Clinical Trials /

Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies



This phase I/II trial studies the side effects and best dose of donor natural killer cells when given together with donor stem cell transplant and to see how well they work in treating patients with myeloid malignancies that are likely to come back or spread. Giving chemotherapy, such as busulfan and fludarabine phosphate, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells and natural killer 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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting


Phase 1/Phase 2

Trial Eligibility



  • Brief Title: Natural Killer (NK) Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies
  • Official Title: Natural Killer (NK) Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2012-0819
  • SECONDARY ID: RP110553-P3
  • SECONDARY ID: NCI-2013-00993
  • NCT ID: NCT01823198


  • Leukemia


BusulfanBusulfex, Myleran+ Chemotherapy + NK Cell infusion + Stem Cell Transplant
Fludarabine+ Chemotherapy + NK Cell infusion + Stem Cell Transplant
Interleukin-2IL-2, Aldesleukin, Proleukin+ Chemotherapy + NK Cell infusion + Stem Cell Transplant
G-CSFFilgrastim, Neupogen+ Chemotherapy + NK Cell infusion + Stem Cell Transplant
TacrolimusPrograf+ Chemotherapy + NK Cell infusion + Stem Cell Transplant
Methotrexate+ Chemotherapy + NK Cell infusion + Stem Cell Transplant


Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant. The goal of this clinical research study is to find the highest tolerable dose of immune cells called natural killer (NK) cells that can be given with chemotherapy and a stem cell transplant to patients with AML and MDS. Researchers want to learn if adding NK cells will help make the stem cell transplant more effective in treating the disease. The safety of this treatment will also be studied. NK cells may kill cancer cells that remain in your body after your last chemotherapy treatment. The NK cells will be separated from blood from a relative of yours or from umbilical cord blood. These separated NK cells will then be grown in the lab to increase the number of NK cells that can be given to you by vein. The chemotherapy given on this study will consist of the following drugs: - Busulfan is designed to kill cancer cells by binding to DNA (the genetic material of cells), which may cause cancer cells to die. Busulfan is commonly used in stem cell transplants. - Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the cancer cells to die. - IL-2 (interleukin-2) is a naturally occurring protein (cytokine) that can enhance NK cell function. This is an investigational study. Busulfan, fludarabine, and IL-2 are FDA approved and commercially available for the treatment of other types of cancer. Their use for the treatment of AML and MDS is investigational. The use of NK cells is investigational. The NK cell process is not FDA approved or commercially available. It is currently being used for research purposes only. Up to 72 patients will take part in this study. All will be enrolled at MD Anderson.

Detailed Description

      Central Venous Catheter:

      If you choose to take part in this study, the chemotherapy, some of the other drugs in this
      study, the NK cells, and the stem cell transplant will be given by vein through your central
      venous catheter (CVC). A CVC is a sterile flexible tube and needle that will be placed into a
      large vein while you are under local anesthesia. Blood samples will also be drawn through
      your CVC. The CVC will remain in your body during treatment. Your doctor will explain this
      procedure to you in more detail, and you will be required to sign a separate consent form.

      NK Cell Dose Levels:

      You will be assigned to a dose level of NK cells based on when you joined this study. Up to 4
      dose levels of NK cells will be tested. The first group of participants will receive the
      lowest dose level. Each new group will receive a higher dose than the group before it, if no
      intolerable side effects were seen. This will continue until the highest tolerable dose of NK
      cell is found.

      Chemotherapy, NK Cell infusion, and Stem Cell Transplant:

      For a stem cell transplant, the days before you receive your stem cells are called minus
      days. The day you receive the stem cells is called Day 0. The days after you receive the stem
      cells are called plus days.

      You will receive a dose of busulfan by vein over about 3 hours as an outpatient within 2
      weeks of your hospital admission or as an inpatient on Day -15. With the first busulfan
      infusion, about 11 samples of blood (about 1 teaspoon each time) will be drawn for
      pharmacokinetic (PK) testing at various time points before and after you receive your first
      dose of busulfan. The study staff will tell you the blood testing schedule. PK testing
      measures the amount of study drug in the body at different time points. The PK testing will
      help the doctor decide your dose of busulfan for Days -13 through -10.

