Combination treatment of bullous skin gvhd with ANTI-CD20 and ANTI-CD25 antibodies

We report on a novel treatment for bullous skin GVHD prompted by immunologie monitoring. A 9 year old boy with ALL in CR3 received a 4/6 HLA-matched unrelated placental graft. Grade 3 aGVHD of the gut 5 weeks after transplant was controlled with steroids, FK506, and 10 weeks of Daclizumab. Chronic GVHD of the skin developed 4 months post BMT responding to steroids, Imuran + MMF. 7 months post BMT new hemorrhagic bullae developed over the entire body. On biopsy spongiosis, hemorrhagic infiltrate of lymphocytes.eosinophils were seen. He briefly improved with OKT3 but new lesions recurred. To understand the pathogenesis of his disease 4 color FACS staining of his lymphocytes was performed along with immunohistochemical stains on skin sections. Striking B cell lymphocytosis was noted in the absence of CD3+ cells (see table for lab profile). Immunofluorescence revealed linear deposits of IgG and C3 at the basement membrane along with IgG bound to the epidermal side of the split skin. Immunoprecipitation showed strong reactivity to BPAg2, and faint reactivity to BPAgl confirming Bullous Pemphigoid (BP) as the manifestation of his GVHD. Circulating EBV genome was not detected. Based on these results Rituxan was started at 375mg/m2 qW x 4 doses. Over the first week his skin condition worsened. B cells were depleted post Rituxan but with a surge of CD25+ CD4+ T cells. Brief steroid pulse + Daclizumab was initiated. No new lesion was noted after 1 week and a complete response was reached in 4 weeks with declining BP titers and absent CD25+ T cells. He came off Daclizumab after 10 weeks while steroids and MMF were weaned. 1 small bulla developed 2 months later along with a rise in BP titer and CD25+ cells responding to Daclizumab alone. He has been in clinical and sérologie remission since with further wean of both his steroids (0.5mg/kg/QOD)and MMF. This case demonstrates that selective B cell ablation with activated helper CD4+ T cell targeting can result in complete clinical and sérologie response. Careful trials with laboratory monitoring are warranted to explore the potential of such immunomodulatory combination designed to avoid global immunosupression in patients with cGVHD. Months post BMT 8 8.5 9 12 15 17 Bullous lesion +++ +++ - - 1 new BP titer >1:1280 1:320 1:40 >1:320 1:40 ALC/nl 779 178 350 189 248 226 B cells/Hi 559 40 27 9 14 CD3+/U1 0 109 241 126 159 28 %CD25+/CD3+ - 29 0 <1 21 0.

Duke Scholars

Author Joanne Kurtzberg Pediatrics, Transplant and Cellular Therapy

Author Russell P. Hall III Dermatology