IS BONE MARROW TRANSPLANTATION HELPFUL IN AMELIORATING THE SYMPTOMS OF RECESSIVE DYSTROPHIC EPIDERMOLYSIS BULLOSA?
Wagner, J., Ishida-Yamamoto, A., McGrath, J., Hordinsky, M., Keene, D., Woodley, D., et al. (2010). Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. New England Journal of Medicine, 363, 629-639.
Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited mechanobullous disease caused by mutations in the gene COL7A1, which encodes type VII collagen. Type VII collagen is a major component of anchoring fibrils, whose function is to tether the epidermal basement membrane to the dermis. This disease is often very severe and characterized by cycles of extensive blistering of mucocutaneous sites followed by ulcerations and scarring. Complications of scarring in the skin include flexion contractures of limbs and pseudosyndactyly or "mitten deformities" of the hands and feet. Complications of scarring in mucosal sites include narrowing of the oral cavity, limitation of tongue movement, loss of teeth, esophageal stricture formation, and narrowing of the airway. Because of these complications as well as the extensive wounds, caloric needs are increased, and the combination leads to malnutrition, anemia, and growth retardation. In the past, these patients died in infancy of sepsis and other complications of extensive blistering. Now, with improved nutritional and wound care, patients can survive into their teens or adulthood. Unfortunately, at that time, aggressive squamous cell carcinomas often occur within the abnormal skin, and many die of metastatic disease.
To date, the care of RDEB patients has been palliative and restricted to treatment of individual wounds and systemic complications as they arise. This group hypothesized that allogeneic marrow contains stem cells capable of producing Type VII collagen, and therefore if transferred to patients deficient in this protein, it would ameliorate the manifestations of RDEB. They first studied this in mouse models and then conducted these Phase 1 and Phase 2 clinical trials. Between October 2007 and August 2009, they enrolled seven children aged 15 months to 14.5 years who were severely affected by RDEB. The patients underwent immunomyeloablative chemotherapy followed by allogeneic stem cell transplantation.
Unfortunately, one patient developed severe chemotherapy toxicity and died before receiving the transplant. The remaining six children who received the transplant all had improved wound healing and a decrease in blister formation between days 30 and 130 after transplantation. There was increased type collagen VII deposition at the dermal-epidermal junction in five of six patients, and all had a substantial proportion of donor cells in their skin. Normalization of the anchoring fibrils did not occur. A second patient died at day 183 from graft rejection and subsequent infection.
REMARK: This study showed that allogeneic stem cell transplantation can partially correct type VII collagen deficiency and improve skin and mucosal integrity in patients with RDEB. The rates of recovery and the ultimate outcomes varied among the surviving patients. A limitation of this study was the short follow-up time, which varied from 130 to 799 days after transplantation. This is a high-risk procedure, and therefore more studies will be necessary to better understand the long-term risks and benefits in this patient population.
DOES TOPICAL RAPAMYCIN IMPROVE FACIAL ANGIOFIBROMAS IN PATIENTS WITH TUBEROUS SCLEROSIS?
Haemel, A., O'Brian, A., & Teng J. Topical rapamycin, a novel approach to facial angiofibromas in tuberous sclerosis. (2010). Archives of Dermatology, 146, 715-718.
Tuberous sclerosis is an inherited neurocutaneous disorder that can be debilitating and disfiguring. Facial angiofibromas occur in 70% to 80% of patients with this disorder. They present as pink papules primarily on the central face. They progressively enlarge and multiply over time. They may spontaneously bleed and impair vision and are a significant cause of morbidity in this condition. Current treatment options include destructive approaches such as dermabrasion, surgical excision, and laser therapy, but most angiofibromas are typically resistant to these treatment modalities and/or recur after treatment. In addition, many of these modalities can result in scarring and may require sedation to perform.
This case report describes a 16-year-old girl with many severe systemic and cutaneous manifestations of tuberous sclerosis. She had numerous angiofibromas that remained prominent, progressive, and disfiguring despite multiple attempts at treatment with shave excisions, pulsed dye, and CO2 laser therapies. None of these procedures had lasting effects on the progression of her condition.
This group noted that the literature described several studies showing the success of rapamycin orally for multiple manifestations of tuberous sclerosis. Rapamycin is an immunosuppressant medication with additional antiangiogenic and antineoplastic effects. The group hypothesized that the topical application of rapamycin could be a novel and practical therapeutic option for facial angiofibromas and would avoid systemic exposure and therefore decrease the risk of adverse side effects. They developed a 1% ointment of rapamycin in petrolatum. This was applied to the face of the study patient twice daily. The estimated amount used was 0.5 g per application.
