OBJECTIVES:
Primary
* Determine the clinical efficacy and toxicity profiles of a nonmyeloablative preparative regimen comprising busulfan and fludarabine with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation in patients with hematologic cancers or other diseases.
* Determine the feasibility of this regimen in these patients.
* Establish a treatment-related mortality during the first 6 months that is less than 20% in patients treated with this regimen.
Secondary
* Determine the response rates (disease-specific partial response and complete response) in patients treated with this regimen.
* Determine overall and progression-free survival of patients treated with this regimen.
* Determine the percent donor chimerism and immunologic recovery, including dendritic cell recovery, in patients treated with this regimen.
* Determine the risk of acute and chronic graft-versus-host disease and other toxicities in patients treated with this regimen.
* Assess the overall nonhematologic grades 3 and 4 toxicity of this regimen, including the incidence of veno-occlusive disease and pulmonary toxicity, in these patients.
OUTLINE: Patients are assigned to 1 of 4 treatment groups according to disease type and donor type.
* Preparative regimen:
* Group 1 (patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), IPSS (International Prognostic Scoring System score) high-risk myelodysplastic syndromes (HR MDS), or chronic myelogenous leukemia (CML) with an human leukocyte antigen (HLA)-matched related donor (MRD): Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV continuously over 48 hours on days -6 and -5.
* Group 2 (patients with AML, ALL, IPSS HR MDS, or CML with an HLA-matched unrelated donor (MUD) or mismatched related donor (MMRD)): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on day -8.
* Group 3 (patients with all other diseases with a MRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin as in group 2.
* Group 4 (patients with all other disease with a MUD or MMRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on days -8 and -7.
* Allogeneic stem cell transplantation: All patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously once daily beginning on day 5 (groups 1 and 2) or day 7 (groups 3 and 4) and continuing until blood counts recover.
* Graft-vs-host disease (GVHD) prophylaxis: All patients receive oral tacrolimus twice daily on days -1 to 120 followed by a taper until day 180. Patients in groups 1 and 2 also receive methotrexate IV on days 1, 3, and 6.
* Donor lymphocyte infusion (DLI): After day 120, patients with progressive disease or stable disease while off immunosuppression and with no evidence of active GVHD may receive DLI. Treatment with DLI may repeat every 8 weeks for up to 3 total infusions in the absence of disease response or GVHD.
Peripheral blood and/or bone marrow samples are collected at baseline and then at 30, 60, 90, 120, and 180 days post-transplantation. Chimerism (including the following subsets: whole blood, T-cells as defined by cluster of differentiation 3 (CD3) positivity, B-cells as defined by Cluster of Differentiation 19 (CD19) positivity, and myeloid cells as defined by Cluster of Differentiation 14 (CD14) and Cluster of Differentiation 15 (CD15) positivity is analyzed by polymerase chain reaction technology.
After restaging between Days 90 and 100 and between Days 150 to 180, patients are followed every 6 months for 1 years and then yearly for a maximum of 5 years from study entry.
