Stem Cell Transplant Therapy With Campath-1H for Treating Advanced Mycosis Fungoides and Sezary Syndrome
Condition: Mycosis Fungoides; Sezary Syndrome
MeSH terms: Mycoses; Mycosis Fungoides; Sezary Syndrome; Syndrome
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This study will investigate the safety and effectiveness of a modified donor stem cell
      transplantation procedure for treating advanced mycosis fungoides (MF), a lymphoma primarily
      affecting the skin, and Sezary syndrome (SS), a leukemic form of the disease. Donated stem
      cells (cells produced by the bone marrow that mature into the different blood components
      white cells, red cells and platelets) can cure patients with certain leukemias and lymphomas
      and multiple myeloma. These cells generate a completely new, functioning bone marrow. In
      addition, immune cells from the donor grow and generate a new immune system to help fight
      infections. The new immune cells also attack any residual tumor cells left in the body after
      intensive chemotherapy. However, stem cell transplantation carries a significant risk of
      death, because it requires completely suppressing the immune system with high-dose
      chemotherapy and radiation. In addition, lymphocytes from the donor may cause what is called
      graft vs. host disease (GvHD), in which these cells see the patient s cells as foreign and
      mount an immune response to destroy them. To try to reduce these risks, patients in this
      study will be given low-dose chemotherapy and no radiation, a regimen that is easier for the
      body to tolerate and involves a shorter period of complete immune suppression. In addition, a
      monoclonal antibody called Campath-1H will be given to target lymphocytes, including those
      that have become cancerous.

      Patients with advanced MF or SS who are between 18 and 70 years of age and have a matched
      family donor 18 years of age or older may be eligible for this study. Candidates will have a
      medical history, physical examination and blood tests, lung and heart function tests, X-rays
      of the chest, eye examination, and bone marrow sampling (withdrawal through a needle of about
      a tablespoon of marrow from the hip bone), and small skin biopsy (surgical removal of a piece
      of tissue for microscopic examination) or needle biopsy of the tumor.

      Stem cells will be collected from both the patient and donor. To do this, the hormone G-CSF
      will be injected under the skin for several days to push stem cells out of the bone marrow
      into the bloodstream. Then, the stem cells will be collected by apheresis. In this procedure
      the blood is drawn through a needle placed in one arm and pumped into a machine where the
      required cells are separated out and removed. The rest of the blood is returned through a
      needle in the other arm.

      Before the transplant, a central venous line (large plastic tube) is placed into a major
      vein. This tube can stay in the body and be used the entire treatment period to deliver the
      donated stem cells, give medications, transfuse blood, if needed, and withdraw blood samples.
      Several days before the transplant procedure, patients will start a conditioning regimen of
      low-dose chemotherapy with Campath 1H, fludarabine, and, if necessary, cyclophosphamide. When
      the conditioning therapy is completed, the stem cells will be infused over a period of up to
      4 hours. To help prevent rejection of donor cells and GvHD, cyclosporine and mycophenolate
      mofetil will be given by mouth or by vein for about 3 months starting 4 days before the
      transplantation.

      The anticipated hospital stay is 3 to 4 days, when the first 3 doses of Campath will be
      monitored for drug side effects. The rest of the procedures, including the transplant, can be
      done on an outpatient basis. Follow-up visits for the first 3 months after the transplant
      will be scheduled once or twice a week for a physical examination, blood tests and symptoms
      check. Then, visits will be scheduled at 6, 12, 18, 24, 30, 36, and 48 months
      post-transplant. Visits for the first 3 years will include blood tests, skin biopsies, and
      bone marrow biopsies.
    

