Sirolimus in combination with tacrolimus for the treatment of resistant chronic graft-versus-host disease

Abstract

6657 Introduction: Chronic graft versus host disease (cGVHD) remains a major complication in hematopoietic transplant recipients. We conducted a phase II trial of sirolimus in combination with tacrolimus for patients with steroid-refractory cGVHD. Patients and Methods: The median age of the 35 patients was 45 years (19–69). The median number of prior treatments for chronic GVHD was 3 (range 2–6). Chronic GVHD was defined as GVHD present beyond day 100 post-transplantation. The patients were divided into two groups. One group had continuous or recurrent manifestations of acute GVHD (late acute GVHD group). The remaining 23 patients had clinical manifestations of chronic GVHD (true chronic GVHD group). Results: Six patients had a complete remission and 16 had a partial remission for an overall response rate (ORR) of 63%. Skin was the organ most often involved (n= 29) and had an ORR of 65%. Eight patients with sclerodermatous skin involvement responded to therapy (73%). Responses were also seen in patients with GVHD of the lower GI tract (67%), liver (33%), eye (64%), and oral mucosa (75%). Major adverse events related to sirolimus were hyperlipidemia and cytopenias. Median survival was 15 months, and estimated actuarial survival at 2 years was 41% (95% CI 20–61). A significantly worse non-relapse mortality was noted in patients who had a platelet count of less than 100,000/mm3 (p < 0.0001) or late acute GVHD features (p = 0.001). Actuarial survival at 1 year was 25% in the late acute GVHD group, and 76% in the true chronic group (p = 0.0003). Corresponding estimates at 2 years were 12% (95% CI 1–40) and 62% (95% CI 34–80) (p = 0.0005). Non-relapse mortality at 2 years post initiation of therapy was significantly higher in patients with late acute GVHD (75%, 95% CI 49–99%) than in those with true chronic GVHD (35%, 95% CI 17–64%, p = 0.003). Conclusions: The addition of sirolimus to tacrolimus and methylprednisolone was effective for the treatment of resistant chronic GVHD with an ORR of 63%. It was most effective in patients with true chronic features and sclerodermatous skin involvement. Differentiating between late acute GVHD and true chronic GVHD may result in better interpretation of studies intended to target chronic GVHD. No significant financial relationships to disclose.