The primary objective of this trial is to study the safety and efficacy of a novel regimen of sirolimus, tacrolimus and methotrexate as prophylaxis against acute graft versus host disease (GVHD) in recipients of mismatched unrelated donor stem cell grafts. Methotrexate is administered in a low dose format of 5mg/m2 on days +1,3 and 6 only.

Inclusion Criteria:

• Patients must have an identified 8/10 or 9/10 matched unrelated donor identified following a formal search with confirmatory typing through the national marrow donor program as the best available donor. No matched sibling or fully matched unrelated donor has been identified. HLA typing of donor and recipient will be performed by high resolution molecular typing at HLA A, B, C and DRB1/DQ loci. Patients whose best available donor is matched at 8/10 loci must have at least one of the mismatches at the DQ locus. (no more than one mismatch at HLA A,B,C,DR allowed).

• Candidates for this trial will meet the following criteria:

  1. Adequate organ function for conditioning type:

     For patients receiving ablative conditioning

     • Left Ventricular ejection fraction >45%
     • DLCO >50%
     • Creatinine <1.5
     • Hepatic enzymes <3x upper limit of normal.
     • KPS >70%

     For patients receiving non-ablative conditioning:

     • KPS >70%

  2. Patients with the following diseases will be considered eligible:

     • AML in first remission with high risk features (poor risk cytogenetic abnormalities9, persistent elevated blast count on day +15 or recovery marrow after induction therapy).
     • AML beyond first remission
     • ALL in first remission with high risk features (ph+, t4:11)
     • ALL beyond first remission
     • High risk Myelodysplasia (RAEB-II, RAEB-I with poor-risk cytogenetics)
     • Recurrent Aggressive Non-Hodgkins or Hodgkins lymphoma (indolent histologies excluded) who have failed autologous transplant or have had inadequate response to salvage therapy.
     • CML with transformation
     • CLL with transformation or Fludarabine failure.
     • Severe aplastic anemia with recurrence or failure after immunosuppressive therapy.

Exclusion Criteria:

• Prior allogeneic transplantation
• Active CNS leukemia.
• Female patients who are pregnant or breast feeding
• Karnofsky performance status <70%.
• Active viral, bacterial or fungal infection.
• Patients seropositive for HIV -1,2; HTLV -1,2 (due to the additional immunodeficiency induced by transplantation and immunosuppressive therapy) Requirement for antifungal prophylaxis with Voriconazole for the first 30 days is prohibited.
• Patients not providing informed consent.