Stem Cell Transplantation as Immunotherapy for Hematologic Malignancies
Condition: Leukemia; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Chronic Myeloid Leukemia; Juvenile Myelomonocytic Leukemia; Myelodysplastic Syndrome; Paroxysmal Nocturnal Hemoglobinuria; Hodgkin's Lymphoma; Non-Hodgkin Lymphoma
MeSH terms: Lymphoma; Leukemia; Leukemia, Myeloid; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematologic Neoplasms; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myelomonocytic, Juvenile; Hemoglobinuria; Myelodysplastic Syndromes; Hemoglobinuria, Paroxysmal
Study type: Interventional
Phase: Phase 2

Summary: 
      Blood and marrow stem cell transplant has improved the outcome for patients with high-risk
      hematologic malignancies. However, most patients do not have an appropriate HLA (immune type)
      matched sibling donor available and/or are unable to identify an acceptable unrelated HLA
      matched donor through the registries in a timely manner. Another option is haploidentical
      transplant using a partially matched family member donor.

      Although haploidentical transplant has proven curative in many patients, this procedure has
      been hindered by significant complications, primarily regimen-related toxicity including GVHD
      and infection due to delayed immune reconstitution. These can, in part, be due to certain
      white blood cells in the graft called T cells. GVHD happens when the donor T cells recognize
      the body tissues of the patient (the host) are different and attack these cells. Although too
      many T cells increase the possibility of GVHD, too few may cause the recipient's immune
      system to reconstitute slowly or the graft to fail to grow, leaving the patient at high-risk
      for significant infection.

      For these reasons, a primary focus for researchers is to engineer the graft to provide a T
      cell dose that will reduce the risk for GVHD, yet provide a sufficient number of cells to
      facilitate immune reconstitution and graft integrity. Building on prior institutional trials,
      this study will provide patients with a haploidentical graft engineered to specific T cell
      target values using the CliniMACS system. A reduced intensity, preparative regimen will be
      used in an effort to reduce regimen-related toxicity and mortality.

      Two groups of patients were enrolled on this study. One group included those with high-risk
      hematologic malignancies and the second group included participants with refractory
      hematologic malignancies or undergoing a second transplant. The primary aim of the study was
      to estimate the relapse rate in the one group of research participants with refractory
      hematologic malignancies or those undergoing second allogeneic transplant. Both groups will
      be followed and analyzed separately in regards to the secondary objectives.

      This study was closed to accrual on April 2006 as it met the specific safety stopping rules
      regarding occurrence of severe graft vs. host disease. Although this study is no longer open
      to accrual, the treated participants continue to be followed as directed by the protocol.
    

Detailed description: 
      Secondary outcome evaluations for this clinical study included the following:

        -  To estimate one-year overall survival for research participants with high risk
           malignancies who receive a haploidentical HSCT

        -  To compare overall survival and cumulative incidence of relapse for the two groups of
           patients with their corresponding historical controls

        -  To estimate disease-free survival and event-free survival in participants with
           hematologic malignancies who receive a haploidentical HSCT

        -  To estimate the incidence of overall grade 3-4 acute GvHD in research participants with
           hematologic malignancies who receive a haploidentical HSCT

        -  To estimate the incidence of chronic GvHD and graft failure in research participants
           with hematologic malignancies who receive a haploidentical HSCT

        -  To estimate the incidence of non-hematologic regimen-related toxicity and
           regimen-related mortality in the first 100 days post-transplant in research participants
           with hematologic malignancies who receive a haploidentical HSCT

        -  To estimate the number of research participants who develop evidence of EBV reactivation
           or post-transplant lymphoproliferative disease (PTLPD)

        -  To describe disease-free survival, GvHD and engraftment in research participants
           receiving grafts from Killer immunoglobulin-like receptor (KIR) mismatched and KIR
           matched haploidentical donors
    

Intervention name(s): Systematic chemotherapy and antibodies; Allogeneic stem cell transplantation; Miltenyi CliniMACS
Intervention type(s): Drug; Procedure; Device
Intervention description(s): Systemic chemotherapy and antibodies as follows:
Transplant recipients received a reduced intensity conditioning regimen consisting of OKT-3, fludarabine, thiotepa, and melphalan followed by an infusion of a T-cell depleted haploidentical hematopoietic stem cell graft. The antibody Rituximab was administered within 24 hours of the infusion in an effort to prevent PTLPD. In addition to T -cell depletion of the donor product, Mycophenylate mofetil was provided over several months as prophylaxis for GVHD; An infusion of HLA mismatched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device; Miltenyi Biotec CliniMACS stem cell selection device
Other intervention name(s): Haploidentical donor stem cell transplant; Mismatched family member transplant; Allogeneic stem cell transplant; Reduced intensity conditioning regimen; Hematopoietic stem cell transplant
Intervention MeSH terms: Antibodies
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Allogeneic stem cell transplantation; Haploidentical stem cell transplant; Mismatched family member stem cell donor transplant; Bone marrow transplant; High risk hematological malignancies; T-cell depletion methodology; Miltenyi Biotec CliniMACS stem cell selection device