The Role of Cyclosporine in Blood Cell Transplants With T-Cell Add-Back for Blood Cancers
Condition: Chronic Lymphocytic Leukemia; Graft vs Host Disease; Hematologic Neoplasm; Multiple Myeloma; Myelodysplastic Syndrome
MeSH terms: Leukemia; Multiple Myeloma; Preleukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Hematologic Neoplasms; Myelodysplastic Syndromes; Graft vs Host Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      Cancers of the blood, sometimes referred to as hematologic malignancies, are disorders of
      bone marrow cells that lead to the failure of the normal function of bone marrow and the
      uncontrolled growth of cancerous cells in the bone marrow. These cancerous cells can spill
      over into the bloodstream and affect other organs causing widespread symptoms. The disease is
      life threatening because it blocks the normal function of the marrow, which is to produce red
      cells (preventing anemia), white cells (preventing infection), and platelets (preventing
      progression).

      Bone marrow transplants are a potential form of therapy for patients with hematologic
      malignancies. However, BMT is a complicated procedure and can be associated with dangerous
      side effects.

      In this study researchers are attempting to find ways to reduce the complications of BMT, so
      that it would be possible to use it more safely and can be offered more patients. In order to
      do this, researchers are developing new techniques to make BMT safer. It requires making
      small changes to the standard procedure, which may improve the outcome.

      The experimental procedures researchers are evaluating are:

        1. <TAB>T-cell depleted peripheral blood progenitor cell (PBPC) transplantation

        2. <TAB> Cyclosporine given immediately after the transplant

        3. <TAB>Add-back of donor lymphocytes

      Patients undergoing these experimental techniques must be monitored closely to see if any
      benefit or harmful effects will occur. Information gathered from this study can be used to
      develop further research studies and potential new therapies for hematologic malignancies.
    

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. A CD34 stem cell dose of greater than 3
      x 10(6)/kg was found to increase survival and reduce relapse, while a CD3+ lymphocyte dose of
      less than 1 x 10(5)/kg was associated with a very low incidence of GVHD. Although processing
      of 2 peripheral blood progenitor cell (PBPC) collections with the CellPro immunoabsorption
      method (combined CD34-positive selection and CD2-negative selection) provided an improvement
      over previous methods, the system did not always achieve these optimal cell doses. A recent
      preclinical evaluation by the Department of Transfusion Medicine of a new immunomagnetic cell
      selection system available from Nexell, Inc. has demonstrated improved recovery of CD34+
      cells and increased depletion of T lymphocytes, compared to the CellPro method. Incorporation
      of the Nexell system (Isolex 300i) into this clinical protocol will allow us to more
      consistently achieve CD34+ cell doses above the threshold of 3 x 10(6)/kg and CD3+ lymphocyte
      dosing in the region of 0.5 x 10(5)/kg. This will make it possible to test (1) the potential
      benefit of optimized transplant cell doses, (2) elimination of post transplant
      immunosuppression to enhance immune recovery.

      In this study, we will use the Nexell Isolex 300i system to obtain more data on the
      relationship between CD34+ stem cell dose and outcome. In recipients who receive a T cell
      dose less than 0.5 x 10(5) CD3+ cells/kg the effect of withdrawing cyclosporine on
      development of GVHD will be evaluated in a cohort study: 20 patients will receive low dose
      cyclosporine. If the incidence of grade II or worse GVHD is 10% or less, no post transplant
      immunosuppression will be given to the next cohort and the incidence and severity of acute
      GVHD again assessed. Stopping rules for unacceptable GVHD severity will be applied. Two match
      groups HLA 6/6 and 5/6 donor-recipient pairs will be separately studied using this approach.

      In a second phase of the study we will continue to accumulate data on T lymphocyte add-back
      given on day 45 and day 100 after transplant. For this phase, cyclosporine will be
      reintroduced on day 44 and continued until day 120 to accelerate immune recovery.

      Up to 70 patients aged between 10 and 55 years will be studied in each subset (HLA 6/6 and
      5/6 matched cohorts). The major endpoint of the study is acute GVHD after transplant. We will
      also measure engraftment, acute and chronic GVHD, leukemic relapse, transplant-related and
      all causes of mortality, cytomegalovirus reactivation and leukemia-free survival. Patients
      will be followed for a minimum of 5 years.
    

Intervention name(s): Isolex 300i plus MoAbs
Intervention type(s): Device
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Peripheral Blood Stem Cells; Cyclosporine; Cyclosphosphamide; Whole Body Irradiation; Donor Apheresis; Leukemic Relapse; Graft vs. Host Disease; Graft-Versus-Leukemia; Graft-Versus-Myeloma; Chronic Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Acute Myelogenous Leukemia; Myelodysplastic Syndromes; Multiple Myeloma; Chronic Lymphocytic Leukemia; Non-Hodgkin's Lymphoma