Stem Cell Transplantation From HLA Partially-Matched Related Donors for Patients With Hematologic Malignancies
Condition: Acute Lymphoblastic Leukemia; Acute Myelogenous Leukemia; Myelodysplastic Syndrome; Chronic Myelogenous Leukemia; Non-Hodgkin Lymphoma; Hodgkin Lymphoma
MeSH terms: Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hematologic Neoplasms; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 3

Summary: 
      This clinical pilot trial is intended to evaluate the feasibility, efficacy and safety of
      hematopoietic stem cell transplantation (HSCT) from Human Leukocyte Antigen (HLA)-mismatched
      related donors for children and young adults with hematologic malignancies who lack a
      suitably matched related or unrelated donor. The methodology will be one that has been
      successfully utilized in adult patients at Thomas Jefferson University.
    

Detailed description: 
      Allogeneic HSCT is a potentially curative therapy for a number of malignancies. A barrier to
      the institution of this potentially curative strategy in hematologic malignancies is the
      availability of donors. Only 30% of patients in North America or Europe who may benefit from
      allogeneic HSCT will have an available HLA matched sibling donor. The ability to find a
      matched sibling donor is proportional to the number of children in the family. Because of the
      decreasing size of nuclear families, it is becoming less likely for patients to have an HLA
      identical matched sibling. Registries can provide a matched unrelated allogeneic stem cell
      graft for an additional 30% of patients. However this is not an option for patients who do
      not have a match in the registry, or whose disease status precludes them from waiting to
      identify an appropriate unrelated donor. The ability of finding a well matched unrelated
      donor is even more limited for segments of the population with mixed race ancestry as well as
      for African Americans who, because of a higher degree of HLA diversity, will be unlikely to
      find an unrelated donor who matches their HLA type.

      In these settings it is easier and faster to identify a partially HLA-matched (or
      haploidentical) family member as a stem cell donor. The use of haploidentical donors broadens
      the application of HSCT because it is not as limited by family size or racial/ethnic HLA
      diversity. Because parents and children, as well as siblings can be used as haploidentical
      donors, this type of transplant enfranchises almost every segment of the population.

      Since, in this study, the donor lymphoid and stem cell portions of the graft are collected
      and administered at different time points during the conditioning regimen, this approach to
      haploidentical HSCT is referred to as a 2 Step regimen. The approach does not involve ex vivo
      T cell depletion, but uses cyclophosphamide to tolerize donor lymphocytes within the
      framework of a myeloablative conditioning regimen. Preliminary experience with this approach
      in adult patients at Thomas Jefferson University for myeloablative haploidentical HSCT dates
      back to 2005 with the first trial using myeloablative conditioning formally launched in 2006.
      That initial trial met its accrual goals and the current trial is one of the successor trials
      derived from that experience.

      The conditioning regimen includes total body irradiation (TBI) (1.5 Gray x 8) and CY (60
      mg/kg x 2). Tacrolimus and Mycophenolate Mofetil (MMF) are used as post-transplant
      immunosuppression in relatively standard fashion.

      The novel aspect of the regimen is in the administration of the graft. If one considers that
      a standard allograft consists of two components, a lymphoid portion and a stem cell portion,
      what is unique here is the administration of these two portions separately, at different time
      points during the conditioning regimen rather than together. The lymphoid portion, including
      a fixed dose of CD3+ cells/kg is administered prior to cyclophosphamide while the
      hematopoietic stem cell (HSC) portion of the graft is administered after cyclophosphamide has
      been metabolized and eliminated. Thus, the transplant occurs in 2 steps.
    

Intervention name(s): Radiation; Cyclophosphamide; Donor Lymphocyte Infusion (DLI); Haploidentical Stem Cell Transplantation
Intervention type(s): Radiation; Drug; Biological; Biological
Intervention description(s): 1,200 cGy, delivered in 8 fractions of 150 cGy bid x 4 days; Cyclophosphamide 60 mg/kg IV daily x 2 consecutive days; DLI containing 1 x 10E8/kg donor T-cells; 2-10 x 10E6/kg donor CD34+ selected cells
Other intervention name(s): Total Body Irradiation; Cytoxan
Intervention MeSH terms: Cyclophosphamide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Stem Cell Transplantation; Haploidentical Donors