Chemotherapy Followed by Allogeneic Stem Cell Transplantation for Hematologic Malignancies
Condition: Hematologic Malignancies
MeSH terms: Neoplasms; Hematologic Neoplasms
Study type: Interventional

Summary: 
      The purpose of this study is to determine disease-free survival, overall survival, time to
      progression, regimen-related toxicity and/or treatment-related mortality in patients with
      hematologic malignancies treated with non-myeloablative chemotherapy followed by allogeneic
      stem cell transplant.
    

Detailed description: 
      Allogeneic bone marrow transplantation (BMT) became feasible in the 1960s after elucidation
      of the Human Leukocyte Antigen (HLA) complex. Since then, the therapy has evolved into an
      effective treatment for many hematologic disorders. Otherwise incurable malignancies are
      frequently cured by this approach, with the likelihood of cure ranging from 10% to 85%,
      depending on the disease and the disease status. The treatment strategy incorporates very
      large doses of chemotherapy and often radiation to eliminate cancer cells and to
      immunosuppress the recipient to allow the engraftment of donor cells. Donor cells give rise
      to hematopoiesis within two to three weeks, rescuing the patient from the effects of high
      dose therapy. In the ideal situation, immune recovery and recipient-specific tolerance occurs
      over the following 6-18 months, and the patient is cured of their underlying malignancy, off
      immunosuppression, with a functionally intact donor-derived immune system. However,
      complications are common and include fatal organ damage from the effects of high dose
      chemotherapy, infection, hemorrhage, and, in particular, graft-versus-host disease (GvHD). A
      realistic estimate of transplant-related mortality in the standard HLA-matched sibling
      setting is approximately 25%. The risk of treatment-related mortality limits the success and
      certainly precludes its use in older patients. Thus, new strategies in transplantation are
      needed.

      With the growing understanding that much of the curative potential of allogeneic bone marrow
      or stem cell transplant (SCT) is from an immune anti-tumor effect of donor cells, known as
      graft-versus-leukemia (GvL) or graft-versus-tumor (GvT), a new strategy is being employed
      that shifts the emphasis from high-dose chemo-radiotherapy to donor-derived, immune-mediated
      anti-tumor therapy. In this approach, patients receive preparative regimens that, while
      having some anti-tumor activity, are mainly designed to be immunosuppressive enough to allow
      engraftment of donor stem cells and lymphocytes. Engrafted lymphocytes then mediate a GvL
      effect; if the GvL effect of the initial transplant is not sufficient, then additional
      lymphocytes may be infused (achievement of engraftment allows additional lymphocytes to
      "take" in the recipient without requiring any additional conditioning of the recipient). The
      lower intensity of the preparative regimen lessens the overall toxicity by minimizing the
      doses of chemo-radiotherapy. In addition, less intensive preparative regimens may be
      associated with less GvHD, as much evidence suggests that high-dose therapy contributes to
      the syndrome of GvHD by causing tissue damage, leading to a cytokine milieu which enhances
      activation of graft-versus-host (GvH) effector cells. Thus, such an approach may allow the
      safer use of allogeneic transplants in standard populations and may allow extension of
      allogeneic transplantation to patients who could not receive standard (myeloablative)
      transplants because of age or co-morbidities. This protocol investigates a non-myeloablative
      transplant approach, using fludarabine and cyclophosphamide, to allow engraftment of
      allogeneic cells, which may then mediate anti-tumor effects.
    

Intervention name(s): Stem Cell Transplant; G-CSF; Fludarabine; cyclophosphamide; Cyclosporine; Methotrexate
Intervention type(s): Procedure; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Donor: Prior to mobilization, leukapheresis to collect CD3+ cells. The donor will then receive G-CSF (10 mcg/kg/day) with leukapheresis collection of peripheral blood stem cells on days 5, 6 and 7 as needed. Goal of leukapheresis will be > 5 x 106 CD34+cells/kg of recipient.
Patient: Peripheral Blood Stem Cell (PBSC) Transplant. Fludarabine 25mg/m2/d IV over 30 minutes on days -6 to -2, followed by cyclophosphamide 1g/m2/d IV on days -3 and -2. This will be followed by allogeneic stem cell infusion 48 hours later.
Donor Lymphocyte Infusion (DLI) and Adjustment of Immunosuppression: Cyclosporine (CSA) and methotrexate (MTX) will be used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml.; 10 mcg/kg/day on days 5, 6, and 7; 25 mg/m2/d IV over 30 minutes on days -6 to -2; 1 g/m2/d IV on days -3 and -2; used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml; used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml
Other intervention name(s): HLA-Matched Related Allogeneic Stem Cell Transplantation
Intervention MeSH terms: Cyclosporine; Cyclophosphamide; Methotrexate; Fludarabine; Cyclosporins
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Non-myeloablative transplant; Chronic Myelogenous Leukemia; Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Multiple Myeloma; Non-Hodgkin's Lymphoma; Myelodysplastic syndrome; Chronic Lymphocytic Leukemia; Hodgkin's Disease