Haploidentical Stem Cell Transplantation for Patients With Hematologic Malignancies
Condition: Leukemia, Acute Lymphocytic (ALL); Leukemia, Myeloid, Acute(AML); Leukemia, Myeloid, Chronic(CML); Juvenile Myelomonocytic Leukemia(JMML); Hemoglobinuria, Paroxysmal Nocturnal (PNH); Lymphoma, Non-Hodgkin (NHL); Myelodysplastic Syndrome (MDS)
MeSH terms: Leukemia; Neoplasms; Preleukemia; Hematologic Neoplasms; Lymphoma, Non-Hodgkin; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Juvenile; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hemoglobinuria; Myelodysplastic Syndromes; Hemoglobinuria, Paroxysmal
Study type: Interventional
Phase: Phase 3

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
      graft versus host disease (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.

      This research project will investigate the use of particular pre-transplant conditioning
      regimen (chemotherapy, antibodies and total body irradiation) followed by a stem cell
      infusion from a "mismatched" family member donor. Once these stem cells are obtained they
      will be highly purified in an effort to remove T cells using the investigational CliniMACS
      stem cell selection device. The primary goal of this study will be to determine the rate of
      neutrophil and platelet engraftment, as well as the degree and rate of immune reconstitution
      in the first 100 days posttransplant for patients who receive this study treatment.
      Researchers will also study ways to decrease complications that may occur with a transplant
      from a genetically mismatched family donor.
    

Detailed description: 
      Secondary outcome evaluations for this clinical study include the following:

        -  To estimate overall survival, disease free survival and event free survival for these
           patients

        -  To estimate the incidence of grade 2 to 4 acute GvHD in these patients

        -  To estimate the incidence of chronic GvHD and graft failure in these patients

        -  To estimate the incidence of non-hematologic peri-transplant regimen-related toxicity
           and regimen-related mortality in the first 100 days after transplantation in these
           patients

        -  To estimate the number of patients who require donor lymphocyte infusions and/or stem
           cell boosts after transplantation in this group of patients and evaluate its impact on
           immune reconstitution and engraftment

        -  To estimate the number of patients who develop evidence of EBV reactivation or post
           transplant lymphoproliferative disease (PTLPD) post transplant in this group of patients

        -  Describe the pharmacokinetics of rabbit anti-thymocyte globulin (rATG) in patients
           receiving allogeneic transplantation and determine the frequency of rATG antibody
           development

        -  Explore dose and patient characteristics as determinants of active rATG pharmacokinetic
           parameters

      Originally this study began as a randomized comparison of two methods of stem cell selection
      utilizing the CliniMACS device. Both arms provided a purified product of CD34+ hematopoietic
      cells that was depleted of T-lymphocytes. One arm utilized a positive selection methodology
      using an anti-CD34 antibody and the other arm utilized negative selection with the anti-CD3
      antibody OKT-3. There were no toxicities noted that would have required the study to be
      interrupted early, however, due to low accrual, it was decided to redesign the study. The new
      design focused on the standard arm utilizing negative selection, and all subsequent
      participants were treated in that manner. The patients who were treated on the positive
      selection arm are continuing to be monitored as specified in the original protocol, but will
      be reported in a descriptive manner only. The primary and secondary objectives of the current
      version of this study will be answered only by those patients receiving a haploidentical stem
      cell transplant utilizing a negative selection methodology.
    

Intervention name(s): Miltenyi Biotec CliniMACS; Stem Cell Transplantation; TBI, systemic chemotherapy and antibodies as follows:
Intervention type(s): Device; Procedure; Drug
Intervention description(s): A stem cell selection device.; An infusion of HLA mismatched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device.; Transplant recipients received a myeloablative conditioning regimen consisting of total body irradiation, thiotepa, cyclophosphamide, ATG, and OKT3. Rituximab was provided prior to transplant for PTLPD prophylaxis. In addition to T cell depletion of the donor product, cyclosporine was administered for GVHD prophylaxis.
Intervention MeSH terms: Antibodies
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Haploidentical stem cell transplant; Allogeneic stem cell transplant; Mismatched family member stem cell donor transplant; Bone marrow transplantHigh risk hematologic malignancies