A Randomized Single−Blind Study of Extracorporeal Photopheresis with UVADEX® Plus Conventional Therapy (CT) Compared to CT Alone in Chronic GVHD.

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Abstract
Chronic GVHD (cGVHD) is a major limitation of allogeneic hematopoietic cell transplantation. Extracorporeal photopheresis therapy (ECP) has been used in retrospective and Phase II trials of GVHD. The mechanism of ECP is under investigation but it appears to induce apoptosis of lymphocytes and immune tolerance. In this randomized, single−blind study, we comapred ECP plus conventional therapy [calcineurin inhibitor ± mycophenolate mofetil (MMF)] and steroids to conventional therapy alone (non−ECP) in patients (pts) with steroid−refractory/dependent/intolerant cGVHD of the skin. In the ECP arm, photopheresis was administered twice weekly until W12, then twice monthly until W24; pts in the non−ECP arm could withdraw from study after W12 if no response was observed or earlier if cGVHD worsened, and enter a separate extension study that included ECP. The primary efficacy endpoint was change from baseline in skin assessment score (Total Skin Score; TSS) of 10 body regions graded from 0 to 5 (0= normal, 1= discolored, 2= lichenoid, 3= thickened, 4= hidebound, 5= grades 3 or 4 with erythema; maximum score of 50) by a trained blinded observer. All efficacy analyses were conducted on the modified intent−to−treat (MITT) pts who had at least one treatment and one post−baseline TSS. 95 MITT pts (56 M, 39 F; median age = 41 yrs) with steroid refractory (n = 12), intolerant (n = 30) or dependent (n = 57) histologically−confirmed cGVHD were randomized to receive ECP plus conventional therapy (n = 48) or conventional therapy alone (n = 47). Study arms were balanced except for more GI involvement in the non−ECP arm. Missing post−randomization TSS and steroid dose data (mostly because of early withdrawal) were imputed using the last−observation−carried forward (LOCF) method while other missing efficacy endpoints were analyzed without imputation. Percent imputation rates for W12 and W24 were 12.5% and 25% (for ECP) and 19.1% and 76.6% (for non−ECP). The table summarizes the results. Week ECP Non−ECP p Value Median Baseline TSS 9.4 9.2 Median % Improvement in TSS W12 14.5 10.4 0.507 W24 31.4 12.7 0.029 % of Pts with ≥50% Reduction in Steroids W12 29 14 0.089 W24 46 26 0.047 % of Pts with ≥50% Reduction in Steroids AND ≥25% Reduction in TSS W12 10 0 0.040 W24 27 10 0.041 The beneficial skin response and steroid−sparing in the ECP arm was noted in MMF−treated and non−MMF−treated cohorts. The investigator assessment of complete or partial skin response at W12 was 40% in the ECP group and 10% in the non−ECP group. Greater numbers of pts had improvement or resolution of mucosal, eye and joint manifestations of cGVHD in the ECP arm. ECP was well−tolerated with a safety profile consistent with previous studies. ECP is effective in skin manifestations and steroid sparing in steroid−refractory/dependent/intolerant chronic GVHD.

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