Detailed description: 
      Primary cutaneous T-cell lymphomas (CTCL) are a group of lymphoproliferative disorders
      characterized by localization of neoplastic T cells to the skin at presentation. Mycosis
      fungoides (MF) and its leukemic variant Sezary syndrome (SS) are the most prevalent forms of
      CTCL. While early stage MF is restricted to patches and plaques involving the skin, most
      patients eventually develop cutaneous tumors, generalized erythroderma, or dissemination to
      peripheral blood, lymph nodes or visceral organs. Currently existing therapy of tumor-stage
      and disseminated CTCL is palliative, with most patients dying within 1-5 years. The presence
      of CD8+ cells in close proximity to dermal neoplastic infiltrates in early stages of the
      disease, and the clinical response seen with some immunomodulatory agents suggests that CTCL
      may be potential targets for immunotherapy-based interventions.

      Allogeneic stem cell transplantation is a curative treatment modality successfully employed
      in a number of hematologic malignancies. The curative effect of this approach is in part
      mediated by donor-derived T lymphocytes with reactivity for patient leukemic cells. The power
      of this graft versus leukemia effect (GVL) is best illustrated in patients with relapsed
      Chronic Myeloid Leukemia (CML) after an allogeneic bone marrow transplant, in whom a single
      donor lymphocyte infusion (DLI) can induce remission. We hypothesize that neoplastic T cells
      in MF/SS may similarly be susceptible to a graft vs. tumor (GVT) effect. Unfortunately,
      advanced patient age and a 25% to 35% risk of transplant related mortality (TRM) preclude the
      use of conventional 'dose- intensive' allogeneic peripheral blood stem cell transplantation
      (PBSCT) in patients with advanced CTCL who might otherwise benefit from this approach. The
      risk of TRM related to conditioning can be circumvented at least partially by using a
      reduced-intensity conditioning regimen to prepare the patient for transplantation.

      In this study, we will treat male and non-pregnant female subjects between the ages of 18 and
      70 years (both inclusive) suffering from advanced MF/SS with an allogeneic peripheral blood
      stem cell (PBSC) transplant from an HLA-matched family donor or an HLA matched (10/10 allele
      level match) unrelated donor. A low intensity, nonmyeloablative conditioning regimen
      employing the anti-CD52 monoclonal antibody Campath-1H (alemtuzumab) and fludarabine will be
      used to induce host immunosuppression to facilitate donor hematopoietic and lymphoid
      engraftment. We anticipate minimal host myelosuppression and consequently reduced early
      transplant toxicity with this conditioning regimen. Immune and hematopoietic reconstitution
      will be achieved by infusion of unmanipulated donor-derived granulocyte colony stimulation
      factor (G-CSF) mobilized peripheral blood stem cells. Infusion of donor lymphocytes in
      incremental doses will be used to promote engraftment or disease regression when indicated.
      Cyclosporine A (CSA) will be used as prophylaxis against graft vs host disease (GVHD), with
      dose adjustments made as necessary to favor complete donor chimerism and disease regression.

      A total of up to 25 subjects (transplant recipients) will be treated on this protocol. The
      primary end point of this study is efficacy (proportion of subjects achieving a complete
      response). Other end points include assessment of donor-host chimerism in various
      hematopoietic and lymphoid cells, overall response, incidence of acute and chronic GVHD,
      graft failure, assessment of lymphoid subset reconstitution, transplant related morbidity and
      mortality and disease-free and overall survival and the outcomes of transplantation by the
      donor type (related vs. unrelated).
    

Intervention name(s): A matched peripheral donor stem cells; cyclosporine; fludarabine; Campath
Intervention type(s): Other; Drug; Drug; Drug
Intervention description(s): A matched peripheral donor stem cells; cyclosporine; fludarabine; Campath
Other intervention name(s): Allogeneic peripheral stem cell transplant; CSA; fludara; Alemtuzumab
Intervention MeSH terms: Cyclosporine; Fludarabine; Alemtuzumab; Cyclosporins
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cutaneous T Cell Lymphoma; Allogeneic PBSCT; Low Intensity Regimen; Mycosis Fungoides; Sezary Syndrome; CTCL