Adhesion Molecule Blockade with the Humanized Anti-LFA-1 Monoclonal Antibody Efalizumab Improves Steroid Refractory Acute and Chronic Graft-Versus-Host Disease of the Skin

The integrin LFA-1 is important for naive T-cell homing to lymph nodes and bronchial associated lymphoid tissue (BALT), and appears to play a major role in the trafficking of effector T-cells to cutaneous and possibly hepatic sites of inflammation. Efalizumab, a humanized monoclonal antibody directed against the CD11a subunit of LFA-1, is currently approved for the management of moderate to severe plaque psoriasis. Given the pathophysiologic similarities between psoriasis and cutaneous graft-versus-host disease (GVHD), we launched a small exploratory study examining the use of efalizumab for steroid refractory GVHD of the skin. Methods: Patients with evidence of an inflammatory, erythematous rash and a skin biopsy consistent with cutaneous GVHD who had failed to improve after at least 4 weeks of methylprednisilone at 0.5mg/kg were eligible for enrollment. Patients were scheduled to receive weekly subcutaneous efalizumab at 1mg/kg for a total of 8 weeks. Using digital photography and “ImageJ” software obtained from The National Institutes of Health, each patient’s rash was quantified as a percentage of their total body surface area (BSA) at baseline and after completing therapy. A complete response (CR) was defined as the total resolution of skin disease, and a partial response was defined as ≥ 50% reduction in the proportion of BSA involved by rash. Skin biopsies were taken before and after therapy to study baseline pathology and to assess for histological improvement. Results: Two patients were treated at our institution. Patient #1 presented with longstanding chronic GVHD of the skin, and received 8 doses of study medication according to schedule. After therapy, she demonstrated a PR, with a reduction in cutaneous involvement from 15% to 6%. The efalizumab appeared to be well tolerated, with the exception of grade II nausea. Patient #2 exhibited grade IV acute GVHD of the skin that developed shortly after an allogeneic transplant for refractory Hodgkin’s lymphoma following an autologous transplant two years earlier. The patient received 6/8 scheduled efalizumab doses, but was subsequently taken off study after developing transient coagulase negative staphylococcal bacteremia. In spite of his abbreviated therapeutic course and advanced disease, he attained a CR. Approximately 6 weeks after his final efalizumab dose, the patient developed parainfluenza pneumonia that ultimately proved fatal. Both subjects showed histological improvement following efalizumab therapy, with a reduction in dermal T-cell infiltration (see table). Neither demonstrated elevated levels of IL-17 in the skin by RT-PCR at any time point. Conclusions: Efalizumab appears to show signs of activity against acute and chronic cutaneous GVHD. While the late infectious complications that developed in patient #2 are concerning, the current sample size is too small to draw firm conclusions regarding the toxicity profile of this agent in the bone marrow transplant (BMT) setting, particularly given the heavily pretreated status of both subjects. Our digital photography technique proved to be a feasible method for assessing response to therapy, and would allow for central review by a blinded operator. Further studies to better characterize the efficacy and toxicity of efalizumab in the BMT setting appear warranted.