      A heparin lock line will be placed in your vein to lower the number of needle sticks needed
      for these draws. If it is not possible for the PK tests to be performed, you will receive the
      standard dose of busulfan.

      On Days -13 through -10, you will receive fludarabine by vein over 1 hour, then busulfan by
      vein over 3 hours.

      On Day -9, you will rest.

      On Day -8, you will receive NK cells by vein over about 1 hour.

      On Days -8 through -4, you will receive IL-2 as an injection under your skin.

      On Day -3, you will rest.

      On Day 0, you will receive the stem cell transplant by vein.

      On Days +3 and +4, you will receive cyclophosphamide by vein over 3 hours. Cyclophosphamide
      is given to lower the immune system in order to lower the risk of graft-versus-host disease
      (GVHD -- when transplanted immune tissue, such as donor NK and stem cells, attacks the
      tissues of the recipient's body). You will also receive mesna by vein over 30 minutes every 4
      hours for a total of 10 mesna doses on Days +3 and +4. Mesna is given to lower the risk of
      side effects to the bladder caused by cyclophosphamide.

      Beginning on Day +5, you will receive tacrolimus nonstop by vein. This will continue until
      you are able to take it by mouth. Tacrolimus is given to help prevent transplant rejection.

      When you are able to take tacrolimus by mouth, you will take it 1 time or 2 times a day for
      about 6 months and then your doctor will tell you how to taper it off (gradually stop taking

      You will receive filgrastim as an injection under the skin 1 time a day, starting 1 week
      after the transplant, until your blood cell levels return to normal. Filgrastim is designed
      to help with the growth of white blood cells.

      You will be given standard drugs to help decrease the risk of side effects. You may ask the
      study staff for information about how the drugs are given and their risks.

      Study Visits:

      On about Days -7, -5, and +7, blood (about 5 tablespoons each time) will be drawn to check
      the level of the infused NK cells and to check your immune system.

      After you finish chemotherapy and the cell infusion, your follow-up care will be the standard
      of care for stem cell transplants. Before you are able to go home from the hospital, you will
      be given written information and be taught how often you will come to the hospital/clinic,
      take drugs at home, and what side effects you may have and what to do for them.

      The study staff will also stay in contact with your local doctor to find out if the disease
      comes back and to check how you are doing.

      Length of Study:

      You will be on active study for up to about +30 days. You may be taken off study early if the
      disease gets worse, if you are unable to receive the NK cell infusion due to product
      contamination or insufficient cell dose, if your transplant does not "take" (graft failure),
      if you have any intolerable side effects, if you are unable to follow study directions, if
      your doctor thinks it is in your best interest, if the study is stopped, or if you choose to
      leave the study early.

      You should talk to the study doctor if you want to leave the study early. If you are taken
      off study early, you still may need to return for routine post-transplant follow-up visits,
      if your transplant doctor decides it is needed.

      If you are thinking about dropping out of this study, please tell the study doctor. The
      doctor can tell you about the effects of stopping treatment. You and the doctor can talk
      about what follow-up care and testing would help you the most.

      If you leave the study, your test results and information cannot be removed from the study

Trial Arms

+ Chemotherapy + NK Cell infusion + Stem Cell TransplantExperimentalBusulfan "test dose" of 32 mg/m2 within 2 weeks of the preparative regimen. Fludarabine 40 mg/m2 by vein on Day -13 to Day -10. Busulfan adjusted dose determined to achieve systemic exposure represented by an average daily AUC of 6000 µMol-min ± 5% for the entire 4-day treatment period on Day -13 to Day -10. Patients over age 60 and/or with performance status =2 receive and AUC of 4000 microM x min for each dose. Alloreactive NK infusion on Day -8. Alloreactive NK cell infusion given at one of 4 dose levels based on the number of NK cells (CD3-,CD 56+ cells)/kg recipient body weight. Dose levels are: 10^6, 10^7, 3 x 10^7, 10^8. Interleukin-2 0.5 million units subcutaneously on Day -8 to Day -4. Hematopoietic stem cell infusion on Day 0.
  • Busulfan
  • Fludarabine
  • Interleukin-2
  • G-CSF
  • Tacrolimus
  • Methotrexate

Eligibility Criteria

        Inclusion Criteria:

          1. Patients with age </= 65 years with one of the following:

          2. Acute myeloid leukemia who fail to achieve complete remission with one course of
             induction chemotherapy or after relapse. Patients must have less than 20% bone marrow
             or peripheral blood blasts.

