Non-Myeloablative Conditioning for Unrelated Donor Umbilical Cord Blood Transplant
Condition: Myeloproliferative Disorders; Leukemia; Lymphoma; Myelodysplastic Syndromes
MeSH terms: Myelodysplastic Syndromes; Myeloproliferative Disorders
Intervention: anti-thymocyte globulin; cyclophosphamide; Fludarabine; mycophenolate mofetil; umbilical cord blood transplantation; total body irradiation; Sirolimus
Intervention description: Equine ATG dose is 15 mg/kg intravenously (IV) every 12 hours for 6 doses on days -6, - 5, and -4.; Cyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6.; Fludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2.; Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.; One or 2 UCB units may be infused to achieve the required cell dose.; Administered Day -1, 200 cGy; Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation.
Intervention MeSH terms: Mycophenolic Acid; Sirolimus; Cyclophosphamide; Fludarabine; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 295.0
Sex: All
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in
      different ways to stop the growth of cancer cells, either by killing the cells or by stopping
      them from dividing. Radiation therapy uses high-energy x-rays to kill cancer cells. An
      umbilical cord blood transplant may be able to replace blood-forming cells that were
      destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells from a
      donor can make an immune response against the body's normal cells. Giving sirolimus and
      mycophenolate mofetil after the transplant may stop this from happening.

      PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide
      together with total-body irradiation followed by an umbilical cord blood transplant,
      sirolimus, and mycophenolate mofetil works in treating patients with hematologic cancer.
    

Eligibility criteria:

        Inclusion Criteria:

        Age, Graft Cell Dose and Graft HLA Criteria

          -  Subjects must be <70 years old. Subjects ages ≥ 70 and ≤ 75 may be eligible if they
             have a Co-Morbidity Scoring (HCT-CI) score ≤ 2.

          -  The UCB graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient.

          -  Patients co-enrolled in MT-2006-01 Phase I Study of Infusion of Umbilical Cord Blood
             Derived CD25+CD4+ T-Regulatory (Treg) Cells after Non-Myeloablative Cord\Blood
             Transplantation will receive grafts composed of 2 UCB units.

        Disease Criteria:

          -  Acute Leukemias:

               -  Acute myeloid leukemia: high risk complete remission 1 (CR1) (as evidenced by
                  preceding myelodysplastic syndrome (MDS), high risk cytogenetics such as those
                  associated with MDS or complex karyotype, > 2 cycles to obtain CR or
                  erythroblastic and megakaryocytic); second or greater CR.

               -  Acute lymphoblastic leukemia/lymphoma: high risk CR1 as evidenced by high risk
                  cytogenetics (e.g. t(9;22), t(1;19),t(4;11), other myeloid/lymphoid or mixed
                  lineage leukemia [MLL] rearrangements, hypodiploidy or Ikaros family zinc finger
                  1 [IKZF1]), > 1 cycle to obtain CR or evidence of minimal residual disease (MRD).
                  Patients in second or greater CR are also eligible.

          -  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 or been intolerant to Gleevec

          -  Myelodysplastic syndrome:

          -  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.

          -  Refractory leukemia or MDS.

          -  Bone marrow failure syndromes, except for Fanconi Anemia

          -  Myeloproliferative syndromes Patients who have undergone an autologous transplant >12
             months prior to allogeneic transplantation

        Adequate Organ Function and Performance Status

        Exclusion Criteria:

          -  < 70 years with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor

          -  Pregnancy or breastfeeding

          -  Evidence of human immunodeficiency virus (HIV) infection or known HIV positive
             serology

          -  Current active serious infection

          -  Unless in post-chemotherapy and radioimmunoconjugated antibody induced aplasia, when
             he/she would be eligible for Arm 3, patients with acute leukemia in morphologic
             relapse/ persistent disease defined as > 5% blasts in normocellular bone marrow OR any
             % blasts if blasts have unique morphologic markers (e.g. Auer rods) or associated
             cytogenetic markers that allows morphologic relapse to be distinguished are not
             eligible.

          -  Chronic myelogenous leukemia (CML) in refractory blast crisis

          -  Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressive on
             salvage therapy. Stable disease is acceptable to move forward provided it is
             non-bulky.

          -  Active central nervous system malignancy