Preventing Stem Cell Transplant Complications With a Blood Separator Machine
Condition: MDS (Myelodysplastic Syndrome); Myeloproliferative Disorder; Lymphoma, Non-Hodgkin; ALL (Acute B-Lymphoblastic Leukemia); AML (Acute Myelogenous Leukemia
MeSH terms: Leukemia; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Myelodysplastic Syndromes; Myeloproliferative Disorders
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      - Researchers are working to make stem cell transplant procedures safer and more effective.
      One complication of transplants is graft-versus-host disease (GVHD). This complication
      happens when certain white blood cells from the donor attack the recipient's own body.
      Researchers want to test a blood separator machine that may help remove more of the donor's
      white blood cells before transplant. They will study donors and recipients during stem cell
      transplant to see how well this process can prevent GVHD and other complications.

      Objectives:

      - To see if a new blood separator machine can improve outcomes of stem cell transplants.

      Eligibility:

        -  Individuals between 10 and 75 years of age who are having a stem cell transplant for
           leukemia or other blood-related cancers.

        -  Donors for the stem cell transplant.

      Design:

        -  Recipients and donors will be screened with a physical exam and medical history.

        -  Donors will have two blood collection procedures. The first will collect only white
           blood cells, and return the rest of the blood. After the first collection, participants
           will have filgrastim injections to help their stem cells enter their blood. Then, they
           will have a second blood collection for the stem cells.

        -  Recipients will have radiation and chemotherapy to prepare for the stem cell transplant.
           They will then have the stem cell transplant with the donor cells that have been treated
           with the blood separator machine.

        -  Recipients will be monitored closely after the procedure. They may receive some of their
           donor's white blood cells if needed to fight serious infections.

        -  Recipients will have the regular standard of care after their transplant. Blood samples
           will be taken and any side effects will be monitored and treated.
    

Detailed description: 
      Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on
      transplant techniques designed to decrease graft versus host disease (GVHD), increase the
      graft-versus-leukemia (GVL) effect and reduce the risk of post-transplant graft rejection.

      Through incremental transplant clinical trials we have shown that by controlling the stem
      cell (CD34+ cell) and T lymphocyte (CD3+ cell) dose, severe GVHD can be reduced whilst
      beneficial GVL effects can be preserved. We found that T cell depleted transplants using the
      Nexell/Baxter Isolex 300i system and subsequently, the Miltenyi CliniMACS[registered] CD34+
      system to obtain high CD34+ doses depleted of lymphocytes were safe to administer and
      associated with less severe acute GVHD and promising response rates and overall survival. Our
      previous trials have helped us to create the transplant environment (significant
      lymphodepletion and minimal post transplant immunosuppression) that make for an ideal
      platform for adoptive cellular immunotherapy. Adoptive cell transfer is the passive transfer
      of immune cells, into a new recipient host with the goal of transferring the immunologic
      functionality and characteristics into the new host.

      This protocol is designed to evaluate the safety and efficacy of the Miltenyi
      CliniMACS[registered] CD 34 selection system in HLA-matched sibling allogeneic peripheral
      blood stem cell transplant. The manipulation of the graft is the primary research
      intervention, subject to IDE# 15632, and all other aspects of clinical management on this
      protocol are standard care. The target CD34+ dose range will be >3 x 10(6)/kg and the target
      CD3+ dose range will be 5 x 10(4)/kg to 1 x 10(6)/kg. Once we demonstrate adequacy of this
      platform for engraftment and absence of significant GVHD in ten consecutive recipients, we
      will seek IRB permission to proceed with planned adoptive cellular therapies.

      The protocol will accrue up to 96 transplant recipients aged 10-80 with a hematological
      malignancy and their HLA-matched sibling donors, in whom allogeneic stem cell transplantation
      from an HLA-matched sibling would be routinely indicated. Diagnostic categories will include
      acute and chronic leukemia, myelodysplastic syndromes, lymphomas, multiple myeloma and
      myeloproliferative syndromes.

      Subjects will receive a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg
      total), fludarabine (125 mg/m(2) total) and total body irradiation (1200 cGy with lung
      shielding to 600 cGy), followed by an infusion of a stem cell product selected for CD34+
      progenitors using the Miltenyi CliniMACS[registered] system. Older subjects will receive a
      lower dose of irradiation (800 or 600 cGy based on age) to reduce the regimen intensity.

      The overall objective is to assess the feasibility of using this system as a platform for
      cellular immunotherapy initiatives. The primary study endpoint will be overall survival at
      day +200. Stopping criteria for safety will monitor non-relapse mortality at day +200 and
      late disease free survival at 2 years. Secondary endpoints will be standard transplant
      outcome variables such as non-hematologic toxicity, incidence and severity of acute and
      chronic GVHD and relapse of disease.
    

Intervention name(s): Graft Manipulation (CD34+ Selection)
Intervention type(s): Device
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Lymphoblastic Leukemia (ALL); Acute Myelogenous Leukemia (AML); Chronic Lymphocytic Leukemia (CLL); Chronic Myelogenous Leukemia (CML); Myelodysplastic Syndrome (MDS)