Alloreactive Haploidentical Natural Killer (NK) Cells With Busulfan and Fludarabine/ATG
Condition: Leukemia; Chronic Myelogenous Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Intervention: Fludarabine; Busulfan; NK cell infusion:; Interleukin-2; Anti-Thymocyte Globulin; Allogeneic related Stem Cell Transplant; Tacrolimus; Methotrexate; G-CSF
Intervention description: 40 mg/m2 intravenous over one (1) hour on each of four (4) consecutive days, Days -13 to -10.; 130 mg/ m2 by vein for 2 doses on Days -11 to -10.; Natural killer cell infusion will be administered by vein on Day -8.; 0.5 million units subcutaneously daily for 5 days on Day -8 to day -4.; 2.5 mg/kg by vein for 3 doses on Days -3 to -1.; Allogeneic related stem cell transplant by vein on day 0.; Starting dose of 0.015 mg/kg (ideal body weight) as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml.; 5 mg/m2 by vein Days 1, 3 and 6 post transplant.; 5 mcg/kg/day subcutaneously beginning on Day + 7, and continuing until the absolute neutrophil count (ANC) is > 500 x 10/L for 3 consecutive days.
Intervention MeSH terms: Aldesleukin; Methotrexate; Fludarabine phosphate; Fludarabine; Busulfan; Interleukin-2; Tacrolimus; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Alloreactive haploidentical NK cells; Natural killer cells; Stem Cell Transplantation; Immune cells; Chronic myelogenous leukemia; CML; Human leukocyte antigen; HLA; Graft-vs-host disease; GVHD; Antithymocyte globulin; ATG; Thymoglobulin; Interleukin-2; IL-2; Aldesleukin; Proleukin; Fludarabine; Fludarabine phosphate; Fludara; Tacrolimus; Prograf; Busulfan; Busulfex; Myleran; Methotrexate

Summary:

      The goal of this clinical research study is to learn if giving a kind of immune cell called
      natural killer (NK) cells after chemotherapy will improve the response to a stem cell
      transplant in patients with CML. The safety of this treatment will also be studied.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients who meet the following eligibility criteria are eligible for inclusion in
             this study. Pediatric team to assess eligibility appropriate for patient age.

          2. Age </= 70 years of age.

          3. Patients with diagnosis of CML in first chronic phase or accelerated phase with less
             than 15% blast in the blood and bone marrow at study entry which has failed to respond
             adequately to imatinib by the consensus criteria of Baccarani et al: a) no hematologic
             remission at 3 months, b) no cytogenetic response at 6 months, c) no major cytogenetic
             response at 12 months, d) no complete cytogenetic response or major molecular response
             at >18 months, or e) loss of a response with increasing cytogenetic or molecular
             evidence of disease. Or are intolerant to tyrosine kinase inhibitor therapy. Or with
             second or greater chronic phase (with prior transformation who respond to treatment
             and have <15% blasts at study entry).

          4. Histocompatible stem cell donor: Patients must have an HLA matched related or
             unrelated donor (HLA A, B, C and DR) willing to donate for allogeneic hematopoietic
             transplantation.

          5. Haploidentical NK cell donor: Patients must have a haploidentical relative with the
             absence of a KIR-ligand (HLA molecule).

          6. Performance status: Zubrod </= 2 or Lansky PS greater or equal to 70%.

          7. Cardiac function: left ventricular ejection fraction >/= 40%. No uncontrolled
             arrhythmias or uncontrolled symptomatic cardiac disease.

          8. Pulmonary function: no symptomatic pulmonary disease. forced expiratory volume at one
             second (FEV1), forced vital capacity (FVC) and diffusion capacity of lung for carbon
             monoxide (DLCO) >/= 50% of expected, corrected for hemoglobin. For pediatric patients,
             if unable to perform pulmonary function tests (most children < 7 years of age), pulse
             oximetry >/= 92% on room air by pulse oximetry.

          9. Renal function: Serum creatinine </= 1.8mg/dl or creatinine clearance greater or equal
             than 40 cc/min. Creatinine for pediatric patients </= 1.5 mg/dl or </= 2 times upper
             limit of normal for age (whichever is less).

         10. Liver function: Bilirubin </= 1.5 mg/dl (unless Gilbert's syndrome), ALT or AST </=
             200 IU/ml for adults unless related to underline disease. For pediatric patients
             conjugated (direct) bilirubin <2x upper limit of normal, ALT or AST <5 times upper
             limit of normal.No evidence of chronic active hepatitis or cirrhosis. If positive
             hepatitis serology, discuss with Study Chairman and consider liver biopsy.

         11. Patient or patient's legal representative, parent(s) or guardian able to provide
             written informed consent. Assent as is age appropriate.

        Exclusion Criteria:

          1. Uncontrolled infection, not responding to appropriate antimicrobial agents after seven
             days of therapy. The Protocol PI is the final arbiter of eligibility.

          2. Pleural/pericardial effusion or ascites estimated to be >1L

          3. HIV-positive.

          4. Breast feeding or pregnancy. Pregnancy means a positive beta human chorionic
             gonadotropin (HCG) test in a woman with child bearing potential defined as not
             post-menopausal for 12 months or no previous surgical sterilization.

          5. Known allergy to mouse proteins

          6. Active hepatitis B or C infection.