Within 1 week of treatment, a decrease in facial erythema was noted. Thereafter, there was gradual improvement in her skin texture. At her 6-week follow-up appointment, she was noted to have fewer angiofibromas, decreased facial erythema, smaller papules on the cheeks, and complete resolution of papules on the temples and forehead. After 12 weeks of treatment, a sustained effect was noted with continued improvement in skin texture. No local or systemic adverse effects were noted. No measurable systemic absorption was noted over the 3 months of application.
REMARK: From this initial case report, it appears that topical rapamycin therapy could be an effective treatment of facial angiofibromas with minimal or absent systemic toxic effects. There are many questions that remain unanswered, including the following: Are there any local or systemic consequences of long-term therapy? Will angiofibromas recur after down-titration or discontinuation of treatment? Is maintenance therapy necessary? Large-scale clinical trials will be necessary to validate the safety and effectiveness of this novel treatment approach.
ARE THERE NEW DEVELOPMENTS IN THE FIELD OF METASTATIC MELANOMA?
Hodi, F., O'Day, S., McDermott, D., Weber, R., Sosman, J., Haanen, J., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine, 363, 711-723.
The incidence of metastatic melanoma (MM) has increased over the past three decades. The World Health Organization estimates that 80% of deaths from skin cancer are due to MM. The median survival of patients with MM is less than 1 year. No previous therapy has been shown in a Phase 3 randomized controlled trial to improve overall survival in this group of patients.
Ipilimumab is a fully human monoclonal antibody that blocks CTLA-4 and promotes antitumor activity. CTLA-4 or cytotoxic T lymphocyte associated antigen 4 is an immune checkpoint molecule that down-regulates pathways of T-cell activation. Ipilimumab has shown activity when used as monotherapy in Phase 2 clinical trials. It has also shown activity when combined with other agents. The other drug used in this study was a cancer vaccine, gp100, which when used as monotherapy induces an immune response but has limited antitumor activity.
This was a randomized, double-blind, Phase 3 clinical trial of 676 patients with unresectable Stage 3 or 4 melanoma who had been previously treated with a regimen containing one of several specified chemotherapeutic and/or immunotherapeutic agents. Patients were enrolled in 125 centers in 13 countries in North America, South America, Europe, and Africa between 2004 and 2008. The patients were randomized to one of three groups in a 3:1:1 ratio. Four hundred three patients received ipilimumab and gp100 peptide vaccine (Group A), 137 received ipilimumab plus a gp100 placebo (Group B), and 136 received gp100 plus an ipilimumab placebo (Group C). All were administered therapies once every 3 weeks, for a total of four treatments.
The primary end point of this study was originally to determine the group with the best overall response rate. This end point was amended to overall survival. Sixty percent of Group A, 64.2% of Group B, and 57.4% of Group C patients received all four treatment doses. The most frequent reason for stopping the medications was disease progression. Median overall survival for Group A was 10 months, for Group B was 10.1 months, and for Group C was 6.4 months. There was no difference in overall survival detected between the two groups that received ipilimumab. The effect of ipilimumab on overall survival was independent of age, gender, baseline lactate dehydrogenase levels, metastatic stage of disease, and receipt or nonreceipt of previous interleukin 2 therapy. The highest percentage of patients with an objective response or stable disease was in the group that received ipilimumab alone.
Immune-related adverse events occurred in 60% of patients treated with ipilimumab and 32% treated with gp100. These most often affected the skin and GI tract, with the most common adverse effect being diarrhea. Other reported adverse effects included injection site reactions, vitiligo, endocrine immune-related adverse events, rash, pruritus, anorexia, and fatigue. Fourteen deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.
This study showed that ipilimumab either alone or with gp100 improved overall survival as compared with gp100 alone in patients with MM who had undergone previous treatment. The efficacy of ipilimumab was not improved by the addition of gp100. Ipilimumab monotherapy resulted in a 1-year survival rate of 39.3% and a 2-year survival rate of 24.2%. The adverse event profile was consistent with that reported in Phase 2 trials. Most adverse events were immune related and consistent with the proposed mechanism of action of the medication. Prompt medical attention and early administration of corticosteroids were critical to managing these problems.
REMARK: If melanoma is detected early, it has a very favorable prognosis, yet the prognosis for advanced melanoma is dismal. It has therefore been the subject of a significant amount of research to better understand the disease and how best to treat it. Despite the research and development of many medications, no previous therapy has been shown in a Phase 3 randomized controlled trial to improve overall survival in these patients. This study was well designed and is exciting because it is the first of its kind to show a survival benefit in patients with MM. This and potentially other new therapies hold promise to improve treatment options for this subset of patients.