Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant For Hematological Cancer

OBJECTIVES:

Primary

• To determine the incidence and severity of acute- and chronic-graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor hematopoietic peripheral blood transplantation in patients with hematologic malignancies scheduled to receive immunosuppressive combination of sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis.
• To determine the safety of this combination in the first six months post-transplant.

Secondary

• To determine the time-to-engraftment, non-relapse mortality rate, overall and disease-free survival, incidence of disease relapse, and incidence of opportunistic infections with this GVHD prophylaxis.

OUTLINE: Patients are stratified according to conditioning regimen (fludarabine phosphate and melphalan vs fractionated total-body irradiation [FTBI] and etoposide vs FTBI and cyclophosphamide) and degree of donor/recipient HLA mismatch (high-risk vs low-risk).

• Conditioning regimen: Patients receive 1 of 3 standard conditioning regimens beginning on day -9 or -8 and continuing to day -1 or 0.
• Peripheral blood stem cell transplantation: Patients receive HLA-matched or mismatched unrelated donor peripheral blood stem cells on day 0.
• Graft-versus-host disease prophylaxis: Patients receive tacrolimus IV continuously beginning on day -3 and then orally when tolerated, oral sirolimus on days -3 and -2, anti-thymocyte globulin IV over 4-8 hours on days -3 to 0, and methotrexate* IV on days 1, 3, and 6. Tacrolimus and sirolimus continue for 3-6 months (with taper).

NOTE: *Only patients with high-risk HLA mismatch receive treatment with methotrexate.

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

DISEASE CHARACTERISTICS:

• Diagnosis of hematological malignancy including any of the following:

• Non-Hodgkin lymphoma (NHL) in any complete remission (CR) or partial response (PR)
• Hodgkin lymphoma in any CR or PR
• Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in any CR

• Bone marrow blasts < 20% within 4 weeks of transplant and peripheral blood absolute blast count < 500/µL on the day of initiation of conditioning for patients with non-CR AML or ALL
• Myelodysplastic syndromes (MDS) treated or untreated
• Chronic myelogenous leukemia (CML) in chronic or accelerated phase
• Multiple myeloma in any CR or PR
• Chronic lymphocytic leukemia in CR or PR 2 or greater
• Myelofibrosis and other myeloproliferative disorders

• Bone marrow blasts < 20% within 4 weeks of transplant and peripheral blood absolute blast count < 500/µL on the day of initiation
• High-risk disease defined as AML or ALL > CR1, accelerated phase CML, recurrent aggressive lymphoma, or active lymphoproliferative disease at transplant
• Low-risk disease defined as AML or ALL in CR1, chronic phase CML, or low-grade lymphoproliferative disorder with controlled disease at transplant
• Must be planning to receive 1 of the following conditioning regimens at City of Hope:

• Fludarabine phosphate and melphalan for patients with hematological malignancies and contraindications for conventional myeloablative regimens due to age, co-morbidity, or previous transplant
• Fractionated total-body irradiation (FTBI) and etoposide for patients with AML and ALL or CML in accelerated phase
• FTBI and cyclophosphamide for patients with NHL, AML, CML, and MDS
• Suitable unrelated donor available

• HLA-matched or mismatched
• Peripheral blood stem cells available
• No bone marrow or ex vivo-engineered or processed graft (e.g., CD34-positive, T-cell depletion)
• No uncontrolled CNS disease

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 70-100% or ECOG PS 0-2
• Creatinine < 1.3 mg/dL or creatinine clearance ≥ 70 mL/min
• Ejection fraction > 45%
• Direct bilirubin < 3 times upper limit of normal (ULN)
• ALT and AST < 3 times ULN
• Forced vital capacity, FEV1, and DLCO > 45% of predicted
• Able to cooperate with oral medication intake
• No active donor or recipient serology positive for HIV
• No known contraindication to administration of sirolimus, tacrolimus, or anti-thymocyte globulin
• No active hepatitis B or C
• Negative pregnancy test

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Concurrent participation in other clinical trials for prevention or treatment of viral, bacterial, or fungal disease allowed provided agents do not interact with agents used in the current study