NK Cell Based Non-Myeloablative Transplantation in Acute Myeloid Diseases
Condition: Acute Myeloid Leukemia; Myelodysplastic Syndrome
MeSH terms: Myelodysplastic Syndromes
Intervention: Preparative Regimen; NK Cells; Interleukin-2; CD34 Graft/Anti-thymocyte globulin; Donor TCR α/β-depleted Graft/ATG
Intervention description: Preparative Regimen:
1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,; CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.; Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion; Single donor filgrastim mobilized CD34+ selected peripheral blood stem cell graft (minimum cell dose of 5 x 10^6/kg) on day 0. Rabbit anti-thymocyte globulin (ATG) will be administered on day -1 (0.5 mg/kg) and day +1 and +2 (2.5 mg/kg) pretransplant per institutional guidelines. ATG dosing not identical for all patients.; Single donor TCR α/β-depleted filgrastim-mobilized peripheral blood stem cells (PBSC) graft (minimum cell dose of 5 x 10^6/kg) on day 0. ATG will be administered on days -6 and -5 (3mg/kg) for most patients.
Intervention MeSH terms: Interleukin-2; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: non-myeloablative haploidentical transplant; hematopoietic cell transplant; natural killer cells; adoptive cellular therapy

Summary:

      This is a phase II multi-institutional therapeutic study of NK-cell based nonmyeloablative
      haploidentical transplantation for the treatment of high-risk acute myeloid diseases.
      Enrollment will use a two-stage design. Stage 1 will enroll 15 patients unless an early
      stopping rule is met. If 9 or more of these first 15 patients achieve leukemia free
      neutrophil engraftment at day +28 accrual will move to stage 2. In stage 2, an additional 28
      patients will be enrolled for a total of 43 patients. Patients will be followed for disease
      response for 2 years.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

        RAEB-1 or RAEB-2 fitting within one of the following disease groups:

          -  Primary induction failure (PIF): Patients who have not achieved a complete remission
             (CR) after two induction cycles of cytotoxic therapy (i.e. 7+ 3, MEC, FLAG, etc.) and
             having ≤ 10,000 absolute circulating blasts measured at least 21 days from prior
             therapy. Hydroxyurea may be used to control blasts count. Demethylating agents do not
             count as induction therapy; however early re-induction therapy based on residual
             disease on a day 14 BM will count as a 2nd cycle

          -  Relapsed Disease with low disease burden (AML or MDS with ≤ 10,000 absolute
             circulating blasts. No re-induction attempts are required, but a maximum of 2
             reinduction attempts are allowed to be eligible.

          -  CR3 or greater: This will include CRp defined as CR without platelet recovery to
             100,000/mcL.

          -  CR1 or CR2 with high risk features: Includes therapy induced, prior MDS or MPD, high
             risk cytogenetic or molecular phenotype with no available donor (sibling or unrelated
             adult)

        Patients with known prior central nervous system (CNS) involvement are eligible provided
        that it has been treated and CSF is clear for at least 2 weeks prior to enrollment. CNS
        therapy (chemotherapy or radiation) should continue as medically indicated during the study
        treatment.

          -  Available related HLA-haploidentical adult donor by at least Class I serologic typing
             at the A&B locus

          -  Karnofsky score > 50%

          -  Adequate organ function within 28 days of study registration defined as:

               -  Hepatic: AST ≤ 3 x upper limit of institutional normal, total bilirubin ≤ 2.0
                  mg/dl

               -  Renal: estimated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m^2

               -  Pulmonary: Oxygen saturation ≥ 90% on room air and DLCOcor ≥ 40%

               -  Cardiac: Ejection Fraction ≥ 35% and no uncontrolled angina, severe uncontrolled
                  ventricular or arterial arrhythmias, or any evidence of acute ischemia or active
                  conduction system abnormalities (rate controlled atrial fibrillation is not an
                  exclusion)

          -  Able to be off prednisone or other immunosuppressive medications for at least 3 days
             prior to NK cell infusion (except for those prescribed as part of the study)

          -  Women of child bearing potential must have a negative pregnancy test within 28 days
             prior to study registration and agree to use adequate birth control during study
             treatment

          -  Voluntary written consent

        Exclusion Criteria:

          -  Biphenotypic leukemia

          -  Allogeneic transplant for AML within previous 6 months

          -  New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan
             that has not been evaluated with bronchoscopy, if feasible. Infiltrates attributed to
             infection must be stable/improving (with associated clinical improvement) after 1 week
             of appropriate therapy (4 weeks for presumed or documented fungal infections).

          -  Uncontrolled bacterial, fungal or viral infections including HIV - chronic
             asymptomatic viral hepatitis is allowed

          -  Known hypersensitivity to any of the study agents

          -  Received any investigational drugs within the 14 days before 1st dose of fludarabine

          -  Requires agents other than hydroxyurea to control blast count

        Donor Selection:

          -  Related donor (sibling, parent, offspring, parent or offspring of an HLA identical
             sibling) 12-75 years of age. (It is recognized individual institutions may have
             differing donor age guidelines. This is acceptable as long as no donor is younger than
             12 years or older than 75 years).

          -  Body weight of at least 40 kilograms

          -  In general good health as determined by the medical provider

          -  HLA-haploidentical donor/recipient match by at least Class I serologic typing at the
             A&B locus

          -  Able and willing to have up to 4 separate apheresis collections

          -  Not pregnant

          -  Voluntary written consent