Rituximab, an anti-CD20 chimeric monoclonal antibody, is widely used in hematologic malignancies and has been introduced as a therapeutic option in autoimmune disorders. In recent studies, rituximab has shown promising activity in steroid-refractory chronic graft-versus-host disease (cGvHD) at a weekly dose of 375 mg/m2. We now report on 13 subjects after peripheral blood stem-cell transplantation receiving low-dose rituximab (50 mg/m2) for steroid-refractory cGvHD and autoimmune disorders (membranous glomerulonephritis and immune thrombocytopenic purpura). The overall response rate was 69%, including two patients with complete responses. In accordance, we observed clearance of peripheral blood B cells even after the first dose of rituximab in four patients. We conclude that low-dose rituximab seems to be active and safe in intensively pretreated patients with steroid-refractory cGvHD.
The anti-CD20 chimaeric monoclonal antibody Rituximab has recently been shown to induce significant clinical response in a proportion of patients with refractory chronic graft-versus-host disease (cGVHD). We now report 38 patients, median age 48 years (22-61), receiving Rituximab for refractory cGVHD, assessed for clinical response and survival. Median duration of cGVHD before Rituximab was 23 months (range 2-116), the median number of failed treatment lines was 3 (range 1 to > or =6) and the median follow-up after Rituximab was 11 months (1-88). Overall response rate was 65%: skin 17/20 (63%), mouth 10/21 (48%), eyes 6/14 (43%), liver 3/12 (25%), lung 3/8 (37.5%), joints 4/5, gut 3/4, thrombocytopaenia 2/3, vagina 0/2, pure red cell aplasia 0/1 and, myasthenia gravis 1/1. During the study period 8/38 died: causes of death were cGVHD progression (n=3), disease relapse (n=1), infection (n=3), sudden death (n=1). The actuarial 2 year survival is currently 76%. We confirm that Rituximab is effective in over 50% of patients with refractory cGVHD and may have a beneficial impact on survival.
B cells may be implicated in the pathophysiology of chronic graft-versus-host disease (GVHD), as evidenced by antibody production against sex-mismatched, Y chromosome-encoded minor HLA antigens in association with chronic GVHD. We therefore designed a phase 1/2 study of anti-B-cell therapy with rituximab in steroid-refractory chronic GVHD. Twenty-one patients were treated with 38 cycles of rituximab. Rituximab was tolerated well, and toxicity was limited to infectious events. The clinical response rate was 70%, including 2 patients with complete responses. Responses were limited to patients with cutaneous and musculoskeletal manifestations of chronic GVHD and were durable through 1 year after therapy. The median dose of prednisone among treated subjects fell from 40 mg/day to 10 mg/day, 1 year after rituximab therapy (P < .001). A chronic GVHD symptom score improved in the majority of treated patients. Antibody titers against Y chromosome-encoded minor HLA antigens fell and remained low, whereas titers against infectious antigens (EBV, tetanus) remained stable or rose during the treatment period. We conclude that specific anti-B-cell therapy with rituximab may be beneficial for patients with steroidrefractory chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00136396.
Chronic graft-versus-host disease (cGVHD) is an important determinant of long-term morbidity and mortality in allogeneic stem cell transplantation patients. Because cGVHD has clinical, histologic, and laboratory findings of autoimmune diseases and anti-B-cell therapy has shown efficacy in autoimmune diseases, we hypothesized that monoclonal anti-CD20 antibody therapy might improve patients with cGVHD. We treated 5 men and 1 woman with therapy-refractory extensive cGVHD with anti-CD20 monoclonal antibody. Intravenous infusion was given at a weekly dose of 375 mg/m(2) for 4 weeks. In case of incomplete clinical response, additional courses of 4 weeks were given. Five patients responded to treatment with marked clinical, biochemical, and histologic improvement. One patient failed to respond. Anti-CD20 monoclonal antibody seems to be effective in cGVHD. A controlled trial is mandatory to confirm these results. The outcome of this study suggests a participating role of B cells in the pathogenesis of cGVHD.
We reviewed the clinical outcome of 8 patients with steroid-refractory chronic graft-versus-host disease (GVHD) who received an anti-CD20 chimeric monoclonal antibody (rituximab). Rituximab was given by intravenous infusion at a weekly dose of 375 mg/m(2) for 4 weeks. All patients had received extensive treatment with various immunosuppressive agents; 6 patients had also received extracorporeal photopheresis. All patients had extensive chronic GVHD with diffuse or localized sclerodermoid GVHD and xerophthalmia. Other extracutaneous involvements included cold agglutinin disease with the Raynaud phenomenon, membranous glomerulonephritis, and restrictive or obstructive lung disease. Four patients responded to treatment with ongoing resolution or improvement ranging from 265 to 846 days after therapy, despite recovery of B cells in 3 patients. Rituximab seems to have significant activity in the treatment of refractory chronic GVHD and should be considered for further study in patients with early disease. This study suggests a participating role of B cells in the pathogenesis of chronic GVHD.
