Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplant

• Incidence and severity of acute graft-versus-host disease (GVHD) [ Time Frame: Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria ] [ Designated as safety issue: No ]
  
• Safety, as defined by serious adverse events and adverse events related to study treatment. [ Time Frame: Within 6 months after PBSCT ] [ Designated as safety issue: Yes ]
  

• Incidence of chronic GVHD. [ Time Frame: Within 2 years after PBSCT ] [ Designated as safety issue: No ]
  
• Time to engraftment (i.e., absolute neutrophil recovery [ANC > 1,500/mm³] and platelet recovery [platelet count > 25,000/mm³]) [ Time Frame: At screening, post transplant, 30, 60, 90 & 180 days after PBSCT ] [ Designated as safety issue: No ]
  
• Overall and disease-free survival. [ Time Frame: At 2 years after PBSCT ] [ Designated as safety issue: No ]
  
• Length of hospital stay. [ Time Frame: Within 100 days after PBSCT ] [ Designated as safety issue: No ]
  
• Incidence of infections, including bacterial, fungal, and viral infections (i.e., CMV and EBV reactivation, including post-transplant lymphoproliferative disorders) [ Time Frame: Within 6 months after PBSCT ] [ Designated as safety issue: No ]
  
• Incidence of thrombotic microangiopathy [ Time Frame: Within 100 days after PBSCT ] [ Designated as safety issue: No ]
  
• Karnofsky performance status [ Time Frame: At baseline and at 100 days, 6 months, 1 year, and 2 years after PBSCT ] [ Designated as safety issue: No ]
  
• Biomarkers and immunocorrelative studies (i.e., T-cell, B-cell, NK-cell, regulatory T-cell, and allo-reactive T-cell quantitation studies by flow cytometry) [ Time Frame: At 30, 60, 90, and 180 days after PBSCT ] [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• To determine the incidence and severity of acute graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor peripheral blood stem cell transplantation (PBSCT) in patients with hematologic malignancies treated with immunosuppressive therapy comprising sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis.
• To determine the safety of this regimen in these patients at 6 months after PBSCT.

Secondary

• To determine the time to engraftment (i.e., platelet and absolute neutrophil recovery) in patients treated with this regimen.
• To determine the length of hospital stay of these patients within 100 days after PBSCT.
• To determine the incidence of infections, including CMV and EBV reactivation and post-transplant lymphoproliferative disorders, in patients treated with this regimen.
• To determine the incidence of thrombotic microangiopathy and veno-occlusive disease in patients treated with this regimen.
• To determine the incidence of chronic GVHD in patients treated with this regimen.
• To determine the overall and disease-free survival of these patients at 2 years after PBSCT.
• To determine the Karnofsky performance status of these patients at baseline and at various time points after PBSCT.
• To conduct immunocorrelative studies prior to and at various time points after PBSCT.

OUTLINE:

• Conditioning regimen: Patients receive 1 of 6 conditioning regimens between days -9 and -3, based on diagnosis and the treating physician's preference regarding regimen intensity.

  • Regimen I: Patients receive fludarabine phosphate IV and busulfan IV.
  • Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV.
  • Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV.
  • Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV.
  • Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV.
  • Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI.
• Allogeneic peripheral blood stem cell transplantation: Patients undergo filgrastim (G-CSF)-mobilized allogeneic peripheral blood stem cell transplantation on day 0.
• Graft-versus-host disease prophylaxis (GVHD): Patients receive tacrolimus IV continuously over 24 hours or orally and sirolimus orally beginning on day -3 and continuing until day 30 or day 90, followed by a taper in the absence of GVHD. Patients also receive anti-thymocyte globulin IV over 4-8 hours on days -3 to -1.

Blood samples are obtained at baseline and periodically during study for correlative biomarker studies. Samples are analyzed by T-cell immunophenotyping, absolute subset number quantification, and multi-parameter flow cytometry for evaluation of immune reconstitution, T-cell differentiation status, NK-cell recovery, allo-reactivity of donor T-cells after transplantation, and regulatory T-cell reconstitution.

After completion of study therapy, patients are followed periodically for up to 2 years.