Chemotherapy and a Donor Natural Killer Cell Infusion in Treating Patients With Relapsed or Persistent Leukemia or Myelodysplastic Syndrome After a Donor Stem Cell Transplant
Condition: Leukemia; Myelodysplastic Syndromes
MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: natural killer cell therapy; cyclophosphamide; fludarabine
Intervention description: The patient must be admitted by Day -8 to the Bone Marrow Transplant Service. On Day 0, patients will receive a single dose of allogeneic NK cells isolated from a HLA-haploidentical related donor and will be monitored for hematopoietic recovery.; Day -6 cyclophosphamide 60mg/kg infused over 1 hour (dose adjusted for body weight) for 2 days; Day -5 fludarabine 25mg/m2 CIV for 5 days
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Maximum age: 120 Years
Healthy volunteers: No
Keywords: recurrent adult acute lymphoblastic leukemia; recurrent adult acute myeloid leukemia; blastic phase chronic myelogenous leukemia; previously treated myelodysplastic syndromes; childhood myelodysplastic syndromes; recurrent childhood acute lymphoblastic leukemia; recurrent childhood acute myeloid leukemia; childhood chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; 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)

Summary:

      The goal of this study is to see if there is a benefit to giving chemotherapy and then
      natural killer (NK) cells. The NK cells must come from a family member who shares half of the
      patients HLA proteins. NK cells are a type of white blood cell. They can recognize and kill
      abnormal cells in the body.

      Patients whose blood cancer is not cured with a stem cell transplant do not have standard
      treatment options. Studies have shown that NK cells from a donor can be given safely and can
      be helpful in treating some blood diseases. These NK cells are collected from the patients
      donor and purified using a separation system called CliniMACS that has been used safely in
      previous studies and is used in this study with the approval of the Federal Food and Drug
      Administration. The researchers want to find out what effects the NK cells will have on blood
      cancer and bone marrow function and how to maximize its benefits in treating blood cancers.
      The researchers hope that giving chemotherapy and then NK cells will be a better treatment
      for the disease than the current available treatment options.

      Funding Source - Food and Drug Administration/Office of Orphan Products Development
    

Eligibility criteria:

        Subject Inclusion Criteria:

        Diagnosis and Status

          -  Patients with a pathologically confirmed diagnosis of relapsed or persistent resistant
             AML, MDS, or blastic CML following HSCT and who have been deemed ineligible for second
             HSCT after consideration of adequacy of their physical function, extent of disease,
             and prior treatment-related toxicities.

        Eligible patients have evidence of disease with ≥5% bone marrow involvement detected by
        morphology or abnormal cytogenetics (by karyotype or FISH). Patients with molecular
        detection of markers characteristic of the patient's disease from two consecutive bone
        marrow biopsies are also eligible. Following diagnosis of relapsed disease, treatment to
        reduce leukemic burden is allowed prior to protocol therapy without the need for additional
        disease documentation prior to cyclophosphamide and fludarabine.

          -  Patients with extramedullary relapse are eligible except for those with CNS
             involvement.

          -  Patients must have received an allogeneic HSCT.

          -  Patient must not be pregnant and must be using adequate form of birth control.

          -  Patients must have a Karnofsky (adult) or Lansky (pediatric) Performance Status ≥ 60%.

          -  Hospitalization does not preclude enrollment, as long as the patient's performance
             status is ≥ 60% according to the KPS grading scale.

          -  Patients must have adequate physical function measured by :

        Cardiac: asymptomatic and LVEF at rest must be > 50%. Hepatic: < 2x ULN ALT and < 1.5 total
        serum bilirubin, unless liver is involved with disease, there is congenital benign
        hyperbilirubinemia, or other reversible causes of hepatic abnormalities are documented.

        Renal: serum creatinine <1.5 mg/dl or if serum creatinine is outside the normal range, then
        CrCl > 50 ml/min Pulmonary: Patient cannot be oxygen-dependent.

          -  Patients with documented GVHD are not excluded from this trial, but either must not
             have used systemic immunosuppression for two weeks, or during immunosuppression taper
             have documented two subtherapeutic levels at least one week apart. Immunosuppressive
             agents include but are not limited to systemic steroids, calcineurin inhibitors,
             MTOR-inhibitors, Budesonide, anti-thymocyte globulin. The maximal allowable dose of
             corticosteroids is the equivalent of 10 mg/day prednisone.

          -  Patients with grade I/II acute GVHD or limited chronic GVHD and receiving localized
             GVHD therapy (e.g. topical steroids) are not excluded from this trial.

          -  Patients having received previous adoptive cellular therapy such as donor lymphocyte
             infusion (DLI) are not excluded from this trial as long as their disease has been
             documented to progress within two months of receiving DLI or if the patient has not
             received DLI within two months of NK cell infusion.

          -  Patients who have received cytoreductive therapy following documentation of relapse
             and prior to enrollment are not excluded from this trial. The interval between
             standard reinduction chemotherapy and start of protocol chemotherapy should be a
             minimum of 2 weeks, and all induction chemotherapy-related toxicities should be
             documented to be completely resolved. For patients receiving nonintensive
             chemotherapies such as hydroxyurea or low-dose cytarabine, nonintensive chemotherapies
             should be discontinued upon initiation of protocol chemotherapy.

          -  Each patient must be willing to participate as a research subject and must sign an
             informed consent form. Parents or legal guardians of patients who are minors may sign
             the informed consent form

          -  Patients must have an eligible NK donor.

          -  There are no age restrictions to this protocol.

        NK Cell Donor Eligibility

          -  Donor is blood-related and HLA-haploidentical to the recipient.

          -  Donor has undergone serologic testing for transmissible diseases as per blood banking
             guidelines for organ and tissue donors. Tests include but are not limited to: HepBsAg,
             HepBsAb, HepBcAb, HepC antibody, HIV, HTLV I and II, VZV, CMV and VDRL, and West Nile
             Virus . Donor must have normal negative test results for HIV, HTLV I and II, and West
             Nile Virus. Donor exposure to other viral pathogens will be discussed on a
             case-by-case basis by the Transplant team.

          -  Donor has a CXR and EKG performed.

          -  Donor must be able to undergo leukopheresis for total volume of 10-15 liters.

          -  Donor is not pregnant.

          -  Donor does not have concurrent malignancy or autoimmune disease.

          -  There is no age restriction for the donor.

        Subject Exclusion Criteria:

          -  Patients on systemic immunosuppression with therapeutic drug levels. Patients whose
             immunosuppression is being actively tapered and have documentation of subtherapeutic
             drug levels one week apart are not excluded from enrollment. For patients receiving
             corticosteroids, the maximal allowable dose of corticosteroids is the equivalent of 10
             mg/day prednisone.

          -  Patients with untreated or uncontrolled active infection. Infections that are
             controlled or being appropriately treated does not exclude a patient from enrollment.

        NK Cell Donor Exclusion

          -  Donor has cardiac risk factors precluding ability to undergo leukopheresis.

          -  Donor has evidence of concurrent malignancy or autoimmune disease.

          -  Donor is pregnant.