Bone Marrow is the Preferred Graft for Allogeneic Hematopoietic Cell Transplantation in Severe Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB), an incurable blistering genodermatosis, is due to deficiency of type VII collagen (C7) resulting in lack of attachment between the epidermis and dermis, a poor quality of life, and early death. Between 2007 and 2012, 18 patients with severe generalized RDEB have undergone allogeneic HCT at the University of Minnesota. Thirteen patients were treated with a myeloablative (MA) conditioning (busulfan IV with pharmacokinetic targeting 1,000 mmol/min for the area under curve; fludarabine [FLU] IV 75 mg/m², and cyclophosphamide [CY] IV 200 mg/kg); 5 patients were treated with non-MA conditioning (CY IV 50 mg/kg, FLU IV 200 mg/m², anti-thymocyte globulin IV 90 mg/kg, and total body irradiation 200 cGy) with cyclosporine A and mycophenolate mofetil as GVHD prophylaxis. Patients were transplanted with bone marrow (BM) from an HLA-matched sibling (n=10) or HLA-matched unrelated donor (n=3), or partially matched umbilical cord blood (UCB, n=5). The primary endpoint of the analysis was survival with skin improvement. Importantly, non-MA conditioning was well tolerated, with a marked reduction in risk of infection, and pulmonary and renal toxicity. Thus far, for the entire cohort, the overall probability of survival is 73% (95% CI, 49-96%) with 11 demonstrating partial to marked biochemical and clinical improvement in mucocutaneous disease on the basis of protein expression and resistance to blistering. Transplant outcomes are shown in the Table. We conclude that BM is the preferred source of HSC (alive and engrafted: 11 of 13 [85%] with BM versus 1 of 5 with CB [20%], p-value = 0.02) and that early results with the non-MA conditioning are promising in terms of toxicity profile and engraftment. Overall, HCT has the potential of being a durable, systemic therapy for many people with different forms and severities of EB, and sets the stage for using BM cells in the treatment of a broad spectrum of extracellular matrix disorders.

Graft	N	Regimen	N	C7 Protein expression	Skin Healing1	Skin chimerism, N (range)3	GvHD acute/chronic	Alive	Alive and Engrafted
UCB	5	MA	4	2	1	1 (11-30%)	1 / 1	2	1
		RIC	1	0	0	0	0 / 0	1	0
BM	13	MA	9	6	72	7 (2-97%)	1 / 0	7	7
		RIC	4	1	32	2 (3-23%)	0 / 0	4	4
Total	18		18	10	11	10	2 / 1	14	11

¹Defined as a change from > 50% (before HCT) to < 10% (after HCT) skin covered with blisters and erosions.

²Remarkably, significant clinical improvement can be achieved even in the absence of any detectable C7 early after HCT.

³Approximately 30% of wild-type levels of C7 are believed to be sufficient to protect from extensive blistering.

Keywords: Bone marrow, umbilical cord blood, transplantation, myeloablative conditioning, reduced intensity conditioning, epidermolysis bullosa