Methods to Enhance the Safety and Effectiveness of Stem Cell Transplants
Condition: Chronic Myelogenous Leukemia; Acute Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome
MeSH terms: Leukemia; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Bone marrow stem cell transplants (otherwise called bone marrow transplants) from healthy
      donors are sometimes the only means of curing hematological malignant diseases such as acute
      and chronic leukemias, myelodysplastic syndrome, myeloproliferative diseases and lymphomas.
      Before transplant the patient receives chemotherapy and radiation treatment to reduce the
      malignancy to low levels and to prevent rejection of the transplant. The transplant restores
      the blood counts to normal and replaces the patients immunity with that of the donor. The
      donors immune cells increase the effect of the transplant by attacking remaining malignant
      cells. Donor immune cells (especially those called T lymphocytes) also attack healthy
      non-cancerous cells and tissues of the recipient causing "graft-versus-host-disease" (GVHD).
      Strong GVHD reactions occurring within weeks after the transplant can be life-threatening .
      In this study we remove most of the T lymphocytes from the transplant to minimize the risk of
      GVHD. However to improve immunity against residual malignant cells and boost immunity to
      infections, donor T cells (stored frozen at time of transplant) are given back around 90 days
      after the transplant when they have a reduced risk of causing serious GVHD.

      Any patient between 10 and 75 years of age with acute or chronic leukemia, myelodysplastic
      syndrome, myeloproliferative syndromes or lymphoma, who have a family member who is a
      suitable stem cell donor may be eligible for this study. Candidates are screened with a
      medical history and various tests and examinations.
    

Detailed description: 
      Peripheral blood stem cell transplant research carried out by the National Heart Lung and
      Blood Institute (NHLBI) Bone Marrow Transplantation (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.

      We have found 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 by postponed
      donor lymphocyte infusion (DLI). We found that T cell depleted transplants using the
      Nexell/Baxter Isolex 300i 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, when combined with a delayed T cell add-back (DLI). This protocol is
      designed to evaluate safety and efficacy of an improved T cell depletion procedure using the
      Miltenyi CliniMACs system (CD34 reagent system) with a delayed T cell add back in the
      HLA-matched peripheral blood stem cell transplant setting.

      The protocol will accrue up to 68 subjects ages 10-75 with a hematological malignancy, in
      whom allogeneic stem cell transplantation from an HLA-matched sibling would be routinely
      indicated. 68 sibling donors will also be recruited. Diagnostic categories will include acute
      and chronic leukemia, myelodysplastic syndrome, lymphoma, multiple myeloma and
      myeloproliferative syndromes.

      Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine
      and total body irradiation, followed by an infusion of a stem cell product prepared using the
      Miltenyi CliniMacs system for CD34 selection, and a delayed T-cell add back as donor
      lymphocyte infusion (DLI) at day 90. Older subjects will receive a lower dose of irradiation
      to reduce the regimen intensity.

      Participants undergo apheresis to collect lymphocytes for research studies. This procedure
      involves collecting blood through a needle in the arm, extracting the lymphocytes through a
      cell separator machine and returning the rest of the blood through a needle in the other arm.
      Before treatment begins, patients have a central intravenous line (plastic tube) placed in a
      vein in the neck. This line remains in place during the transplant and recovery period for
      drawing and transfusing blood, giving medications, and infusing the donated cells.

      To prepare patients for transplantation their immune system is suppressed by a combination of
      chemotherapy and radiation which will also help to fight remaining malignant cells. The
      chemotherapy consists of two anti-cancer drugs (fludarabine and cyclophosphamide) and will be
      infused over the central line starting eight days before the transplant. Patients will
      receive eight doses of total body irradiation, administered in two 30-minute sessions per day
      for 4 days. Patients above 55 years of age who tolerate transplants less well than younger
      individuals will receive a lower dose of radiation. One day after the preparative treatment
      is finished, patients receive the transplant of donors stem cells as an infusion through the
      central line.

      Patients receive cyclosporine, an immunosuppressive drug starting 6 days before the
      transplant until 21 days post-transplant. This helps prevent both transplant rejection and
      GVHD. The drug is stopped to allow the donor immunity to function and is restarted on day 89
      to prevent GVHD from the infusion of T lymphocytes on day 90.

      Patients are followed with various tests, treatments and examinations periodically for the
      first 3 years and then yearly thereafter.

      Primary endpoint will be overall survival at day +200. Non-relapse mortality at day +200 will
      be monitored for safety. 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): Miltenyi reagent system; Fludarabine; Cyclosporine; Cyclophosphamide; FILGRASTIM (G-CSF)
Intervention type(s): Device; Drug; Drug; Drug; Other
Intervention description(s): Miltenyi Clinimax CD34 Reagent System for CD34 selection and delayed T cell depletion add back; Therapeutic; Therapeutic; Therapeutic; An HLA 6/6 identical family member will be co-enrolled into this study as a stem cell donor. Stem cell Donors will receive G-CSF for stem cell mobilization. The stem cell collection aspect of this protocol is not investigational.
Other intervention name(s): Miltenyi Clinimax CD34 Reagent System; Fludara; Neoral; Cytoxan; Neupogen
Intervention MeSH terms: Cyclosporine; Cyclophosphamide; Fludarabine; Cyclosporins
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chronic Myelogenous Leukemia (CML); Acute Myelogenous Leukemia (AML); Chronic Lymphocytic Leukemia (CLL); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndrome (MDS); Leukemia; Chronic Myelogenous Leukemia; CML; Acute Myeloid Leukemia; AML; Chronic Lymphocytic Leukemia; CLL; Acute Lymphoblastic Leukemia; ALL; Myelodysplasia Syndrome