Inclusion Criteria:

- Suitable candidates are patients with classic chronic GVHD or overlap syndrome
(classic chronic plus acute GVHD)that is: a)Previously untreated (newly diagnosed) as
defined by having received < 14 days of prednisone (or equivalent) before
enrollment/randomization to study therapy; b)Previously treated but inadequately
responding after ≤ 16 weeks of initial therapy with prednisone and/or CNI ±
additional non-sirolimus agent (started at the time of chronic GVHD diagnosis).

- Patient or guardian willing and able to provide informed consent.

- Stated willingness to use contraception in women of childbearing potential.

- Stated willingness of patient to comply with study procedures and reporting
requirements.

Exclusion Criteria:

- Patients with late persistent acute GVHD or recurrent acute GVHD only.

- Inability to begin prednisone therapy at a dose of greater than 0.5 mg/kg/day.

- Receiving sirolimus for treatment of chronic GVHD (sirolimus for prophylaxis or
treatment of acute GVHD is acceptable).

- Already receiving sirolimus (for prophylaxis or treatment of acute GVHD) with
prednisone at ≥ 0.25 mg/kg/day (or equivalent) ± additional agents.

- Receiving therapy for chronic GVHD for more than 16 weeks.

- Invasive fungal or viral infection not responding to appropriate antifungal or
antiviral therapies.

- Inadequate renal function defined as measured creatinine clearance less than 50
mL/min/1.73 m^2 based on the Cockcroft-Gault formula (adults) or Schwartz formula
(age less than or equal to 12 years). Adults: eCCr (mL/min/) = (140 - age) x mass
(kg) x (0.85 if female)/72 x serum creatinine (mg/dL; Creatinine clearance
(mL/min/1.73m^2) = eCCr x 1.73/BSA (m^2); Children: eCCr (mL/min/1.73 m^2) = k x
height (cm) / serum creatinine (mg/dL) k = 0.33 (pre-term), 0.45 (full term to 1 year
old), 0.55 (age 1-12 years).

- Inability to tolerate oral medications.

- Absolute neutrophil count less than 1500 per microliter.

- Requirement for platelet transfusions.

- Pregnancy (positive serum β-HCG) or breastfeeding.

- Receiving any treatment for persistent, progressive or recurrent malignancy.

- Progressive or recurrent malignancy defined other than by quantitative molecular
assays.

- Known hypersensitivity to sirolimus.