Donor Umbilical Cord Blood Natural Killer Cells, Aldesleukin and Umbilical Cord Blood Transplant in Patients With Refractory Hematologic Cancers.
Condition: Leukemia; Myelodysplastic Syndromes
MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: aldesleukin; filgrastim; natural killer cell (NK) therapy; cyclophosphamide; cyclosporine; fludarabine phosphate; methylprednisolone; mycophenolate mofetil; Umbilical Cord Blood Transplantation (UCBT); Total body irradiation (TBI)
Intervention description: 10 Million units subcutaneous every other day on days -13 (after Natural killer cell graft), -11, -9, -7, -5, -3) If < 45 kilograms (Kg) - interleukin (IL)-2 at 5 MU/m2; All patients will receive filgrastim (same as granulocyte-colony stimulating factor or G-CSF) 5 mcg/kg/day intravenous (IV) (dose rounded to vial size) based on the actual body weight beginning on day +1 after umbilical cord blood (UCB) infusion. Granulocyte Colony Stimulating Factor (G-CSF) will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10^9/L for three consecutive days and then discontinued. If the ANC decreases to <1.0 x 10^9/L, G-CSF will be reinstituted.; All CD3 depleted cells will be given (less those required for product monitoring). The minimum size of a starting NK cell unit will be 700 million mononuclear cells before processing. NK cells (CD56+) and NK cell precursors (CD34+/CD7-, CD34+/CD7+, CD34-/CD7+) will be monitored and reported but will not serve as lot release.; Cyclophosphamide to be administered with high volume fluid flush and mesna on days-18 and -17 after fludarabine. Cyclophosphamide 60 mg/kg/day intravenously (IV) x 2 days, total dose 120 mg/m2 (days -18 and -17); Patients will receive cyclosporine (CSA) therapy beginning on day -1 maintaining a level of >200 ng/mL. For adults the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours. For children <40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours.; Fludarabine 25 mg/m2/day intravenously (IV) x 3 days, total dose 75 mg/m2 (days -18 to -16); This modification will be enacted based on the engraftment stopping rule on all subsequent patients to stop natural killer (NK) cell reaction.
Methylprednisolone bolus 1000 mg intravenously (IV) will be administered day -1 and day 0 (before umbilical cord blood transplant) to suppress natural killer (NK) cell activity before transplant. Starting cyclosporin and mycophenolate mofetil (MMF) will also contribute to suppressing residual NK cell activity.; All patients will begin mycophenolate mofetil (MMF) on day -1. Patients
≥ 45 kilograms will receive MMF at the dose of 3 grams/day divided into 2 or 3 doses. Pediatric patient (<45 kilograms) will receive MMF at the dose of 15 mg/kg. Use intravenous (IV) route between days -1 and +5, then, if tolerated, may change to by mouth (PO) between days +6 and +30.
Stop MMF at day +30 or 7 days after engraftment, whichever day is later, if no acute Graft Versus Host Disease. (Definition of engraftment is 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 x 10^9 /L).; The product is infused via intravenous (IV) drip directly into the central line without a needle, pump or filter.; TBI 165 Gray (cGy) will be given twice daily for a total dose of 1320 cGy (days
-16 to -13).
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Aldesleukin; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Interleukin-2; Cyclosporins; Lenograstim; Prednisolone hemisuccinate; Prednisolone phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Maximum age: 45 Years
Healthy volunteers: No
Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); atypical chronic myeloid leukemia; blastic phase chronic myelogenous leukemia; childhood chronic myelogenous leukemia; previously treated myelodysplastic syndromes; recurrent adult acute myeloid leukemia; recurrent childhood acute myeloid leukemia; relapsing chronic myelogenous leukemia; secondary acute myeloid leukemia; secondary myelodysplastic syndromes; childhood myelodysplastic syndromes

Summary:

      RATIONALE: Giving chemotherapy, natural killer cells, aldesleukin, and total-body irradiation
      before a donor umbilical cord blood stem cell transplant helps stop the growth of abnormal
      cells and cancer cells. It also helps stop the patient's immune system from rejecting the
      donor's 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. Sometimes the transplanted cells from a donor can make an immune response
      against the body's normal cells. Giving cyclosporine, mycophenolate mofetil, and
      methylprednisolone before and after transplant may stop this from happening.

      PURPOSE: This clinical trial is studying how well giving fludarabine and cyclophosphamide
      together with total-body irradiation followed by donor umbilical cord blood natural killer
      cells, aldesleukin, and umbilical cord blood transplant works in treating patients with
      refractory hematologic cancer or other diseases.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of 1 of the following:

               -  Acute myeloid leukemia with active leukemia (i.e., not in complete remission
                  [CR]), defined by light microscopy (bone marrow) and having failed ≥ 1 round of
                  standard chemotherapy

               -  Chronic myelogenous leukemia with myeloid blast crisis not in second chronic
                  phase after ≥ 1 course of standard chemotherapy and imatinib mesylate

               -  Myelodysplastic syndromes (MDS) or other myeloproliferative disorders more than
                  10% blasts after ≥ 1 course of standard chemotherapy

          -  Unrelated umbilical cord blood (UCB) donor(s) available - Each unit must be 4-6/6
             HLA-A, -B, and -DRB1 matched with the recipient (and to each other if 2 units are
             utilized) (for UCB graft) AND 3/6 HLA-A, -B, and -DRB1 matched with the recipient (for
             UCB natural killer [NK] cells)

          -  Karnofsky performance status (PS) 80-100% (adult patients) or Lansky PS 50-100%
             (pediatric patients)

          -  Creatinine ≤ 2.0 mg/dL (adult patients) OR creatinine clearance > 40 mL/min (pediatric
             patients)

          -  Bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline
             phosphatase ≤ 5 times upper limit of normal (ULN)

          -  Corrected Carbon Monoxide Diffusing Capacity (DLCO) > 50% normal OR oxygen saturation
             > 92% (in pediatric patients who cannot undergo pulmonary function tests)

          -  Left ventricular ejection fraction ≥ 45%

        Exclusion Criteria:

          -  Pregnant or nursing

          -  Positive pregnancy test (Fertile patients must use effective contraception)

          -  History of HIV infection

          -  Active infection at time of transplantation

               -  Active infection with Aspergillus or other mold within the past 120 days

          -  Less than 6 months since prior myeloablative transplant (≤ 18 years old)

          -  Prior myeloablative allotransplant or autologous transplant (> 18 years old)

          -  No prior extensive therapy including > 12 months of any alkylator chemotherapy or > 6
             months of alkylator therapy with extensive radiation (e.g., mantle irradiation for
             Hodgkin's lymphoma)

          -  Prior radiation therapy that would make the patient ineligible for total-body
             irradiation