Selective T-Cell Depletion to Reduce GVHD (Patients) Receiving Stem Cell Tx to Treat Leukemia, Lymphoma or MDS
Condition: Graft vs Host Disease; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myelomonocytic, Chronic; Leukemia, Lymphocytic; Lymphoma; Lymphoma, Mantle-cell; Lymphoma, Non-Hodgkin; Hodgkin Disease
MeSH terms: Lymphoma; Leukemia; Hodgkin Disease; Lymphoma, Non-Hodgkin; Leukemia, Myeloid; Leukemia, Lymphoid; Lymphoma, Mantle-Cell; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Graft vs Host Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will evaluate the safety and effectiveness of stem cell transplantation in which
      the donors T lymphocytes have undergone "selective depletion." Certain patients with cancers
      of the blood undergo transplantation of donated stem cells to generate new and normally
      functioning bone marrow. In addition to producing the new bone marrow, the donor's
      T-lymphocytes also fight any tumor cells that might have remained in the body. This attack on
      tumor cells is called a "graft-versus-leukemia" (GVL) effect. However, another type of
      T-lymphocyte from the donor may cause what is called "graft-versus-host-disease" (GVHD), in
      which the donor cells recognize the patient's cells as foreign and mount an immune response
      to reject them. Selective depletion is a technique that was developed to remove the
      T-lymphocytes that cause harmful GVHD, while keeping those that produce the desirable GVL
      effect.
    

Detailed description: 
      Despite improved prophylaxis and treatment, graft-versus-host disease (GVHD) remains a major
      complication after allogeneic stem cell transplantation. Although the most effective way to
      prevent GVHD is T cell depletion, this process results in poor immune function leading to
      increased rates of relapse, graft rejection, and post-transplant infections. Ideally, a
      method of removing GVHD- producing effector cells while retaining a broad T cell repertoire,
      including preservation of 3rd party, antiviral and anti-tumor responses would be desirable.
      Preclinical studies from our lab have demonstrated that alloreactive T cells can be
      selectively removed from the donor lymphocyte pool in vitro with the use of a specific
      immunotoxin directed against the interleukin-2 receptor.

      To test this clinically, we will perform nonmyeloablative allogeneic stem cell transplants in
      older patients with hematologic malignancies. Although these patients can be cured with this
      approach, they have significant morbidity and mortality from GVHD. At our institution,
      nonmyeloablative transplantation is associated with an incidence of grade II-IV acute GVHD of
      approximately 50%. Although well tolerated in younger patients, patients over the age of 50
      years have a transplant-related mortality (TRM) of approximately 35%, which is mostly related
      to GVHD. Through selective depletion of alloreactive donor lymphocytes, we hope to reduce
      GVHD mortality, while preserving the transplant efficacy.

      Patients receive a reduced intensity preparative regimen, followed by a mobilized peripheral
      blood stem cell allograft from an HLA-identical sibling donor, containing
      "selectively-depleted" donor lymphocytes. To obtain such a graft, colony stimulating factor
      (G-CSF)-mobilized peripheral blood from the donor undergoes a positive cluster of
      differentiation (CD34) selection followed by a negative T cell selection using the "Nexell"
      Isolex 300i system. This stem cell-rich, T cell-depleted product will contain a CD34+ cell
      dose of at least 5x10(6)/kg. The unabsorbed fraction, remaining after the positive CD34
      selection, is then co-cultured for 72 hours with irradiated lymphocytes from the patient. The
      immunotoxin, RFT5-SMPT-dgA, is added during the last 24 hours of culture to remove
      alloreacting cells. The washed T cell product (CD3+ cell dose of 1-4 x 10(8)/kg) is
      cryopreserved. Following the preparative regimen, the patient receives successive infusions
      of the stem cell product and selected lymphocytes. All patients receive standard post
      transplant immunosuppression with cyclosporine for a minimum of 30 days, followed by dose
      reduction depending on the degree of donor lymphocyte chimerism.

      The primary end point of this study is the incidence and severity of acute GVHD. We will also
      examine the incidence of chronic GVHD, engraftment, degree of donor-host chimerism,
      transplant related morbidity and mortality, as well as disease-free and overall survival.
      Stopping rules will minimize the risk of untoward or unexpected side effects.
    

Intervention name(s): RFT5-SMPT-dgA; Isolex system
Intervention type(s): Drug; Drug
Intervention description(s): A specific anti-interleukin-2 receptor immunotoxin; CD34 selection/ T cell depletion used this system
Other intervention name(s): anti-interleukin-2 receptor immunotoxin; Nexell Isolex system
Intervention MeSH terms: Interleukin-2; Immunotoxins
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Peripheral Blood Stem Cell; Melphalan; Fludarabine; Donor Apheresis; Non-Myeloablative; MDS; Chronic Myeloid Leukemia; CML; Chronic Lymphocytic Leukemia; CLL; Lymphoma; Non-Hodgkin's Lymphoma; Hodgkin's Disease; Mantle Cell Lymphoma; Acute Myelogenous Leukemia (AML); Chronic Myeloid Leukemia (CML); Chronic Lymphocytic Leukemia (CLL); Myelodysplasia (MDS); Acute Lymphoblastic Leukemia (ALL); Bone Marrow Transplant