Allogeneic Hematopoietic Stem Cell Transplant For Epidermolysis Bullosa

• Number of Patients With >70% Donor Chimerism [ Time Frame: Days 21, 100, 180, 365 and 730 Post Transplant ] [ Designated as safety issue: Yes ]
  Number of patients with donor chimerism - percentage of donor cells in the patient via the peripheral blood or bone marrow.
• Number of Patients With Transplant-Related Mortality [ Time Frame: Day 180 Post Transplant ] [ Designated as safety issue: Yes ]
  Number of patients who died due to complications of the transplant (includes all deaths without previous relapse or progression).
• Number of Patients With Platelet Engraftment [ Time Frame: Day 180 Post Transplant ] [ Designated as safety issue: No ]
  Number of patients with a platelet count >5 x 10^10 cells/liter for 3 consecutive measurements.
• Number of Patients With Acute Graft-Versus-Host Disease (GVHD) [ Time Frame: Day 100 Post Transplant ] [ Designated as safety issue: No ]
  Number of patients with GVHD. Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
• Number of Patients With Chronic Graft-Versus-Host Disease (cGVHD) [ Time Frame: Day 365 Post Transplant ] [ Designated as safety issue: No ]
  Number of patients with cGVHD; a severe long-term complication created by infusion of donor cells into a foreign host.
• Overall Survival [ Time Frame: 1 year and 2 years Post Transplant ] [ Designated as safety issue: No ]
  Survival is defined as the number of patients that were alive post transplant.
• Number of Patients With Donor Derived Cells in Skin [ Time Frame: Day 90 Post Transplant ] [ Designated as safety issue: No ]
  Number of patients who had donor skin chimerism - donor cells in the patient's epidermis (a state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease).
• Number of Patients With Resistance to Blister Formation [ Time Frame: Month 1 through Month 24 Inclusive ] [ Designated as safety issue: No ]
  Resistance to Blister Formation demonstrated by response to negative pressure.
• Number of Patients With Neutrophil Engraftment [ Time Frame: Day 42 Post Transplant ] [ Designated as safety issue: No ]
  Number of patients with an absolute neutrophil count >5 x 10^8 cells/liter for 3 consecutive days.

• Incidence of transplant-related mortality at 180 days
• Incidence of chimerism at 21, 100, 180, 365, and 730 days
• Incidence of neutrophil recovery at day 42 and platelet recovery at 180 days
• Incidence of acute graft-versus-host disease (GVHD) at day 100
• Incidence of chronic GVHD at 1-year
• Probability of survival and disease-free survival at 1 and 2 years
• Incidence of donor skin-derived epidermal cell survival 90 days after epidermal cell transplantation

RATIONALE: In animal models, stem cells have been shown to home to the skin and repair the biochemical and structural abnormalities associated with recessive dystrophic epidermolysis bullosa (RDEB) (collagen 7 deficiency).

PURPOSE: To determine the safety and effectiveness of stem cell infusion in the treatment of RDEB.

OBJECTIVES:

Primary

• Estimate the incidence of detectable donor-derived collagen type VII at day 100 in patients with epidermolysis bullosa by donor.

Secondary

• Determine the incidence of transplant-related mortality at day 180
• Determine the incidence of blood chimerism at days 21, 100, 180, 365, and 730
• Determine the incidence of neutrophil recovery at day 42 and platelet recovery at day 180
• Determine the incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV at day 100
• Determine the incidence of chronic GVHD at 1 year
• Determine the probability of survival at 1 and 2 years
• Determine the incidence of donor derived cells in the skin
• Determine resistance to blister formation OUTLINE: This is an open-label, pilot study.
• Conditioning regimen: Busulfan intravenously (IV) over 2 hours every 6 hours on days -9 to -4, fludarabine phosphate IV over 1 hour on days -5 to -3, and high-dose cyclophosphamide IV over 1 hour on days -5 to -2.
• Stem cell transplantation on day 0.

After completion of study treatment, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: 30 patients

• Drug: busulfan
  Day -9 through Day -6: 1.1 mg/kg if < 12 kg IV every 6 hours; 0.8 mg/kg if > 12 kg.
  Other Name: Bulsulfex
• Drug: cyclophosphamide
  Day -5 through Day -2: 50 mg/kg IV over 120 min.
  Other Name: Cytoxan
• Drug: fludarabine phosphate
  Day -5 through Day -3: 25 mg/m2 IV over 60 min.
  Other Names:

  • Fludarabine
  • Fludara
• Procedure: hematopoietic bone marrow transplantation
  allogeneic bone marrow, peripheral stem cell or umbilical cord blood transplantation
  Other Name: Bone marrow transplant

Inclusion criteria:

• Diagnosis of epidermolysis bullosa (EB)

  • Documented collagen type VII deficiency by:

    • Antigenic mapping (LH7.2 antibody)
    • Ultrastructure analysis of anchoring fibrils
    • DNA mutation analysis
• Performance status: >50% Lansky; >50% Karnofsky

• Adequate organ function

  • Renal: glomerular filtration rate > 60ml/min/1.73m2 patients aged ≤ 10 years
  • Hepatic: bilirubin, aspartate aminotransferase/alanine aminotransferase (AST/ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal 4.2.3 Pulmonary: oxygen saturation >92% 4.2.4 Cardiac: left ventricular ejection fraction > 45%.

• Healthy related hematopoietic stem cell donor available and meeting 1 of the following criteria:

  • HLA-A, B, DRB1-identical sibling bone marrow and/or umbilical cord blood donor (first priority)
  • HLA-A, B, DRB1-matched or partially matched related donor (second priority)
  • Donor may be a carrier but must be unaffected by EB
  • 8/8 HLA A, B, C, DRB1 allele level matched unrelated marrow donor (third priority)
  • 7/8 HLA-A, B, C, DRB1 allele level matched unrelated marrow donor or 4/6 HLA-A, B (antigen level), DRB1 (allele level) matched unrelated cord blood donor (fourth priority)

Exclusion criteria:

• Active infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days)
• Squamous cell carcinoma of the skin
• History of human immunodeficiency virus (HIV) infection
• Prior transplantation with donor skin