• To determine the efficacy of two 4 week courses of Rituximab as first-line treatment for chronic GVHD. Efficacy endpoint will be defined as the ability to successfully taper prednisone to a dose of 0.25 mg/kg/day by 6 months without clinical relapse.
  

• To have physician documentation of clinical GVHD response using organ staging and scoring scale (see Appendix)
  
• To evaluate steroid use at one year after enrollment on the trial.
  
• To monitor patient reported outcomes of GVHD response (see Appendix)
  
• To monitor infectious complications
  
• To report freedom from progression (FFP), event free survival (EFS), and overall survival (OS)
  
• To document treatment failure-defined as initiation of another immunosuppressive agent
  

Effective treatments for chronic GVHD are currently limited to corticosteroids, and often requires prolonged treatment. The addition of a calcineurin inhibitor is not associated with an increased response rate or transplant-related mortality. Our laboratory studies have demonstrated allogeneic antibodies develop in association with chronic GVHD after HSCT. This implicates allogeneic B cell responses in the pathogenesis of chronic GVHD and supports testing anti-B cell therapy for chronic GVHD. In our DFCI phase I trial of 21 patients with steroid refractory chronic GVHD, rituximab provided 70% overall responses and 2 complete responses. Rituximab therapy facilitated corticosteroid tapering with a median dose of prednisone falling from 40 mg/day at trial initiation to 10 mg/day at one year (p = 0.0002). We hypothesize the addition of rituximab to prednisone for the initial treatment of chronic GVHD will increase the overall response rate, and enable a more rapid and effective steroid taper. If B cells or their product antibodies are contributing to chronic GVHD pathogenesis, and prednisone efficacy is partially active through a less-specific B cell effect, then it follows that rituximab addition to prednisone may increase chronic GVHD response rates and enable successful steroid tapering. To test this hypothesis, we have initiated a phase II clinical trial of rituximab and corticosteroids as front line therapy for patients with newly diagnosed chronic GVHD. Reported cGVHD trials have tested the benefit of adding an experimental agent to prednisone dosed 1mg/kg for 4 or 9 months before slowly tapering again on a fixed schedule. In these trials the primary endpoint was the cGVHD complete response rate, and 1mg/kg every other day prednisone yielded a 33% CR and 62% overall response rate after 9 months therapy thereby setting a standard for what single agent high-dose prednisone can achieve alone. However, long-term single-agent high-dose corticosteroid treatment of cGVHD causes significant morbidity being associated 20% incidence avascular necrosis. On that trial, only 50% could be weaned from steroids at 5 years. With this steroid toxicity in mind, we believe a clinically meaningful endpoint for phase II testing of promising cGVHD drugs may be their addition to high-dose steroids enables a successful steroid taper. As such, our primary endpoint is the ability to successfully taper prednisone to a dose of 0.25 mg/kg/day or less by six months without cGVHD relapse. The 0.25mg/kg/day primary endpoint was chosen for both physiological and clinical practice reasons. Patients receiving prednisone 20mg daily or greater are assumed to have functional suppression of hypothalamic-pituitary-adrenal function, frequently suffer steroid toxicities. Clinically, many HSCT clinicians taper patients to 10-20 mg prednisone a day and then only slowly further taper to avoid chronic GVHD recurrence.