Sirolimus as Treatment of Steroid-Refractory or Steroid-Dependent Chronic Graft-Versus-Host Disease

• Clinical activity will be monitored at 3 month intervals after the initiation of sirolimus until 2 years after the initiation of sirolimus [ Time Frame: every 3 months until 2 years after enrollment ] [ Designated as safety issue: No ]
• Clinical activity will be determined by ability to discontinue immunosuppression with resolution of all reversible CGVHD manifestations and no additional systemic therapy before or after the 2 year time-point [ Time Frame: every month x 3 then every 3 months until 2 years post enrollment ] [ Designated as safety issue: No ]

• Clinical activity will be monitored at 3 month intervals after the initiation of sirolimus until 2 years after the initiation of sirolimus
• Clinical activity will be determined by ability to discontinue immunosuppression with resolution of all reversible CGVHD manifestations and no additional systemic therapy before or after the 2 year time-point
• The primary endpoint will be evaluated at 2 years after enrollment
• Patients will remain enrolled until death or closure of the study

• Monitoring toxicities including renal insufficiency, hyperlipidemia and post-transplant microangiopathic hemolytic anemia [ Time Frame: every month x 3 then every 3 months until 2 years after enrollment ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: every 3 months until 2 years after enrollment and with each clinic follow-up until death ] [ Designated as safety issue: Yes ]
• Cumulative incidence of secondary systemic treatment for chronic GVHD [ Time Frame: every 3 months until 2 years after enrollment ] [ Designated as safety issue: No ]
• Cumulative incidence of death without recurrent malignancy [ Time Frame: every 3 months until 2 years after enrollment and with each clinic follow-up until death ] [ Designated as safety issue: Yes ]
• Cumulative incidence of recurrent malignancy [ Time Frame: every 3 months until 2 years after enrollment and with each clinic follow-up until death ] [ Designated as safety issue: Yes ]
• Monitoring the clinical response based on completed chronic GVHD staging sheets, patient photographs, care provider documentation and physical therapy evaluations [ Time Frame: every 3 months until 2 years after enrollment ] [ Designated as safety issue: No ]
• Duration of treatment with prednisone [ Time Frame: every 3 months until 2 years after enrollment ] [ Designated as safety issue: No ]
• Treatment failure defined as inability to taper immunosuppression or need to begin additional systemic treatment for chronic GVHD [ Time Frame: every 3 months until 2 years after enrollment ] [ Designated as safety issue: No ]

• Monitoring the clinical response based on completed chronic GVHD staging sheets, patient photographs, care provider documentation and physical therapy evaluations
• Duration of treatment with prednisone
• Treatment failure defined as inability to taper immunosuppression or need to begin additional systemic treatment for chronic GVHD
• Monitoring toxicities including renal insufficiency, hyperlipidemia and post-transplant microangiopathic hemolytic anemia
• Overall survival
• Cumulative incidence of secondary systemic treatment for chronic GVHD
• Cumulative incidence of death without recurrent malignancy
• Cumulative incidence of recurrent malignancy

To study the effectiveness of an immunosuppressive drug, sirolimus in the treatment of chronic graft versus host disease in combination with prednisone.

The purpose of this trial is to study the effectiveness of an immunosuppressive drug, sirolimus, in the treatment of chronic graft versus host disease in combination with prednisone. Graft versus host disease (GVHD) is a common complication in patients who have received blood or marrow transplantation from a related or unrelated donor. Chronic GVHD occurs approximately 100 days after transplantation and is the result of the donor immune system recognizing the patient's tissues as foreign and creating harmful effects on the patient';s organs. We hope the use of sirolimus will decrease the significant disabling effects and deaths caused by chronic GVHD.

• Graft vs Host Disease
• Blood and Marrow Transplant (BMT)

• Drug: Sirolimus
  Patients will receive sirolimus at 2 mg/day orally with monitoring of trough drug levels weekly for 2 weeks to achieve trough drug levels 7-12 ng/ml.
• Drug: Prednisone
  Prednisone therapy will remain at the dose the patient received at the time sirolimus was begun.

Inclusion Criteria:- Histologically-confirmed active chronic GVHD >100 days following allogeneic bone marrow/peripheral blood/umbilical cord blood transplantation that has failed prior therapy. In the event that histological confirmation poses undue risk, clinical evaluation is sufficient.

• Women must have a negative pregnancy test before sirolimus administration and women of child-bearing potential agree to use a medically acceptable contraceptive throughout the treatment period and for 3 months after discontinuation of sirolimus. Any woman becoming pregnant during the treatment period must discontinue the use of sirolimus.
• Absolute neutrophil count (ANC) >1000/mm^3, unless receiving G-CSF to maintain neutrophil count >500/mm^3
• Discontinuation of cyclosporine or FK506 at the time of initiating sirolimus with cyclosporine trough level <100 mg/dl and FK506 level < 5 mg/dl
• Karnofsky performance score > or = 50 during pre-study screening
• Written, signed, and dated informed consent

Exclusion Criteria:- Uncontrolled systemic infection

• Unstable disease states (i.e., hepatic failure, ventilatory-dependent respiratory failure, etc.)
• Serum creatinine > or = 3.0 mg/dL, platelet count < or = 50,000/mm^3
• History of Post-transplant microangiopathic hemolytic anemia
• Uncontrolled hyperlipidemia
• Use of any investigational drug within 4 weeks of entry into the study
• Use of methotrexate or antibody therapies within 24 hours of sirolimus administration
• Inability to tolerate oral therapy for any reason
• Evidence of infiltrate, cavitation, or consolidation on chest x-ray during pre-study screening
• Known hypersensitivity to macrolide antibiotics