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

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 (standard of care treatment) 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.

DISEASE CHARACTERISTICS:

• Diagnosis of a hematological malignancy, including any of the following:

• Non-Hodgkin lymphoma in complete remission (CR) or partial remission (PR)
• Hodgkin lymphoma in CR or PR
• Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) meeting either of the following criteria:

• In CR
• Not in CR and meets the following criteria:

• Bone marrow blast < 20% within 4 weeks of transplantation
• Peripheral blood absolute blast count < 500 per microliter on the day of initiating conditioning therapy
• Myelodysplastic syndromes, treated or untreated
• Chronic myeloid leukemia in chronic phase or accelerated phase
• Multiple myeloma in CR or PR
• Chronic lymphocytic leukemia in second or greater CR or PR
• Myelofibrosis or other myeloproliferative disorders meeting the following criteria:

• Bone marrow blasts < 20% within 4 weeks of transplantation
• Peripheral blood absolute blast count < 500 per microliter on the day of initiating conditioning therapy
• Patients with ascites not allowed
• No prior bone marrow or ex vivo engineered or processed graft (i.e., CD34+ enrichment, T-cell depletion, etc)
• Scheduled to undergo peripheral blood stem cell transplantation from a suitable HLA-matched or -mismatched unrelated donor, as determined by treating physician

• High resolution molecular HLA typing is required for HLA class I and II
• No more than one antigen or allele mismatch
• No documented uncontrolled CNS disease

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2
• Karnofsky PS 60-100%
• Creatinine clearance > 50 mL/min
• Bilirubin < 3 times upper limit of normal (ULN)
• ALT and AST < 3 times ULN
• LVEF > 50%
• FVC, FEV_1, or DLCO > 50% predicted

• Patients on home oxygen not allowed
• Able to cooperate with oral medication intake
• HIV negative
• No active hepatitis B or hepatitis C
• No known contraindication to sirolimus, tacrolimus, or anti-thymocyte globulin

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics