Stem Cell Transplant for Epidermolysis Bullosa

• Incidence of transplant-related mortality (TRM) [ Time Frame: 180 Days Post Transplant ] [ Designated as safety issue: Yes ]
• Pattern of biochemical improvement measured by increase in protein expression (collagen, laminin, integrin or plakin) [ Time Frame: Through 1 Year Post-Transplant ] [ Designated as safety issue: No ]
• Quality of Life [ Time Frame: Pretreatment, Day 365 and Day 730 ] [ Designated as safety issue: No ]

• Incidence of transplant-related mortality (TRM) [ Time Frame: 180 Days Post Transplant ] [ Designated as safety issue: Yes ]
• Pattern of biochemical improvement measured by increase in protein expression (collagen, laminin, integrin or plakin) [ Time Frame: Through 1 Year Post-Transplant ] [ Designated as safety issue: No ]
• Quality of Life [ Time Frame: Pretreatment, Day 365 and Day 730 ] [ Designated as safety issue: No ]
• Overall Survival [ Time Frame: 6 Months, 1 Year and 2 Years Post-Transplant ] [ Designated as safety issue: No ]
• Pattern and durability of hematopoietic stem cell transplant [ Time Frame: 6 Months, 1 Year and 2 Years Post-transplant ] [ Designated as safety issue: No ]
• Mesenchymal stem cell (MSC) transplant engraftment [ Time Frame: Day 28, 60 and 100, 6 months, 1 year and 2 Years Post Transplant ] [ Designated as safety issue: No ]
• Incidence of Acute and Chronic Graft Versus Host Disease [ Time Frame: Day 100, 6 Months, 1 Year and 2 Years Post-Transplant ] [ Designated as safety issue: Yes ]

This is an open-label, single institution, phase II study in patients with epidermolysis bullosa (EB). The underlying hypothesis is that the infusion of bone marrow or umbilical cord blood from a healthy unaffected donor will correct the collagen, laminin, integrin, or plakin deficiency and reduce the skin fragility characteristic of severe forms of EB. A secondary hypothesis is that mesenchymal stem cells from a healthy donor will enhance the safety and efficacy of the allogeneic hematopoietic stem cell transplant as well as serve as a source of renewable cells for the treatment of focal areas of residual blistering.

• Drug: Cyclophosphamide
  50 mg/kg/day intravenously on Day -6.
  Other Name: Cytoxan
• Drug: Fludarabine
  40 mg/m^2/day intravenously on Days -5, -4, -3 and -2.
  Other Name: Fludara
• Drug: Anti-thymocyte globulin
  30 mg/kg on Days -4, -3 and -2.
  Other Name: ATG
• Drug: Cyclosporine A
  Days -3 to 100+ to maintain a level of >200 ng/ml; initial dose 2.5 mg/kg over 2 hours every 8-12 hours for children.
  Other Name: CSA
• Drug: Mycophenolate mofetil
  15 mg/kg intravenous twice per day on days -3 through 30.
  Other Name: CellCept(R)
• Procedure: Hematopoietic stem cell transplant
  infused via intravenous drip on Day 0
  Other Names:

  • Bone marrow transplant
  • Umbilical cord blood transplant
• Procedure: Mesenchymal stem cell transplant
  infused via intravenous drip on Day 0
  Other Name: MSC
• Radiation: Total body irradiation
  200 cGY on Day -1 administered in a single fraction at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.

Inclusion Criteria:

• Diagnosis of severe form of epidermolysis bullosa (EB) characterized by collagen, laminin, integrin, keratin or plakin deficiency. Assessment criteria for severe EB:

  • Severe blistering disease requiring dressings on >50% of the body surface area
  • Documented collagen, laminin, integrin, keratin or plakin deficiency (by immunofluorescence staining with protein specific antibodies or Western blotting and by mutation analysis)
  • Poor performance status as a result of EB (Lansky or Karnofsky <50%)

• Adequate Organ Function Criteria

  • 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
  • Pulmonary: oxygen saturation >92%
  • Cardiac: left ventricular ejection fraction ≥ 45%, normal electrocardiogram (EKG) or approved by Cardiology for transplant.
  • Performance status: ≥ 50% Lansky; ≥ 50% Karnofsky

• Available Healthy HSC Donor (order of preference)

  • Related Donor (marrow or UCB)

    • HLA-A, B, C, DRB1 genotypic identical (sibling) donor
    • HLA-A, B, C, DRB1 phenotypic identical donor
    • 7/8 HLA matched donor at HLA-A, B, C, DRB1

  • Unrelated Donor

    • Marrow

      • HLA-A, B, C, DRB1 phenotypic identical donor
      • 7/8 HLA matched donor at HLA-A, B, C, DRB1
      • UCB
      • HLA-A, B (antigen level) and DRB1 (allele level) matched donor
      • 5/6 HLA matched donor at HLA-A, B, DRB1
      • 4/6 HLA matched donor at HLA-A, B, DRB1
• Voluntary written consent

Exclusion Criteria:

• Active systemic infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days).
• History of human immunodeficiency virus (HIV) infection
• Prior transplantation with donor skin
• Evidence of squamous cell carcinoma
• Donor has EB
• Pregnancy or breast feeding. Females of child-bearing age must have a documented negative pregnancy test and agree to use contraception as a condition for enrollment.