Specialized Blood Cell Transplants for Cancers of the Blood and Bone Marrow
Condition: Myeloproliferative Disorders; Acute Myelogenous Leukemia; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      The are a variety of cancerous diseases of the blood and bone marrow that can be potentially
      cured by bone marrow transplantation (BMT). Diseases like leukemia, lymphoma, and multiple
      myeloma are among the conditions that can be treated with BMT.

      Some patients with these diseases can be treated with medical chemotherapy alone. However,
      patients who relapse following chemotherapy are usually not curable with additional
      chemotherapy treatments. The only option known to provide a potential cure if this occurs is
      BMT.

      Allogenic transplants are cells collected from relatives of the patient. The transplant
      requires additional high intensity chemotherapy and radiation in order to destroy cancerous
      cells. In the process, many normal bone marrow cells are also destroyed. This is the reason
      for transplanting stem cells. The stem cells help to build new functioning bone marrow, red
      cells, white cells, and platelets. In addition, the immune cells from the donor are implanted
      into the recipient s body and help to fight off infection and kill remaining cancerous cells.

      Unfortunately, the powerful doses of chemotherapy and radiation therapy associated with
      allogenic BMT have toxic side effects and often make BMTs too dangerous to attempt in many
      patients.

      In order to reduce the complications of BMT, and make it a safer available option for
      patients with cancers of the blood and bone marrow, researchers have developed a new approach
      to the BMT.

      In this study researchers plan to use stem cells collected from the blood stream of patient s
      relatives rather than from the bone marrow (blood progenitor/stem cell transplant). In
      addition, researchers plan to use low doses of chemotherapy and no radiation therapy to
      reduce side effects. The majority of the cancer killing effect will be the responsibility of
      the stem cell transplant rather than the chemotherapy.
    

Detailed description: 
      Patients with malignant and non-malignant hematologic diseases including severe aplastic
      anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS),
      acute and chronic leukemias, Hodgkin's and non-Hodgkin's lymphoma and multiple myeloma (MM)
      can now be cured by allogeneic bone marrow transplantation (BMT). This curative effect has
      been ascribed to the use of high dose chemo-radiotherapy and the anti-tumor or anti-bone
      marrow effect of the allograft. Dose intensification of conditioning regimens in attempts to
      reduce disease recurrence has been largely unsuccessful because of increased toxicity and
      mortality. Indeed, most evidence now points to donor-derived T-cells as being the principal
      modality leading to the complete eradication of both malignant and non-malignant host
      hematopoietic cells.

      The assumption that successful allogeneic BMT relies on the myeloablative effect of intensive
      but hazardous chemo-radiotherapy has largely restricted this therapeutic modality to patients
      with malignant or life-threatening hematologic disorders under the age of 55 years.
      Treatment-related mortality increases substantially with age, prior intensive treatment with
      chemo-radiotherapy, worsening performance status, and co-morbid medical conditions. An
      unacceptable risk of death from conventional BMT renders many patients ineligible for what
      may otherwise be curative therapy.

      Several in vitro studies have demonstrated the existence of donor-derived CD4 and CD8
      positive lymphocytes with specific reactivity for the patient s leukemia. These cells provide
      a potent graft-versus-leukemia (GVL) effect. This GVL effect is best seen in patients with
      CML relapsing after BMT, where a single infusion of donor lymphocytes has been shown to
      induce complete remission. In addition to the potent anti-leukemia effect of these cells,
      there is now strong evidence that donor T-cells are capable of completely eradicating
      residual host hematopoietic cells in a non-myeloablative transplant setting
      (graft-versus-marrow) leading to successful and complete donor hematopoietic engraftment.

      Non-myeloablative allogenic peripheral blood stem cell transplants are currently being
      investigated in phase I/II trials assessing engraftment efficacy and toxicity at a number of
      transplant centers. Preliminary data, including our own experience with greater than 150
      patients undergoing this type of procedure, have shown a high rate of complete donor
      engraftment with a low toxicity profile. Two recent studies investigating non-myeloablative
      allo-transplantation in standard risk patients revealed an extremely low rate of
      transplant-related complications and mortality.

