Improving Blood Stem Cell Collection and Transplant Procedures
Condition: Myelodysplastic Syndrome (MDS); Chronic Myelogenous Leukemia; Acute Lymphoblastic Leukemia; CML (Chronic Myelogenous Leukemia; CLL (Chronic Lymphocytic Leukemia)
MeSH terms: Leukemia; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      - People who have some kinds of cancer can benefit from donated bone marrow stem cells. These
      stem cells help produce healthy bone marrow and slow or stop the spread of abnormal cells.
      However, stem cells transplants do not always work. Also, they may have serious side effects
      that can cause illness or death. The Bone Marrow Stem Cell Transplant Program is studying
      methods to make stem cell transplant procedures safer and more effective.

      Objectives:

      - To test a new procedure that may improve the success and decrease the side effects of stem
      cell transplants.

      Eligibility:

        -  Individuals 10 to 75 years of age who have a life-threatening illness that may require a
           stem cell transplant.

        -  Healthy siblings who are able to provide stem cells for transplant.

      Design:

        -  Participants will be screened with a medical history, physical exam, and blood and urine
           tests.

        -  Donor procedures:

        -  Stem cell donors will start by having apheresis to donate white blood cells.

        -  Donors will receive filgrastim shots for 5 days to help move stem cells into the blood
           for collection.

        -  Donors will have another round of apheresis to donate the stem cells for transplant.

        -  Recipient procedures:

        -  Before the transplant, recipients will have radiation twice a day for 3 days and
           chemotherapy for 7 days.

        -  After the radiation and chemotherapy, recipients will receive the stem cells provided by
           the donor.

        -  After the transplant, recipients will receive the white blood cells provided by the
           donor.

        -  Recipients will be monitored closely for 4 months to study the success of the
           transplant. They will have more followup visits at least yearly thereafter.

        -  Recipients will have a research apheresis prior to transplant and at 3 months.
    

Detailed description: 
      Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on
      transplant techniques designed to decrease graft versus host disease (GVHD), increase the
      graft-versus-leukemia (GVL) effect and reduce the risk of post-transplant graft rejection.

      Through incremental transplant clinical trials we have shown that by controlling the stem
      cell (CD34+ cell) and T lymphocyte (CD3+ cell) dose, severe GVHD can be reduced whilst
      beneficial GVL effects can be preserved. We found that T cell depleted transplants using the
      Nexell/Baxter Isolex 300i system and subsequently, the Miltenyi CD34+ CliniMACs system to
      obtain high CD34+ doses depleted of lymphocytes were safe to administer and associated with
      less severe acute GVHD and promising response rates and overall survival. Our previous trials
      have helped us to create the transplant environment (significant lymphodepletion and minimal
      post transplant immunosuppression) that make for an ideal platform for adoptive cellular
      immunotherapy

      This protocol is designed to evaluate the safety and efficacy of an improved ex vivo graft
      manipulation procedure using the Miltenyi CliniMACs CD 34, 3 and 19 selection system in
      HLA-matched sibling allogeneic peripheral blood stem cell transplant. The manipulation of the
      graft is the primary research intervention and all other aspects of clinical management on
      this protocol are the standard of care. The target CD34+ dose range will be 3 times 10(6)/kg
      to 10 times 10(6)/kg and the target CD3+ dose range will be 5 x 10(4)/kg to 1 times 10(6)/kg.
      The technique will preserve greater numbers of NK cells. Once we demonstrate adequacy of
      engraftment in the first ten recipients, we plan an amendment to permit further use of this
      protocol to serve as a platform for several planned adoptive cellular therapy initiatives.

      The protocol will accrue up to 44 subjects aged 10-75 with a hematological malignancy and
      their HLA-matched sibling donors, in whom allogeneic stem cell transplantation from an
      HLA-matched sibling would be routinely indicated. Diagnostic categories will include acute
      and chronic leukemia, myelodysplastic syndromes, lymphomas, multiple myeloma and
      myeloproliferative syndromes.

      Subjects will receive a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg
      total), fludarabine (125 mg/m(2) total) and total body irradiation (1200 cGy with lung
      shielding to 600 cGy), followed by an infusion of a stem cell product prepared using the
      Miltenyi CliniMACS system for CD34, 3 & 19 selection. Older subjects will receive a lower
      dose of irradiation (600 cGy) without lung shielding to reduce the regimen intensity.

      The overall objective is to assess the feasibility of using this system as a platform for
      cellular immunotherapy initiatives. The primary study endpoint will be overall survival at
      day plus 200. Non-relapse mortality at day plus 200 will be monitored for safety. Secondary
      endpoints will be standard transplant outcome variables such as non-hematologic toxicity,
      incidence and severity of acute and chronic GVHD and relapse of disease.
    

Intervention name(s): Stem Cell Transplantation
Intervention type(s): Procedure
Intervention description(s): Myeloablative conditioning (Flu/Cy/TBI) followed by CD3/19/34 selected stem cell graft.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Peripheral Blood Stem Cell Transplantation; Stem Cell Transplant; Transplant; Myelodyplastic Syndrome; MDS; Leukemia