Comment to: Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomized, placebo-controlled trial by Kirsner RS, Marston WA, Snyder RJ, Lee TD, Innes Cargill D, Slade HB. Lancet 2012;380:977–85.

Stefano Ricci

Abstract

Standard treatment with infection control, primary dressings, and the application of high-strength compression heals between 30% and 75% of venous leg ulcers.
Skin autografts, sheets of cultured allogeneic adult keratinocytes, allogeneic neonatal fibroblasts cultured within a bovine collagen matrix have been successively tried with uncertain success. HP802-247 is a novel spray-applied cell therapy containing growth-arrested allogenic neonatal keratinocytes and fibroblasts. In vitro studies have allowed optimization of the cellular formulation to enhance release of essential growth factors including vascular endothelial growth factor, basic fibroblast growth factor, keratinocyte growth factor, transforming growth factor α, and, when the cells are combined, granulocyte-macrophage colony stimulating factor.
Here is reported a phase 2, multicenter, randomized, placebo controlled trial at outpatient facilities in the USA (34 centers) and Canada (one center), between June 15, 2009, and May 5, 2011.
Eligible patients were at least 18 years of age, with venous reflux confirmed by duplex ultrasonography and up to three venous leg ulcers between the knee and ankle, at or above the malleolus, at least one between 2 and 12 cm2 in area without exposed tendon, muscle, or bone wound duration ranging from 6 to 104 weeks.
After a 2-week run-in period during which a cadexomer-iodine dressing was applied together with four-layer compression bandaging, patients were randomly assigned in blocks of five. Treatment was with vehicle alone applied every 7 days, or with cells in vehicle (either 0・5×106 cells per mL or 5・0×106 cells per mL) applied either every 7 days or every 14 days, thus creating five parallel groups with a 1:1:1:1:1 allocation.
The vehicle consisted of a human fibrinogen solution and a separate human thrombin solution. Growth-arrested (80 Gy of γ irradiation) neonatal foreskin-derived keratinocytes and fibroblasts in a 1:9 ratio were suspended at double concentration in the thrombin component.
The wound surface was treated with sequential single 130 µL sprays (first fibrinogen, then thrombin to cause polymerization). Foam dressing (changed at each weekly visit) was added after the matrix had formed on the wound surface, and 4-layer compression bandaging was applied. Patients attended weekly assessment visits for 12 weeks, or until healing.
A total of 228 patients were enrolled, 205 (90%) patients completed the trial. Cells produced a greater reduction in wound area than did vehicle alone during the 12-week treatment period. The dose of 0・5×106 cells per mL every 14 days yielded a 16% greater reduction on average than vehicle, with average decreases in the other dose groups ranging from 7・60 to 11・7% relative to vehicle. For the active treatment groups, we identified no significant effects for either high versus low dose, or for application every 7 days versus every 14 days. At week 12, mean wound area in the group assigned 0・5×106/mL every 14 days was reduced by 91% (SD 21%), compared with 80% (30%) with vehicle, while the mean decrease in area was 87% (SD 20%) for the 0・5×106/mL every 7 days group, 84% (26%) for the 5・0×106/mL every 14 days group, and 87% (23%) for the 5・0×106/mL every 7 days group. Overall, patients treated with cells had higher proportions of healed wounds than did those assigned vehicle alone, but only the group assigned 0・5×106/mL every 14 days differed significantly compared with control. Pain associated with the treated wound decreased steadily in all treatment groups during the 12-week treatment period. A total of 194 adverse events were spontaneously reported by 100 patients: most resolved, and generally did not interrupt the patient’s continuation in the trial; 18 serious adverse events, one of which (wound infection) potentially related to treatment. Immunotoxicity testing did not identify any meaningful treatment-induced alloantibody formation or induction of autoimmunity. Results suggest that cell treatment can be expected to close 60–70% of chronic venous leg ulcers of 2–12 cm2 in area within 12 weeks.


Comment by Stefano Ricci

Finding the good solution for healing ulcers is one of the myths of phlebology: an advantage for both patients and industries. Due to the large number of subjects presenting ulcers, patients will be advantaged by the discovery of a cheap method while industries look forward to technological suggestions with better gain possibilities. Compression treatment is the gold standard for ulcer healing, according to international evidence. Its outcome could even be better if compression would be better applied by compression pressure measurement that represents the dosage of this treatment and is the only determinant of compression effectiveness (Mosti – Phlebology Forum, Jul-Sept 2012). However this treatment is hated both by patients (more the bandage than the hosiery) - ugly, uncomfortable, difficult, slow - and by industries – low cost, low profits, limited innovations. As a consequence new ideas are interesting and well accepted, often independently from their true efficacy. In this case, ulcers healing time was 21 days shorter with the best treatment compared the control group, a good result but not exciting, considering what above-mentioned about compression. And what about the costs? It would be really interesting to know if, in terms of cost-effectiveness, treatment is worthwhile to shorten the healing time only by 20 days (Mosti – Phlebology Forum, Jul-Sept 2012). Finally, it is surprising to read about 194 adverse events on the 228 randomised patients. Even excluding minor events, the more than 5% of new skin ulcers and cellulitis reported are not encouraging at all.

Reply by the Authors (Kirsner&Slade)

Venous disease, ulceration and their complications are common, representing a significant public health issue. Using a rigorous methodology to study a potential new therapy, we described the best treatment response reported to date for refractory venous leg ulcers. We would characterize this as exciting. Not only did patients heal faster but also as Mosti fails to point out, substantially more patients healed in a relatively short 12-week study. Three weeks less compression therapy is likely to be very meaningful to patients, and healing more refractory patients in a shorter timeframe is likely to be cost effective.1
Equally important is that the effect of improvement persisted for at least 6 months after the end of the 12 week study, where the standard care group continued to show 25% fewer wounds healed.2 No amount of additional time with standard care is likely to achieve the same high rates of healing as with cell therapy in the population studied. Adverse events with chronic wounds are common, but most of our observed adverse events were simply a reflection of the population under study and the rigor that was used to collect adverse event information. More than 2000 medications were taken by the 228 study participants indicating the health state of these subjects. Importantly, there was no pattern or suggestion of adverse events caused specifically by the cell therapy.
Ideally the most effective and least costly approach to venous leg ulcers should be avoidance. External compression alone may be effective, while in certain cases it will be necessary to ablate the vessel(s) experiencing venous hypertension. We do not yet understand why some wounds fail to heal with standard care. We do know that the longer they remain unhealed, the more resistant they become to therapy.3 Chronically open wounds are a burden to the patient, and ineffective treatments are a financial burden to the healthcare system. Cell-based therapies offer the possibility of healing more wounds initially, and particularly healing wounds, which have become chronic and resistant to standard care.4

References

1. Augustin M, Vanscheidt W. Chronic venous leg ulcers: the future of cell-based therapies. Lancet 2012;380:953-5.[Pubmed]
2. Kirsner RS, Marston WA, Snyder RJ, et al. Durability of healing from spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: A 6-month follow-up. Wound Repair Regen 2013;21:682-7.[Pubmed]
3. Lantis JC 2nd, Marston WA, Farber A, et al. The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts. J Vasc Surg 2013;58:433-9.[Pubmed]
4. Kirsner RS, Marston WA, Snyder RJ, Lee TD, Cargill DI, Slade HB. Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2012;380:977-85.[Pubmed]

[TOP]