      The decreased risk of transplant-related complications associated with non-myeloablative
      transplants expands the eligibility of transplant candidates as well as opens the possibility
      to evaluate non-myeloablative regimens in patients at high risk for complications with
      standard transplantation. Besides hematologic malignancies, allogeneic BMT has been shown to
      be curative in a number of debilitating hematologic diseases which may behave in a relatively
      indolent fashion, such as paroxysmal nocturnal hemoglobinuria (PNH) and refractory anemia
      (RA) or refractory anemia with ringed sideroblasts (RARS). However, the 30% risk of
      treatment-related mortality (TRM) with standard myeloablative allotransplantation usually
      precludes these patients from potentially curative therapy, because of concerns about
      shortening life in patients with these disorders. In this protocol we investigate
      non-myeloablative allogeneic peripheral blood stem cell (PBSC) transplantation in two groups
      of subjects where standard allogeneic transplantation is considered to have unacceptable
      toxicity.

      Group A: Subjects with hematologic malignancies with factors putting them at high risk for
      transplant related complications and mortality, including prior intensive chemo-radiotherapy
      and co-morbid diseases.

      Group B: Subjects with hematologic diseases (both clonal and non-clonal) associated with
      reasonable longevity not currently considered for allogeneic BMT because of prohibitive
      procedural mortality with conventional BMT (enrollment closed October 2010).

      In this protocol, eligible subjects are treated with an allogeneic PBSC transplant from an
      HLA identical or single HLA antigen-mismatched family donor, using an intensive
      immunosuppressive regimen without myeloablation in an attempt to decrease the transplant
      related toxicities while preserving the anti-malignancy and/or anti-host marrow effect of the
      graft. The low intensity non-myeloablative conditioning regimen should provide adequate
      immunosuppression to allow stem cell and lymphocyte engraftment. T-cell replete,
      donor-derived, granulocyte colony stimulating factor (G-CSF)-mobilized PBSCs will be used to
      establish hematopoietic and lymphoid reconstitution. We will add back lymphocytes in
      recipients with less than 100% donor T-cell chimerism in an attempt to prevent graft
      rejection and enhance a graft-versus-malignancy effect.

      The primary endpoint of this study is transplant related mortality (200 day survival). Other
      end points include engraftment, degree of donor-host chimerism, incidence of acute and
      chronic graft versus host disease (GVHD), transplant related morbidity as well as
      disease-free and overall survival.
    

Intervention name(s): T-cell replete PBPC allograft; Methotrexate; Cyclosporine; G-CSF
Intervention type(s): Procedure; Drug; Drug; Drug
Intervention description(s): Subjects will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m2 intravenously (IV) over 30 minutes daily x 5 days with or without ATG followed by a PBPC graft targeted to deliver >5x10^6 CD34+ cells/kg.; IV MTX on days +1, +3, and +6 will be given; CSA will be given beginning on day -4 for graft versus host disease prophylaxis. Participants with mixed T-cell chimerism on day 30 will begin a CSA taper. Participants with 100% donor T-cell chimerism by day 30 will be tapered off CSA from days 60 through 100 (25% reduction in dose every 10 days-off by day 100). CSA will not be tapered in any subjects with grade > II acute GVHD regardless of chimerism results. In addition, participants with evidence of disease progression without grade > II GVHD will have CSA discontinued regardless of chimerism results.; G-CSF will be administered based on body weight for at least 5, and up to 7 days, subcutaneously.
Other intervention name(s): Peripheral blood hematopoietic progenitor cell (PBPC) transplant; MTX; CSA; granulocyte colony-stimulating factor (G-CSF)
Intervention MeSH terms: Cyclosporine; Methotrexate; Cyclosporins; Lenograstim
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Graft vs. Host Disease; Peripheral Blood Stem Cells; Non-Myeloablative Bone Marrow Transplantation; Engraftment; graft versus leukemia