

Dose limiting toxicities (DLT) are defined as any grade 3-4 toxicity within 24 hours of Treg cell infusion, excluding hematological .

Masonic Cancer Center, University of Minnesota

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Umbilical Cord Blood T-Regulatory Cell Infusion Followed by Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Leukemia or Other Hematologic Diseases	NCT00376519	Graft Versus Ho... Leukemia Lymphoma Multiple Myelom... Myelodysplastic... Secondary Myelo...	cyclophosphamid... cyclosporine fludarabine pho... mycophenolate m... Treg cell infus... umbilical cord ... total-body irra...	18 Years - 45 Years	Masonic Cancer Center, University of Minnesota
Umbilical Cord Blood T-Regulatory Cell Infusion Followed by Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Leukemia or Other Hematologic Diseases	NCT00376519	Graft Versus Ho... Leukemia Lymphoma Multiple Myelom... Myelodysplastic... Secondary Myelo...	cyclophosphamid... cyclosporine fludarabine pho... mycophenolate m... Treg cell infus... umbilical cord ... total-body irra...	18 Years - 45 Years	Masonic Cancer Center, University of Minnesota

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