Experimental Bone Marrow Transplant Protocol
Condition: Acute Lymphocytic Leukemia; Chronic Myeloid Leukemia; Acute Myelocytic Leukemia; Myelodysplastic Syndromes; Myeloproliferative Disorders
MeSH terms: Leukemia; Preleukemia; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Bone marrow transplantation (BMT) is a risky procedure. If doctors could reduce the
      complications, BMT would be safer to use for a wider range of conditions. The purposes of
      this study are

        -  to prevent graft rejection by increasing the amount of immunosuppression and by giving
           some lymphocytes from the donor before transplant;

        -  to prevent graft-versus-host disease (GVHD) by transplanting T-cell depleted stem cells;

        -  to improve the immune effect against residual leukemia by the add-back of donor
           lymphocytes before transplant and six or more weeks after transplant.

      Beyond the standard transplant protocol, study participants will undergo additional
      procedures. First, along with total body irradiation, patients will receive two drugs (a high
      dose of cyclophosphamide and fludarabine) to suppress immunity and prevent rejection of the
      transplant. Second, four days before the transplant, patients will be given donor lymphocytes
      that have been irradiated to make them incapable of causing GVHD. On the day of the
      transplant, patients will receive an infusion of T-cell depleted bone marrow stem cells.
      Finally, patients will receive two doses of add-back donor T-cells (45 and 100 days post
      transplant) and the immunosuppressive drug cyclosporine starting on day 44 until about six
      months after transplant.

      Study participants must be between the ages of 10 and 56 and have a family member who is a
      suitable stem cell donor match.
    

Detailed description: 
      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.

      We have found that the outcome from transplant is improved by controlling the stem cell
      (CD34+ cell) and T lymphocyte (CD3+ cell) dose. 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 2 x 10(4)/kg. The use of the cell separator and the monoclonal antibodies
      was covered by IDE 8139. The study measured the incidence of acute GVHD and used chimerism
      assays to determine the percentage of donor and recipient cells circulating at different
      time-points after transplant. We found that in the first six weeks donor T cell chimerism
      varied widely reaching 100% only in 10/22 patients. Thus the goal or rapid donor immune
      recovery was achievable only in about half the patients. Patients with mixed donor-recipient
      T cell populations are known to be at higher risk for late graft rejection and leukemic
      relapse after transplant. Therefore the achievement of full donor chimerism is an important
      therapeutic goal.

      To improve donor T cell chimerism we will test whether the addition of irradiated donor
      lymphocytes during the preparative regimen of the transplant can increase the chance of
      achieving 100% donor T cell chimerism within six weeks of transplant. It is known that
      irradiated lymphocytes do not cause GVHD and that they can suppress residual host immunity,
      thus promoting donor lymphocyte engraftment. The end point of the study will be the
      proportion of patients achieving full donor chimerism six weeks after transplant. Apart from
      this addition of irradiated lymphocytes and some minor modifications, this protocol will be
      identical to the predecessor protocol 02-H-0111. This involves the continued use of the
      Isolex 300i cell separator and the 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): Isolex 300i Stem Cell Selection
Intervention type(s): Device
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chronic Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Acute Myelogenous Leukemia (AML); Chronic Lymphocytic Leukemia; Myelodysplastic Syndrome; Non-Hodgkin's Lymphoma; Graft-Versus Leukemia/Myeloma; Graft-Versus-Host Disease; Cyclosporine; Fludarabine; Myelodysplasia Syndrome