Bone Marrow Transplant Offers Hope in Recessive Dystrophic EB

"Substantial efforts are under way to understand the physiology of the apparent clinical response after bone marrow transplantation and to identify the stem-cell population responsible for this effect," they wrote.

Until this trial was performed, it was not known whether patients with preexisting mucocutaneous disease could tolerate the conditioning regimens used to prepare for allogeneic bone marrow transplantation. In particular, mucositis was feared because it is a common side effect even in patients without mucocutaneous disease. "The unique skin and mucosal membrane defects of this disease pose a particular challenge to any bone marrow transplantation program," the investigators added.

Yet only one of the six patients developed severe cutaneous toxicity. All patients developed mucositis, but the condition responded to therapy. "Notably, no patient had uncontrolled cellulitis, despite pretransplantation bacterial or fungal skin colonization," they noted.

Other adverse events included transient hyperbilirubinemia (four patients) and renal insufficiency requiring 3 days of hemodialysis (two patients). No patient developed acute or chronic graft-vs.-host disease.

"Clearly, much remains to be learned regarding the mechanism of the apparent functional correction as well as the long-term risks and benefits of this therapeutic approach, including the risk of squamous-cell carcinoma, which may occur after chemotherapy or as a result of incomplete correction of the underlying disease," Dr. Wagner and his colleagues noted.

"Already, we and others are considering modifications to enhance safety, such as coinfusion of mesenchymal stromal cells or the use of reduced-dose conditioning before bone marrow transplantation," they added.

This study was supported by the University of Minnesota Academic Health Center; the National institutes of Health; the Ministry of Health, Labor, and Welfare of Japan; the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Epidermolysis Bullosa (Liao Family) Research Fund; the Sarah Rose Mooreland EB Fund; and the Children’s Cancer Research Fund. One of Dr. Wagner’s associates reported previous ties to Johnson & Johnson, Procter & Gamble, Novartis, Astellas, and Allergan.

Despite the still unresolved clinical and scientific issues with this experimental therapy, the systemic approach to this genetic skin disease "represents a leap forward," wrote Dr. Leena Bruckner-Tuderman in an accompanying editorial (N. Engl. J. Med. 2010;363:680-2).

The study by Dr. Wagner and his colleagues "gives cautious hope that effective therapy of recessive dystrophic EB and other genetic skin diseases may one day be available," noted Dr. Bruckner-Tuderman, is in the department of dermatology at the University of Freiburg (Germany) Medical Center.

Future research should focus on the extent and duration of the therapeutic effects, particularly on whether higher C7 levels in the skin and improvements in mucocutaneous integrity can be sustained over the long term. In addition, more objective methods to assess treatment response are needed, as parental and clinical observation can be "quite subjective."

Dr. Wagner and his colleagues demonstrated that some patients with mucocutaneous fragility can tolerate the conditioning regimen and other procedures and medications needed for bone marrow transplantation. But they also showed that some cannot, and that the life-threatening adverse effects must be weighed carefully against potential benefits.

In their report, the investigators did not specifically address the issue of subject age in this clinical trial. Although some may consider it questionable to test an experimental treatment in children, it was important in this instance to conduct the test among patients in optimal clinical condition.

In recessive dystrophic EB, the severe secondary symptoms accrue with time, so it is reasonable to perform the transplantation as early as possible, "with the aim of preventing severe scarring, deformities, and also, ultimately squamous-cell carcinomas."

 She reported no financial disclosures.