• To compare the effectiveness of 4 new study drugs, each combined with either prednisone or methylprednisolone, as treatment for severe graft-versus-host disease (GVHD). [ Time Frame: 3 Years ] [ Designated as safety issue: No ]
  

• The safety of these drug combinations will also be studied. [ Time Frame: 3 Years ] [ Designated as safety issue: Yes ]
  

Inclusion Criteria:

• Prior allogeneic hematopoietic stem cell transplant using either bone marrow, peripheral blood stem cells or cord blood. Recipients of non-myeloablative transplants are also eligible.
• De novo Grade B-D acute GVHD diagnosed within 48 hours of diagnosis. GVHD is defined as the presence of skin rash and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis as the clinical criteria of GVHD when present in the right clinical setting and not directly attributable to other etiologies , such as drug rash, enteric infection, or hepatotoxic syndromes. The patient must have had no previous systemic immune suppressive therapy given for treatment of acute GVHD except for a maximum of 48 hours of prior corticosteroid therapy (>1 mg/kg/day methylprednisolone).
• No previous immune suppressive therapy given for treatment of acute GVHD except for a maximum 48 hours of prior corticosteroid therapy >/= 1 mg/kg/day methylprednisolone.
• Clinical status at enrollment to allow tapering of steroids to not less than 0.6 mg/kg/day methylprednisolone (0.75 mg/kg/day prednisone) at Day 28 of therapy.
• Absolute neutrophil count (ANC) greater than 500/microL
• Estimated creatinine clearance greater than 30 mL/minute. At our institution this will be calculated with the Cockcroft-Gault equation
• Written informed consent from patient, parent or guardian.
• Documentation that the assent document and education materials have been provided to, and reviewed with, patients under the age of 18.
• Greater than or equal to 6 years of age at the time of enrollment.
• DLI (donor lymphocyte infusion) as part of the original transplant therapy plan.

Exclusion Criteria:

• ONTAK, pentostatin, or etanercept given within 7 days of enrollment
• Active uncontrolled infection
• GVHD developing after an unscheduled donor lymphocyte infusion, not part of the original transplant therapy plan, given for treatment of persistent or recurrent malignancy after transplantation
• Patients receiving methylprednisolone>0.5mg/kg/day (or 0.6 mg/kg/day prednisone) within 7 days of onset of acute GVHD. If steroid therapy has been administered for a non-GVHD related condition and tapered to < 0.5 mg/kg/day methylprednisolone (or 0.6mg/kg/day prednisone) for seven or more days prior to the onset of acute GVHD, the patient is eligible.
• Patients unlikely to be available at the transplantation center on Day 28 and 56 of therapy.
• A clinical syndrome resembling de novo chronic GVHD developing at any time after allotransplantation. See Chapter 2 of the BMT CTN Manual of Procedures for details of de novo clinical GVHD.
• Other investigational therapeutics for GVHD within 30 days, including agents used for GVHD prophylaxis
• Patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study.
• Adults unable to provide informed consent
• Patients with a history of intolerance to any of the study drugs.
• Patients with isolated limited skin (stage I) as the sole manifestation of acute GVHD.