Stem Cell Transplantation and T-Cell Add-Back to Treat Bone Marrow Malignances
Condition: Immunosuppression; Leukemia
MeSH terms: Leukemia
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will evaluate the safety and effectiveness of stem cell transplantation in which
      the donor s T cells (a type of lymphocyte, or white blood cell) have been removed and then
      added back. Certain patients with bone marrow malignancies undergo transplantation of donated
      stem cells (cells produced by the bone marrow that mature into the different blood components
      white cells, red cells and platelets) to generate new and normally functioning bone marrow.
      However, T-cells from the donor may see the patient s cells as foreign and mount an immune
      response to reject them, causing what is called graft-versus-host-disease (GVHD). Therefore,
      in this study, T-cells are removed from the donor cells to prevent this complication.
      Nevertheless, there are disadvantages of removing the T-cells, since they are important in
      fighting viral infections as well as any remaining malignant cells. The attack against the
      malignant cells is called a graft-versus-leukemia effect. Therefore, donor T cells are given
      to the patient (added back) later (45 and 100 days after the transplant) when they can
      provide needed immunity with less risk of causing GVHD.

      Patients between 10 and 55 years of age with chronic myelogenous leukemia, acute
      lymphoblastic leukemia, acute myelogenous leukemia, a myelodysplastic syndrome,
      myeloproliferative disorders, or chronic lymphocytic leukemia may be eligible for this study.
      Prospective participants and their donors are screened with a medical history and physical
      examination, blood tests (including a test to match for genetic compatibility), breathing
      tests, chest and sinus X-rays, and tests of heart function. They also undergo a bone marrow
      biopsy and aspiration. For this procedure, done under local anesthetic, about a tablespoon of
      bone marrow is withdrawn through a needle inserted into the hipbone.

      Participants may undergo apheresis to collect lymphocytes for research studies. This
      procedure involves collecting blood through a needle in the arm, similar to donating a unit
      of blood. The lymphocytes are then separated and removed by a cell separator machine, and the
      rest of the blood is returned through a needle in the other arm.

      Before treatment begins, patients have a central venous catheter (flexible plastic tube)
      placed in a vein. This line remains in place during the stem cell transfusion and recovery
      period for drawing and transfusing blood, giving medications, and infusing the donated cells.
      Preparation for the transfusion includes irradiation and chemotherapy. Patients undergo total
      body irradiation in 8 doses given in two 30-minute sessions a day for 4 days. Four days
      before the transfusion, they begin taking cyclophosphamide, and 9days before the procedure
      they start fludarabine. These are anti-cancer drugs that kill the cancer cells and prevent
      rejection of the donated cells. While the patient is receiving chemotherapy, the donor
      receives daily injections for 6 days of G-CSF, a drug that moves stem cells from the bone
      marrow into the blood stream. On days 1 and 2 after chemotherapy is completed, the stem cells
      are infused into the patient through the central line.

      Patients usually stay in the hospital about 20 to 30 days after the transplant to recover
      from treatment side effects, which may include fever, nausea, diarrhea and mouth pain, and
      receive blood transfusions, if needed. Treatment with cyclosporine, a drug that helps
      prevents both rejection of donated cells and GVHD, is started on day 44 one day before the
      first T-cell add-back. Patients return to the clinic for follow-up with various tests,
      treatments and examinations as required, with a minimum of visits at least once or twice a
      week for 2 to 4 months after the transplant; then at 4, 6, 9, and 12 months, and then yearly
      for at least 3 years.
    

Detailed description: 
      Bone marrow stem cell transplant studies carried out by the NHLBI BMT Unit have focused on
      approaches to optimize the stem cell and lymphocyte dose in order to improve transplant
      survival and increase the graft-vs.-leukemia effect. The aim is to create the transplant
      conditions that permit rapid donor immune recovery without causing graft-versus-host disease
      (GVHD) by using no post-transplant immunosuppression in conjunction with a transplant
      depleted of T cells to a fixed low dose, below the threshold known to be associated with
      GVHD. A primary objective of the protocol is therefore to test whether the low dose of T
      cells chosen minimizes the risk and severity of GVHD.

      We have found that the outcome from transplant is improved by using high stem cell doses, and
      in successive protocols we have achieved progressive improvement in transplant-related
      mortality from 35% in the first protocol in 1993 to 22% for the latest study. In the last
      study, in this series, we used the Nexell Isolex 300i system to obtain high CD34+ doses
      depleted of lymphocytes to a fixed CD3+ T cell dose of 5 x 10(4)/kg. The use of the cell
      separator and the monoclonal antibodies is covered by IDE 8139. The study focused on the role
      of cyclosporine in preventing GVHD after T cell depletion. We found that CSA appears to
      protect against both GVHD and graft failure, with a higher incidence of both complications
      occurring in patients not receiving CSA.

      To address the results and shortcomings of the previous protocol, while continuing to avoid
      immunosuppression post-transplant, we will now test two hypotheses: (1) GVHD incidence and
      severity can be reduced by transfusing a T cell dose of 2 x 10(4)/CD3 cell/kg. (2) Graft
      rejection can be prevented by increasing the immunosuppressive intensity of the
      pre-transplant preparative regimen using fludarabine and cyclophosphamide and a reduced dose
      of total body irradiation (12 Gy instead of 13.6 Gy). We will use the same in vitro cell
      separation system namely the Isolex 300i and monoclonal antibodies provided by CTEP (anti CD
      6, anti CD2, anti CD7). This is covered by a continuing IND for the selection of CD34+ and
      CD3+ cells for T cell depleted peripheral blood stem cell transplantation.
    

Intervention name(s): SOLEX 300i Stem Cell Selection
Intervention type(s): Device
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Leukemia; Transplant - Mortality; Immunosuppression; Radiation; Cure; Peripheral Blood Stem Cells; Graft-Versus Leukemia/Myeloma; Graft-Versus-Host Disease; Cyclosporine; Fludarabine