Corticosteroid-Free Primary Treatment of Chronic Graft-Versus-Host Disease with Rituximab Results in Excellent Responses and Rapid Time to Immunosuppression Discontinuation

Chronic graft-versus-host disease (cGVHD) is the most important cause of late morbidity and mortality after allogeneic transplant, occurring in 60% to 70% of long-term survivors. Patients with extensive involvement typically receive long courses of corticosteroids in conjunction with a calcineurin inhibitor, with a median duration of therapy of about 2 years with 15% of patients still requiring immunosuppression at 7yrs post-transplant. Furthermore, steroid-related complications like myopathy, avascular necrosis, diabetes, osteoporosis, and neuropsychiatric issues may be more problematic at times than cGVHD itself. Rituximab is an attractive agent for the upfront treatment of cGVHD due to its favorable toxicity profile, proven efficacy in steroid-refractory cGVHD, and ability to serve as a steroid sparing agent in other autoimmune diseases. We hypothesized that a steroid-free regimen based on the early use of Rituximab would improve outcomes in cGVHD. Twenty-five patients (median age 56 years [range 29–77]) with extensive cGVHD were enrolled on a prospective phase II trial. Enrollment was limited to patients with first onset extensive cGVHD requiring systemic immunosuppression and without residual or concurrent acute GVHD. Chronic GVHD was classified as de novo, interrupted, and progressive in 12, 11, and 2 patients respectively. NIH cGVHD severity was mild, moderate, and severe in 3, 14, and 8 patients respectively. Median NIH symptom score at study onset was 5 (range 4-9). All patients received Rituximab 375mg/m2 x 4 weekly doses, then one dose q3months x 4 doses, in addition to mycophenolate mofetil and tacrolimus (sirolimus could be substituted for tacrolimus). No other systemic immunosuppression was permitted, and only a short-course of steroids (≤4 weeks) was allowed at physician discretion; otherwise patients would be deemed a treatment failure and were treated off study. Twenty-two of 25 patients (88%) responded to treatment, while 2 patients were deemed treatment failures and 1 patient died early of GVHD-related mortality and was thus non-evaluable. Of the 22 responding patients, median time to maximum response was 161 days (range 35–300 days) with maximum response being complete in 21/22 patients and partial in 1 patient defined by improvement in severity grade. Excluding the two patients taken off study for treatment failure, corticosteroids were used sparingly with only 8 patients receiving any steroids for a median of 5 days (range 3-18 days), and only two patients receiving more than one week of steroids. Immunosuppression was ultimately discontinued in 17 of 22 evaluable patients (77%) with median time to discontinuation of 300 days (range 138–488 days). Following immunosuppression discontinuation, cGVHD did recur in 6 patients after a median of 166 days (range 21-393 days), requiring reinstitution of systemic therapy. With a median f/u of 20 months, estimated 2-year overall survival is 82%. Of the surviving patients at 2 years, 74% are predicted to be free of active GVHD while 60% have discontinued systemic immunosuppression. Rituximab-based therapy was overall well tolerated and there were no unexpected severe adverse events. Rituximab has significant activity in chronic GVHD when utilized early in the course of the process. It permits early discontinuation of immunosuppression while obviating the need for long courses of systemic corticosteroids, which may translate into reduced treatment-related morbidity and mortality associated with cGVHD. Prevention of GVHD recurrence remains an issue, and future studies will evaluate the effects of extending the course of Rituximab past 12 months.