Busulfan, Cyclophosphamide, & Antithymocyte Globulin Followed by Stem Cell Transplant in Treating Hematologic Cancer

RATIONALE: Giving chemotherapy before a donor bone marrow transplant or peripheral stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When certain stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving busulfan together with cyclophosphamide and antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer.

OBJECTIVES:

Primary

* To determine the incidence of grade II-IV acute graft-versus-host disease in patients with hematologic cancer or other diseases treated with a myeloablative conditioning regimen comprising targeted (steady-state concentration of 800-1,000 ng/mL) busulfan, cyclophosphamide, and anti-thymocyte globulin followed by matched unrelated donor allogeneic hematopoietic stem cell transplantation.
* To determine the day +100 transplantation-related mortality in these patients.

Secondary

* To determine the effect of cyclophosphamide pharmacokinetic parameters on day +100 transplantation-related mortality in these patients.
* To determine the ability of low-dose anti-thymocyte globulin administered on day +5 to induce activation-induced cell death of activated donor lymphocytes.
* To determine the incidence of chronic graft-versus-host disease in patients treated with this regimen.
* To determine event-free and overall survival of patients treated with this regimen.
* To evaluate pharmacogenomic associations between genetic polymorphisms in drug disposition enzymes with the pharmacokinetics of busulfan and cyclophosphamide.

OUTLINE:

* Myeloablative conditioning regimen: Patients receive busulfan IV over 2 hours on days -8 to -5; cyclophosphamide IV over 4 hours on days -3 to -2; and anti-thymocyte globulin IV over 6 hours on day -3 and then over 4 hours on days -2, -1, and 5.
* Allogeneic hematopoietic stem cell transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell infusion on day 0.
* Graft-versus-host-disease prophylaxis: Patients receive tacrolimus IV continuously or orally on days 6 to150, followed by an even taper to day 180 in the absence of graft-versus-host-disease. Patients also receive mycophenolate mofetil IV or orally beginning on day 6 and continuing to day 28.

Patients undergo blood collection periodically during study for pharmacokinetic, pharmacogenomic, and other translational studies. Genomic DNA extracted from blood samples is analyzed by polymerase chain reaction for genetic polymorphisms in cyclophosphamide/busulfan disposition enzymes. Activated donor lymphocytes are assessed using flow cytometry to measure activation-induced cell death, as reflected by apoptosis in activated T cells. Chimerism on or around day 100 is also assessed using fluorescence in situ hybridization analysis and DNA fingerprinting.

After completion of study treatment, patients are followed periodically.

Eligibility Criteria:
Inclusion Criteria:

* Pathologically confirmed diagnosis of 1 of the following:

  * Acute myeloid leukemia
  * Acute lymphocytic leukemia
  * Chronic myelogenous leukemia beyond first chronic phase (i.e., 2nd chronic phase, accelerated phase, or blast crisis)
  * Multiple myeloma
  * Myelodysplastic syndromes
  * Malignant lymphoma
  * Myelofibrosis
* Requirement for myeloablative conditioning regimen confirmed by attending physician
* Available donor must meet the following criteria:

  * HLA phenotypically identical unrelated donor by low, intermediate, or high resolution for HLA class I antigens, and by high resolution for HLA class II antigens
  * Matched at the A, B, and DRβ1 loci
  * Single HLA-A or HLA-B antigen mismatch allowed
  * Meets all National Marrow Donor Program or foreign registry criteria for allogeneic bone marrow/stem cell donors
  * Peripheral blood stem cells are the preferred product on this study but bone marrow is allowed
* Karnofsky performance status 70-100%
* DLCO ≥ 50% predicted
* LVEF ≥ 45%
* Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 65 mL/min
* Serum total bilirubin ≤ 2.0 mg/dL
* Fertile patients must use effective contraception

Exclusion Criteria:

* No active uncontrolled infection
* Not pregnant or nursing/negative pregnancy test
* No HIV infection
* No chronic active hepatitis B or C or evidence of cirrhosis on liver biopsy