Adoptive TReg Cell for Suppression of aGVHD After UCB HSCT for Heme Malignancies
Condition: Acute Lymphoblastic Leukemia; Burkitt Lymphoma; Natural Killer Cell Malignancies; Chronic Myelogenous Leukemia; Myelodysplastic Syndromes; Large-cell Lymphoma; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Marginal Zone B-Cell Lymphoma; Follicular Lymphoma; Lymphoplasmacytic Lymphoma; Mantle-Cell Lymphoma; Prolymphocytic Leukemia; Hodgkin Lymphoma; Multiple Myeloma; Acute Myelogenous Leukemia; Biphenotypic Leukemia; Undifferentiated Leukemia
MeSH terms: Burkitt Lymphoma; Lymphoma; Leukemia; Multiple Myeloma; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Lymphoma, Mantle-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma, B-Cell, Marginal Zone; Leukemia, Myeloid, Acute; Leukemia, Prolymphocytic; Waldenstrom Macroglobulinemia; Myelodysplastic Syndromes
Intervention: Infusion of Treg
Intervention description: Allopurinol on day -7 to day 0 Cyclophosphamide 50 mg/kg IV over 2 hours on day -6 Fludarabine 30mg/m2 IV over 1 hour on day -6, -5, -4, -3, and -2 Total Body Irradiation 200 cGy as a single dose
Sirolimus 8mg-12mg oral loading dose followed by single dose 4mg/day. Levels are to be monitored 3 times/week in the first week, weekly until day +60, and as clinically indicated until day +100 post-transplantation.
Mycophenolate Mofetil (MMF) 3 gram/day IV/PO divided in 2 or 3 doses. Stop MMF at day +30 or 7 days after neutrophil recovery, whichever day is later, if no acute GVHD.
DUCBT followed Tregs - double umbilical cord blood transplant (FIRST) followed by the Treg cell infusion (SECOND) no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: CML; MDS; CLL; ALL; AML

Summary:

      This is a single center pilot study of a non-myeloablative umbilical cord blood transplant
      for the treatment of a hematological malignancy with a single infusion of T regulatory (Treg)
      given shortly after UCB transplantation.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must be ≥18, but < 70 years of age with no matched 7/8 or 8/8 sibling donor - patients
             ≥ 70 and ≤ 75 years of age may be eligible if they have a Co-Morbidity score ≤ 2
             (http://www.qxmd.com/calculate-online/hematology/hct-ci)

          -  UCB unit(s) composing the graft will be selected according to the current University
             of Minnesota umbilical cord blood graft selection algorithm and an additional cord
             blood unit to be used as the source to manufacture the Treg product. This UCB unit
             must be matched at 4-6/6 to the patient, considering HLA-A, B at the antigen level and
             DRB1 at the allele level

          -  Acute Leukemias: Must be in remission by morphology. Also a small percentage of blasts
             that is equivocal between marrow regeneration versus early relapse are acceptable
             provided there are no associated cytogenetic markers consistent with relapse. Refer to
             Section 5.2 for complete definitions.

          -  Burkitt's Lymphoma in CR2 or subsequent CR

          -  Natural Killer Cell Malignancies

          -  Chronic Myelogenous Leukemia: all types except refractory blast crisis. Chronic phase
             patients must have failed at least two different tyrosine-kinase inhibitors (TKIs), or
             been intolerant to all available TKIs or have T315I mutation.

          -  Myelodysplastic Syndrome: IPSS INT-2 or High Risk; R-IPSS High or Very High; WHO
             classification: RAEB-1, RAEB-2; Severe Cytopenias: ANC < 0.8, Anemia or
             thrombocytopenia requiring transfusion; Poor or very poor risk cytogenetics based on
             IPSS or R-IPSS definitions; therapy-related MDS. Blasts must be be < 5%, preferably <
             20% blasts by morphology by bone marrow aspirate morphology.. If ≥ 5% blasts,
             chemotherapy for cytoreduction to <5% blasts prior to transplantation may be
             considered.

          -  Chronic myeloid neoplasms, including but not limited to CMML with blasts must around
             5% blasts, preferably < 20% blasts by morphology by bone marrow aspirate morphology.
             If ≥5% blasts, chemotherapy for cytoreduction to <5% blasts prior to transplantation
             may be considered.

          -  Large-Cell Lymphoma, Hodgkin Lymphoma and Multiple Myeloma with chemotherapy sensitive
             disease that has failed or patients who are ineligible for an autologous transplant.

          -  Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone
             B-Cell Lymphoma, Follicular Lymphoma, which have progressed within 12 months of
             achieving a partial or complete remission. Patients who had remissions lasting > 12
             months are eligible after at least two prior therapies. Patients with bulky disease
             should be considered for debulking chemotherapy before transplant. Patients with
             refractory disease are eligible, unless has bulky disease and an estimated tumor
             doubling time of less than one month.

          -  Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia are eligible
             after initial therapy if chemotherapy sensitive.

          -  Patients must have undergone an autologous transplant ≤ 12 months prior to transplant
             on this study or have received multi-agent or immunosuppressive chemotherapy within 3
             months of the preparative regimen.

        Performance Status, Organ Function, Contraception Use

          -  Karnofsky score ≥ 70% (Appendix II)

          -  Adequate organ function within 14 days (30 days for cardiac and pulmonary) of
             registration on-study defined as:

               -  Renal: creatinine ≤ 2.0 mg/dL, for patient with a creatinine > 1.2 mg/dL or a
                  history of renal dysfunction an estimated glomerular filtration rate ≥ 40
                  mL/min/1.73 m2 is required

               -  ALT, AST and alkaline phosphatase ≤ 5 x upper limit of normal and total bilirubin
                  ≤ 2.5 mg/dL except for patients with Gilbert's syndrome or hemolysis

               -  Pulmonary function: DLCO, FEV1, FVC ≥ 40% predicted, and absence of O2
                  requirements.

               -  Cardiac: Absence of decompensated congestive heart failure, or uncontrolled
                  arrhythmia and left ventricular ejection fraction ≥ 40%.

          -  Sexually active females of childbearing potential and males with partners of
             child-bearing potential must agree to use adequate birth control during study
             treatment.

          -  Voluntary written consent

        Exclusion Criteria:

          -  Untreated active infection

          -  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 allogeneic transplantation

          -  Less than 3 months from myeloablative conditioning for autologous transplantation (if
             applicable)

          -  Evidence of progressive disease by imaging modalities or biopsy - persistent PET
             activity, though possibly related to lymphoma, is not an exclusion criterion in the
             absence of CT changes indicating progression.

          -  CML in blast crisis

          -  Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressing on
             salvage therapy.

          -  Active central nervous system malignancy