T-Regulatory Cell and CD3 Depleted Double Umbilical Cord Blood Transplantation in Hematologic Malignancies

• Determine incidence of infusional toxicity [ Time Frame: 48 hours ] [ Designated as safety issue: Yes ]
  reaction that occurs with 48 hours of product infusion
• Incidence of neutrophil recovery [ Time Frame: Day 42 ] [ Designated as safety issue: Yes ]
  Determine the incidence of neutrophil recovery (absolute neutrophil count ≥ 500/uL) at day 42
• Incidence of double and single chimerism [ Time Frame: Day +21, Day +180, 1 Year ] [ Designated as safety issue: No ]
  Determine incidence of double and single unit chimerism at various time points
• Incidence of Viral and Fungal Infections [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
  Determine incidence of viral and fungal infections at 1 year
• 1 Year Survival [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  Estimate the probability of survival at 1 year
• Incidence of Grade III-IV Acute Graft-Versus-Host Disease [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
  Determine the incidence of grade III-IV acute GVHD at day 100
• Incidence of Treatment Related Death [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
  Determine the incidence of treatment related mortality (TRM) at 6 months
• Incidence of Platelet Recovery [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  Determine the incidence of platelet recovery (platelet count ≥ 50,000/uL) at 1 year
• Incidence of Chronic Graft-Versus-Host Disease [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  Determine the incidence of chronic GVHD at 1 year
• Incidence of Relapse [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  Determine the incidence of relapse at 1 year

This is a unique dose-escalation trial that will titrate doses of umbilical cord blood (UCB) Treg and CD3+ Teff cells with the goal of infusing as many CD3+ Teff cells as possible without conferring grade II-IV acute graft-versus-host disease (GVHD).

In this study, the investigators propose to add UCB Treg and UCB CD3+ Teff cells to the two TCD UCB donor units with the goal of transplanting as many CD3+ Teff cells as possible without reintroducing risk of acute GVHD. The investigators hypothesize that Treg will permit the reintroduction of CD3+ Teff cells that will provide a bridge while awaiting HSC T cell recovery long term. The co-infusion of Treg will prevent GVHD without the need for prolonged pharmacologic immunosuppression.

Based on prior studies, the first patient will start at lowest dose combination (3 x 10^6/kg of Treg and 3 x 10^6/kg of CD3+ Teff cells).

One patient will be entered at each level with a minimum of 35 days to observe the patient prior to moving to the next dose level. (1) If GVHD does not occur, a "successful step", then the CD3+ Teff cell dose will increase to the next higher level for the next patient; (2) If GVHD occurs, a "failed step", then Treg dose will increase to the next higher level for the next patient. It would take a minimum of 5 (if no GVHD) and maximum of 9 patients (if GVHD is observed at each level) to complete all Treg:CD3+ Teff cell combinations.

An additional 10 patients will be enrolled to verify that this reflects the optimal combination and evaluate its safety profile.

• Hematologic Malignancy
• Acute Myeloid Leukemia
• Acute Lymphocytic Leukemia
• Chronic Myelogenous Leukemia in Blast Crisis
• Anemia, Refractory, With Excess of Blasts
• Chronic Myeloproliferative Disease
• Chronic Lymphocytic Leukemia
• Small Lymphocytic Lymphoma
• Marginal Zone B-cell Lymphoma
• Follicular Lymphoma
• Lymphoplasmacytic Lymphoma
• Mantle-Cell Lymphoma
• Prolymphocytic Lymphoma
• Large Cell Non-Hodgkin's Lymphoma
• Lymphoblastic Lymphoma
• Burkitt's Lymphoma
• High Grade Non-Hodgkin's Lymphoma

• Biological: Treg cells
  Given by infusion on Day 0 after transplantation - Five doses of Treg (3 x 10^6/kg, 10 x 10^6/kg, 30 x 10^6/kg, 100 x 10^6/kg and 300 x 10^6/kg)
• Biological: CD3+ Teff cells
  Given by infusion on Day 0 after transplantation - 5 doses of CD3+ Teff cells (3 x 10^6 cells/kg, 6 x 10^6 cells/kg, 9 x 10^6 cells/kg, 12 x 10^6 cells/kg, and 15 x 10^6 cells/kg with the latter dose representing the median number of CD3+ cells in two UCB unit grafts
• Drug: Fludarabine
  Given intravenously on Days -8 through -6, 25 mg/m^2 over 1 hour
  Other Name: Fludara
• Drug: Cyclophosphamide
  Given intravenously on Day -7 and -6, 60 mg/kg
  Other Name: Cytoxan
• Radiation: Total body irradiation
  Given on Days -4 through -2, 165 cGY twice a day.
• Biological: Umbilical cord blood transplantation
  Infusion given on day 0
  Other Name: UCBT

Inclusion Criteria:

• Only patients requiring a double umbilical cord blood (UCB) transplant are to be considered for this study.

UCB Requirements

• Three UCB units are required - one for Treg production and two for UCB transplant. The unrelated UCB donors must be 4-6/6 HLA-A, B, DRB1 matched with the recipient (HLA matching using molecular techniques: A and B to antigen level resolution and DR to allele level resolution). Suitable UCB units will be selected according to the University Of Minnesota UCB Graft Selection Algorithm.
• Suitable UCB units must be ABO matched.

Disease Criteria:

• Patients aged 18 to 55 years
• Acute Myeloid Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy (if patient refuses or is disqualified from alternative protocols), or in 3rd or higher complete remission (CR).
• Acute Lymphocytic Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy, or in 3rd or higher CR
• Chronic Myelogenous Leukemia in Blast Crisis: with ≤10% residual blasts in the bone marrow aspirate after at least 1 cycle of induction chemotherapy in combination with a tyrosine kinase inhibitor (TKI)
• Refractory Anemia with Excess Blasts: (≤ 10%) in representative bone marrow aspirate sample of blasts after 1 cycle of induction chemotherapy. If treated with hypomethylating agents, patients are eligible if blast count is ≤ 10% after 4 cycles or evidence of stable or progressive disease after at least 2 cycles.
• Chronic Myeloproliferative Disease
• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Marginal Zone B-Cell Lymphoma or Follicular Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
• Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
• Large Cell Non-Hodgkin's Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
• Lymphoblastic Lymphoma, Burkitt's Lymphoma, and other High-Grade NHL: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
• Performance Status, Age, and Organ Function
• Adequate performance status defined as a Karnofsky score ≥ 80%

• Adequate organ function defined as:

  • Renal: creatinine < 2.0 mg/dL,
  • Hepatic: bilirubin, AST/ALT, ALP < 5 x upper limit of normal,
  • Pulmonary function: DLCOcorr > 50% normal,
  • Cardiac: left ventricular ejection fraction > 45%
• Voluntary written informed consent signed before performance of any study-related procedure not part of normal medical care

Exclusion Criteria:

• Available medically suitable HLA-identical related donor
• Active infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days)
• History of HIV infection
• Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy
• Prior myeloablative transplant within the last 6 months
• Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation
• Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tositumomab (Bexxar) as part of their salvage therapy (not eligible for myeloablative umbilical cord blood transplant)