Stem Cell Transplantation for Patients With Hematologic Malignancies
Condition: Acute Lymphoblastic Leukemias; Acute Myelocytic Leukemia; Chronic Myeloid Leukemia; Juvenile Myelomonocytic Leukemia; Myelodysplastic Syndrome; Hemoglobinuria, Paroxysmal; Non-Hodgkin Lymphoma
MeSH terms: Leukemia; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematologic Neoplasms; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myelomonocytic, Juvenile; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Hemoglobinuria; Myelodysplastic Syndromes; Hemoglobinuria, Paroxysmal
Study type: Interventional
Phase: Phase 3

Summary: 
      Childhood leukemias which cannot be cured by chemotherapy alone may be effectively treated by
      allogeneic bone marrow transplantation. Moreover, for patients with chronic myelogenous
      leukemia (CML), allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven
      curative modality of treatment. Patients who have received hematopoietic stem cells from an
      HLA matched sibling donor have proven to be less at risk for disease relapse and regimen
      related toxicity. However, about 70% of patients in need of HSCT do not have an HLA matched
      sibling donor. This necessitates the search for alternative donors, which may increase the
      risk of a poor outcome.

      The nature of the hematopoietic stem cell graft has been implicated as a primary factor
      determining these outcomes. The standard stem cell graft has been unmanipulated bone marrow,
      but recently several advantages of T-lymphocyte depleted bone marrow and mobilized peripheral
      blood progenitor cells (PBPC) have been demonstrated. However, T-cell depletion may increase
      the risk of infectious complications and leukemic recurrence while an unmanipulated stem cell
      graft may increase the risk of graft vs. host disease (GVHD). A key element in long range
      strategies in improving outcomes for patients undergoing matched unrelated donor (MUD) HSCT
      is to provide the optimal graft.

      The primary objective of this clinical trial is to estimate the incidence of acute GVHD in
      pediatric patients with hematologic malignancies who receive HSCT with an unmanipulated
      marrow graft. The results of this study can be used as the foundation for future trials
      related to engineering unrelated donor graft.
    

Detailed description: 
      Secondary outcome evaluations for this clinical study include the following:

        -  To estimate the overall survival in patients with high risk hematological malignancies
           who receive a HSCT with an unmanipulated marrow graft or a peripheral blood stem cell
           graft

        -  To estimate disease-free survival and relapse rates

        -  To estimate the rates of chronic GvHD and graft failure

        -  To estimate the incidence of non-hematologic peri-transplant regimen-related toxicity
           and regimen-related mortality in the first 100 days after transplantation

        -  To estimate the time to neutrophil and platelet engraftment after transplantation

        -  To determine the degree of NK cell and T-cell immune reconstitution at 30 days and 100
           days post-transplant

        -  To estimate the incidence of EBV reactivation or post-transplant lymphoproliferative
           disease (PTLPD)

        -  To determine the pharmacokinetics of anti-thymocyte globulin (rATG) in patients
           receiving allogeneic transplantation and the development of rATG antibodies

      Originally this study began as a randomized comparison between unmanipulated bone marrow and
      T-cell depleted bone marrow utilizing the investigational CliniMACS selection system. The
      hypothesis to be tested at the time was that the incidence of severe acute GvHD was
      significantly reduced in children who received HSCT with a T-cell depleted bone marrow stem
      cell graft as compared to those receiving an unmanipulated graft. Approximately midway
      through the study the evidence indicated that although the incidence of severe acute GvHD
      with T-cell depletion was low, it was not significantly lower than the standard treatment of
      unmanipulated bone marrow. Therefore the study was amended to remove the T-cell depleted arm
      and continue accrual to one arm providing all patients with an unmanipulated bone marrow stem
      cell graft. The primary objective then being to determine if the true incidence of severe
      acute GvHD was below 15% as reported. The observational group receiving PBPC remained open
      for those patients whose donors or donor centers chose to provide PBPC in lieu of bone
      marrow. Only one such patient was assigned to this group; therefore, no valid conclusions can
      be formulated.

      Intervention analysis was based on those patients who received an unmanipulated stem cell
      product only. For this study, the investigators had requested bone marrow for all study
      subjects. However, the final determination of the source of the hematopoietic stem cells,
      bone marrow or peripheral blood, was at the discretion of the donor and the donor center.
      Those participants who received a peripheral blood stem cell product were followed in the
      observational group only. All participants, whether recipients of a bone marrow or blood stem
      cell product, received the same preparative conditioning regimen
    

Intervention name(s): Allogeneic Stem Cell Transplantation; Chemotherapy and antibodies
Intervention type(s): Procedure; Drug
Intervention description(s): An infusion of HLA matched unrelated bone marrow or peripheral blood stem cells.; Participants received a standard conditioning regimen consisting of total body irradiation, cyclophosphamide, thiotepa and ATG. GVHD prophylaxis consisted of cyclosporine and Methotrexate.
Other intervention name(s): Allogeneic stem cell transplant; Matched unrelated donor stem cell transplant; Bone marrow stem cell transplant; Graft versus host disease
Intervention MeSH terms: Antibodies
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: High risk hematologic malignancies; Allogeneic stem cell transplant; Matched unrelated donor transplantation; Unmanipulated stem cell graft; Bone marrow transplantation