Haploidentical Stem Cell Transplant for Treatment Refractory Hematological Malignancies
Condition: Acute Lymphoblastic Leukemia (ALL); Acute Myeloid Leukemia (AML); Secondary AML; Myelodysplastic Syndrome (MDS); Secondary MDS; Chronic Myeloid Leukemia; Juvenile Myelomonocytic Leukemia (JMML); Paroxysmal Nocturnal Hemoglobinuria (PNH); Lymphoma, Non-Hodgkin; Hodgkin Disease
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms; Preleukemia; Neoplasm Metastasis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hematologic Neoplasms; Hodgkin Disease; Lymphoma, Non-Hodgkin; Leukemia, Myelomonocytic, Juvenile; Hemoglobinuria; Myelodysplastic Syndromes; Hemoglobinuria, Paroxysmal
Study type: Interventional
Phase: Phase 2

Summary: 
      Relapsed disease is the most common cause of death in children with hematological
      malignancies. Patients who fail high-intensity conventional chemotherapeutic regimens or
      relapse after stem cell transplantation have a poor prognosis. Toxicity from multiple
      therapies and elevated leukemic/tumor burden usually make these patients ineligible for the
      aggressive chemotherapy regimens required for conventional stem cell transplantation.
      Alternative options are needed. One type of treatment being explored is called haploidentical
      transplant.

      Conventional blood or bone marrow stem cell transplant involves destroying the patient's
      diseased marrow with radiation or chemotherapy. Healthy marrow from a donor is then infused
      into the patient where it migrates to the bone marrow space to begin generating new blood
      cells. The best type of donor is a sibling or unrelated donor with an identical immune system
      (HLA "match"). However, most patients do not have a matched sibling available and/or are
      unable to identify an acceptable unrelated donor through the registries in a timely manner.
      In addition, the aggressive treatment required to prepare the body for these types of
      transplants can be too toxic for these highly pretreated patients. Therefore doctors are
      investigating haploidentical transplant using stem cells from HLA partially matched family
      member donors.

      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 patient's (the host) body tissues 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 infection. However, the presence of T cells in the graft
      may offer a positive effect called graft versus malignancy or GVM. With GVM, the donor T
      cells recognize the patient's malignant cells as diseased and, in turn, attack these diseased
      cells.

      For these reasons, a primary focus for researchers is to engineer the graft to provide a T
      cell depleted product to reduce the risk of GVHD, yet provide a sufficient number of cells to
      facilitate immune reconstitution, graft integrity and GVM.

      In this study, patients were given a haploidentical graft engineered to with specific T cell
      parameter values using the CliniMACS system. A reduced intensity, preparative regimen was
      used to reduce regimen-related toxicity and mortality. The primary goal of this study is to
      evaluate overall survival in those who receive this study treatment.
    

Detailed description: 
      Secondary objectives for this protocol are to 1) assess the kinetics of lymphohematopoietic
      reconstitution and 2) describe the short and long-term (up to 5 years post- transplant)
      toxicity of haploidentical stem cell transplantation, including GVHD, in children with
      refractory hematological malignancies.
    

Intervention name(s): Stem Cell Transplantation; Miltenyi Biotec CliniMACS; Systemic chemotherapy and antibodies
Intervention type(s): Procedure; Device; Drug
Intervention description(s): An infusion of HLA mismatched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device.; stem cell selection device; Transplant recipients received a non-TBI based reduced intensity conditioning regimen consisting of OKT-3, Fludarabine Thiotepa, and Melphalan. Rituximab was administered within 24 hours of the transplant in an effort to prevent PTLPD. In addition to T-cell depletion of the haploidentical stem cell product, Mycophenolate mofetil was provided as prophylaxis for GVHD.
Other intervention name(s): Allogeneic stem cell transplant,; Mismatched family member donor stem cell transplant; Haploidentical donor stem cell transplant,; Reduced intensity conditioning regimen,; T-cell depletion donor stem cell processing
Intervention MeSH terms: Antibodies
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Haploidentical stem cell transplant; High risk hematologic malignancies; Allogeneic stem cell transplant; Mismatched family member stem cell donor