Bone Marrow Transplant Studies for Safe and Effective Treatment of Leukemia
Condition: Graft vs Host Disease; Hematologic Neoplasm; Leukemia; Multiple Myeloma; Myelodysplastic Syndrome
MeSH terms: Leukemia; Multiple Myeloma; Preleukemia; Hematologic Neoplasms; Myelodysplastic Syndromes; Graft vs Host Disease
Study type: Interventional

Summary: 
      Bone marrow transplants (BMT) are one of the accepted therapies used to treat leukemia.
      However, BMT have risks of complications. One potentially life-threatening complication is
      known as graft-versus-host disease (GVHD).

      The GVHD is a reaction caused by an incompatibility between donor cells and recipient cells.
      Antigens found on the recipient s cells are recognized by the donor s transplanted white
      blood cell lymphocytes. These lymphocytes begin attacking the recipient s cells and tissues
      and may lead to death.

      One of the most effective ways to prevent this reaction is to remove the lymphocytes from the
      transplanted marrow. Unfortunately, without lymphocytes the recipient s immune system will be
      lowered and may result in a relapse of leukemia or an infection.

      Researchers have shown they can perform effective BMT by removing the lymphocytes prior to
      the transplant and then later adding the lymphocytes back. This technique can reduce the
      potential for GVHD and preserve the graft-versus-leukemia (GVL) effect of the transplant.

      In this study researchers plan to use peripheral blood with lymphocytes removed rather than
      bone marrow. In order to increase the number of progenitor cells, the cells responsible for
      correcting the leukemia, donors will receive doses of G-CSF prior to the transplant. G-CSF
      (granulocyte colony stimulating factor) is a growth factor that increases the production of
      progenitor cells in the donor s blood stream.

      The study will be broken into two parts. The first part of the study will attempt to
      determine if peripheral blood with lymphocytes removed can prevent GVHD while preserving the
      GVL effect of the transplant.

      In the second part of the study, patients that received the transplant will have the
      lymphocytes added-back on two separate occasions in order reduce the chances of relapse and
      infection.

      The study is designed to treat up to 55 patients ages 10 to 60 years and follow their
      progress for 5 years.
    

Detailed description: 
      One of the most effective ways of preventing lethal graft-versus-host disease (GVHD) after
      allogeneic bone marrow transplantation (BMT) for leukemia is to remove T-lymphocytes from the
      transplanted marrow. The reduced early mortality from T cell depletion is however offset by
      an increased risk of leukemic relapse and infection. We have shown that bone marrow
      transplants for leukemia depleted of T cells by elutriation and followed by delayed add-back
      of donor T cells reduces GVHD while preserving an immune response to the hematologic
      malignancy (the so-called graft-versus-leukemia (GVL) or graft-versus-myeloma effect). The
      study highlighted a possible benefit of large doses of marrow progenitor cells on transplant
      outcome. GVHD was reduced but not prevented by T cell depletion of the marrow. The first
      objective of our BMT studies is to prevent GVHD from the transplant while conserving GVL
      reactivity. This is a prerequisite to our second objective of determining the risk of GVHD
      and the benefit from GVL from add-back of donor lymphocytes. These studies will provide the
      basis for a planned trial adding back donor lymphocytes selected in vitro to confer immunity
      against infectious agents and residual leukemia without causing GVHD.

      In this study we will evaluate the use of T cell depleted peripheral blood progenitor cells
      (PBPC) (instead of bone marrow) to optimize the stem cell and lymphocyte dose. Donors will be
      given G-CSF and their mobilized PBPC harvested by leukapheresis. To minimize acute GVHD, the
      transplant will be T cell depleted, using a new technique developed in normal volunteers
      which improves T cell depletion and reduces stem cell loss (protocol 96-H-0049). The study
      has two phases: The first phase evaluates engraftment and GVHD following T cell depleted PBPC
      transplants. Stopping rules will be used to make modifications to the protocol in the event
      of graft failure. Cyclosporine will be withdrawn from the protocol if the incidence of acute
      GVHD is low or absent. In the second phase patients will receive add-back of donor
      lymphocytes on day 45 and day 100 post transplant to prevent relapse and confer donor-immune
      function. The risk of acute GVHD following this procedure will be determined. It is planned
      to treat up to 55 patients aged between 10 and 60 years. The end points of the study are
      graft take; acute and chronic GVHD, leukemic relapse, transplant-related and all causes of
      mortality, cytomegalovirus reactivation and leukemia-free survival. Patients will be followed
      for 5 years.
    

Intervention name(s): Allogeneic Bone Marrow Transplant
Intervention type(s): Procedure
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Peripheral Blood Stem Cells; Graft-Versus-Leukemia; Graft vs. Host Disease; Whole Body Irradiation; Donor Apheresis; Cyclophosphamide; Graft-Versus-Myeloma; Leukemic Relapse; Multiple Myeloma; Acute Myelogenous Leukemia (AML); Chronic Myelogenous Leukemia (CML); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndromes; Chronic Lymphocytic Leukemia (CLL)