          3. Acute myeloid leukemia in first remission with any of the following high risk features
             defined as: (i) Adverse cytogenetics: -5, del 5q, -7, del7q, abnormalities involving
             3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype [> 3 abnormalities] (ii) Preceding
             myelodysplastic or myeloproliferative syndrome; (iii) Presence of high risk molecular
             abnormalities including FLT3 mutations, DNMT3A, TET2; ras; kit; (iv) FAB M6 or M7
             classification; (v) treatment-related AML. (vi) residual cytogenetic or molecular

          4. Myelodysplastic syndromes with intermediate, high or very high risk R-IPSS score, CMML
             or therapy related MDS.

          5. CML which: (i) failed to achieve a cytogenetic remission to tyrosine kinase inhibitor
             treatment or has a cytogenetic relapse; or (ii) has ever been in accelerated phase or
             blast crisis.

          6. Patient must have an identified a HLA (A,B,C,DR) compatible related or unrelated donor
             who is age 16 years of age or older and weighs at least 110 pounds for the stem cell

          7. Zubrod performance status 0 to 2 or Karnofsky of at least 60.

          8. Left ventricular ejection fraction >/= 45%. No uncontrolled arrhythmias or
             uncontrolled symptomatic cardiac disease.

          9. FEV1, FVC and DLCO >/= 50% of expected, corrected for hemoglobin.

         10. Adequate liver function: a. Bilirubin </= 1.5 mg/dl (unless Gilbert's syndrome). b.
             SGPT </= 200 IU/ml unless related to patient malignancy. c. Hepatitis B surface
             antigen negative and hepatitis C antibody negative. d. No evidence of chronic active
             hepatitis or cirrhosis. e. Patients with a history of hepatitis C, but have a negative
             viral load, are eligible. f. The protocol chairman will determine the eligibility of
             patients related to hepatic abnormalities.

         11. Serum creatinine <1.5 mg%.

         12. Patient or patient's legal representative, parent(s) or guardian able to sign informed
             consent. Patients aged 7 to <18 to provide assent.

         13. Pediatric patients (age 7-18 years) will be entered only after 3 adult patients have
             been entered without dose limiting toxicity.

        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 >1L.

          3. Patients who are known to be HIV-seropositive.

          4. Pregnancy: Positive pregnancy test in a woman with child bearing potential defined as
             not post-menopausal for 12 months or no previous surgical sterilization.

          5. Women of child bearing potential not willing to use an effective contraceptive measure
             while on study.

          6. Patients who are known to have allergy to mouse proteins.
Maximum Eligible Age:65 Years
Minimum Eligible Age:7 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Natural Killer (NK) Cell Dose
Time Frame:42 days
Safety Issue:
Description:Optimal NK cell dose determined in each of three distinct patient subgroups, A = KIR mismatched haplo donors, B = KIR mismatched cord blood donors, C = matched SIB donors. Same dose-finding design used within each subgroup. Four NK cell doses studied are: 106, 107, 3 x 107, and 108 NK cells. Cohorts of 2 patients used, starting at lowest NK cell dose level. Dose-limiting toxicity (DLT) defined as any of the events graft failure, severe (grade 3,4) infusional toxicity, severe grade 4 organ toxicity, or death by day 42.


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Leukemia
  • Acute myeloid leukemia
  • AML
  • Myelodysplastic syndromes
  • MDS
  • Blood And Marrow Transplantation
  • Myeloproliferative Diseases
  • High Risk Myeloid Malignancies
  • Allogeneic stem cell transplant
  • Natural Killer Cells
  • NK
  • Immune cells
  • Stem cell transplant
  • Busulfan
  • Busulfex
  • Myleran
  • Interleukin-2
  • IL-2
  • Aldesleukin
  • Proleukin
  • Thymoglobulin
  • Antithymocyte globulin
  • ATG
  • G-CSF
  • Filgrastim
  • Neupogen
  • Tacrolimus
  • Prograf
  • Methotrexate

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