Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)
Condition: Hemophagocytic Lymphohistiocytosis; Chronic Active Epstein-Barr Virus Infection; Chronic Granulomatous Disease; HIGM-1; Leukocyte Adhesion Deficiency; IPEX
MeSH terms: Epstein-Barr Virus Infections; Granulomatous Disease, Chronic; Lymphohistiocytosis, Hemophagocytic; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes
Study type: Interventional
Phase: Phase 2

Summary: 
      HLH, HLH-related disorders, Chronic Granulomatous (CGD), HIGM1, Immune dysregulation,
      polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) and severe LAD-I represent
      primary immune disorders that are typically fatal without Hematopoietic Cell Transplant
      (HCT). However, transplant is often complicated by inflammation, infection and other
      co-morbidities. In addition, these disorders have been shown to be cured with partial
      chimerism, making them an ideal target for the use of reduced intensity approaches, where a
      portion of patients may not achieve full donor chimerism, but instead achieve stable mixed
      chimerism. Reduced-intensity conditioning strategies have demonstrated improved survival with
      decreased Treatment Related Mortality (TRM) in institutional series for patients with HLH
      (Cooper et al., 2006; Marsh et al., 2010; Marsh et al., 2011). However, graft loss and
      unstable chimerism remain challenges. An institutional case series from Cincinnati Children's
      Hospital demonstrated full or high-level chimerism and improved durable engraftment using
      intermediate (Day -14) timing alemtuzumab (Marsh et al., 2013b). This study aims to test the
      efficacy of the Intermediate RIC strategy in a prospective multi-center study including HLH
      as well as other primary immunodeficiencies where allogeneic transplant with RIC has been
      shown to be feasible and stable chimerism is curative.
    

Detailed description: 
      The primary goal of this Phase II clinical trial is to determine the one-year overall
      survival of patients treated for immune deficiencies including HLH, HLH-like disorders, CGD,
      HIGM1, IPEX syndrome, and severe LAD-I with Matched Related Donor (MRD)/ Matched Unrelated
      Donor (MUD) bone marrow transplant using a reduced-intensity conditioning strategy including
      intermediate-timing of alemtuzumab. The donor choice is an unaffected related bone marrow
      donor who is a 6/6 match at HLA-A, -B (intermediate or higher resolution) and -DRB1 (at high
      resolution using DNA-based typing) OR a 7/8 or 8/8 match for human leukocyte antigen (HLA)-A,
      -B, -C and -DRB1 (at high resolution using DNA-based typing), OR an unrelated bone marrow
      donor who is a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 (at high resolution using
      DNA-based typing). The transplant conditioning regimen will include fludarabine, melphalan,
      and alemtuzumab starting at Day -14 (Flu/Mel/Alem). Graft Versus Host Disease (GVHD)
      prophylaxis will consist of cyclosporine and corticosteroids through engraftment.
      Post-transplant supportive care will include infection surveillance and prophylaxis, and
      disease-specific supportive care.
    

Intervention name(s): Hematopoietic Stem Cell Transplant
Intervention type(s): Biological
Intervention description(s): NOTE: The - sign is the number of days before the transplant and the + sign is the number of days after the transplant.
Alemtuzumab 0.2mg/kg Day-14,-13,-12,-11,-10
Fludarabine 30 mg/m2 on Day -8,-7,-6,-5,-4
Melphalan 140mg/m2 on Day -3
The GVHD prophylaxis will consist of the following:
Cyclosporine on Day -3 to Day +100, maintaining a level of 250-500 ng/mL, then taper to Day +180.
Methylprednisolone 2 mg/kg/day on Day -2 and -1, 1 mg/kg/day on Day 0 to Day +28, then taper over 1 month. Oral prednisone may be substituted starting on Day 0 (1.2 mg/kg/day)
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hemophagocytic lymphohistiocytosis; Chronic Active EBV; Chronic Granulomatous Disease; Hyperimmunoglobulin M Syndrome (Hyper IGM); Leukocyte Adhesion Deficiency; IPEX; Hematopoietic Stem Cell Transplant (HSCT); Non-Myeloablative Transplant (NST); Reduced-Intensity Conditioning (RIC)