Stem Cell Transplantation and T-Cell Add-Back to Treat Bone Marrow Malignancies
Condition: Hematologic Malignancies; Bone Marrow Transplant Rejection
MeSH terms: Neoplasms; Hematologic Neoplasms
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) are removed and then added
      back. Certain patients with bone marrow malignancies undergo transplantation of donated stem
      cells 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 protocol, T-cells are
      removed from the donor cells to prevent this complication. However, because T-cells are
      important in fighting viral infections as well as any remaining malignant cells (called
      graft-versus-leukemia effect), the donor T-cells are given to the patient (added back) at a
      later time after the transplant when they can provide needed immunity with less risk of
      causing GVHD.

      Patients between 10 and 55 years of age with acute or chronic leukemia, myelodysplastic
      syndrome, or myeloproliferative syndrome 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      marrow is withdrawn through a needle inserted into the hipbone.

      They 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 intravenous line (flexible plastic tube)
      placed in a vein in the chest. This line remains in place during the stem cell transplant and
      recovery period for drawing and transfusing blood, giving medications, and infusing the
      donated cells. Preparation for the transfusion includes high-dose radiation and chemotherapy.
      Patients undergo total body irradiation in 8 doses given in two 30-minute sessions a day for
      4 days. Eight days before the transplant, they begin taking fludarabine, and 3 days before
      the procedure they start cyclophosphamide.
    

Detailed description: 
      Bone marrow stem cell transplant studies carried out by the National Heart Lung & Blood
      Institute (NHLBI) Bone Marrow Transplantation (BMT) Unit have focused on approaches to
      optimize the stem cell and lymphocyte dose in order to improve transplant survival and
      increase the graft-versus-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 reduced 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. We use the "Nexell Isolex 300i" system to
      obtain high CD34+ doses depleted of lymphocytes to a fixed CD3+ T cell dose of 2 x 104/kg.
      The use of the cell separator and the monoclonal antibodies is covered by an Investigational
      Device Exemption. A persisting problem with these T cell depleted transplants has been the
      slow acquisition of full donor T cell engraftment (T cell chimerism). Two previous protocols
      have failed to increase the speed of donor T cell chimerism. 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
      remains an important therapeutic goal. In this study we will test whether cyclosporine given
      between day -6 and +21 after transplant can significantly improve day 30 T cell chimerism
      (the principle end-point). The study also will measure the incidence of acute and chronic
      GVHD, day 100 transplant related mortality, cytomegalovirus reactivation, relapse, and
      disease-free survival with appropriate safety stopping rules.

      This protocol follows closely previous studies in this series. Three additional modifications
      will be made however: 1) The first T cell add-back will be delayed until day 60 (instead of
      day 45) so as to continue to allow a 45 day period without cyclosporine immunosuppression. 2)
      No day 100 T cell add-back will be given. (In previous studies many patients have, for
      protocol-defined reasons, not received the second transfusion and there is no evidence that
      it is required). 3) Patients with high-risk leukemias with a high relapse probability will
      receive an additional chemotherapy agent prior to transplant using etoposide (VP16) 60mg/kg
      to improve the chance of remaining in remission.
    

Intervention name(s): allogeneic hematopoietic stem cell transplantation
Intervention type(s): Device
Intervention description(s): Manipulated Peripheral Blood Stem Cell graft on Day 0. Target CD34+ dose 6 x10e6/kg, (range 3 to 8x10e6/kg) CD3+ dose fixed to 2 x 10e4/kg.
Other intervention name(s): Peripheral Blood Stem Cell Transplant; HSCT; BMT
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chronic Myelogenous Leukemia (CML); Acute Lymphoblastic Leukemia (ALL); Acute Myelogenous Leukemia (AML); Chronic Lymphocytic Leukemia (CLL); Myelodysplastic Syndromes (MDS); Peripheral Blood Stem Cells; Graft-Versus Leukemia/Myeloma; Graft-Versus-Host Disease (GVHD); Cyclosporine; Fludarabine; Leukemia; Myelodysplastic Syndrome; Myeloproliferative Syndrome; Non-Hodgkin Lymphoma