t-regulatory cell and cd3 depleted double umbilical cord blood transplantation in hematologic malignancies

Conditions: 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

Summary: 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.

Eligibility criteria:
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)