Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation With a Conditioning Regimen of Targeted Busulfan, Cyclophosphamide, and Thymoglobulin
19 Years
65 Years
Both
Graft Versus Host Disease, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases, Secondary Myelofibrosis
Trial Information
Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation With a Conditioning Regimen of Targeted Busulfan, Cyclophosphamide, and Thymoglobulin
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.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- 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
PATIENT CHARACTERISTICS:
- 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
- No active uncontrolled infection
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No HIV infection
- No chronic active hepatitis B or C or evidence of cirrhosis on liver biopsy
PRIOR CONCURRENT THERAPY:
- Not specified
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Transplantation-related mortality at 100 days post-transplantation
Safety Issue:
Yes
Principal Investigator
Marcel Devetten, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
University of Nebraska
Authority:
United States: Institutional Review Board
Study ID:
122-05
NCT ID:
NCT00611351
Start Date:
June 2005
Completion Date:
September 2008
Related Keywords:
- Graft Versus Host Disease
- Leukemia
- Lymphoma
- Multiple Myeloma and Plasma Cell Neoplasm
- Myelodysplastic Syndromes
- Myelodysplastic/Myeloproliferative Diseases
- Secondary Myelofibrosis
- graft versus host disease
- adult acute myeloid leukemia with 11q23 (MLL) abnormalities
- adult acute myeloid leukemia with inv(16)(p13;q22)
- adult acute myeloid leukemia with t(15;17)(q22;q12)
- adult acute myeloid leukemia with t(16;16)(p13;q22)
- adult acute myeloid leukemia with t(8;21)(q22;q22)
- recurrent adult acute myeloid leukemia
- untreated adult acute myeloid leukemia
- untreated adult acute lymphoblastic leukemia
- accelerated phase chronic myelogenous leukemia
- blastic phase chronic myelogenous leukemia
- chronic phase chronic myelogenous leukemia
- relapsing chronic myelogenous leukemia
- stage III multiple myeloma
- refractory multiple myeloma
- de novo myelodysplastic syndromes
- myelodysplastic/myeloproliferative disease, unclassifiable
- previously treated myelodysplastic syndromes
- secondary myelodysplastic syndromes
- secondary myelofibrosis
- secondary acute myeloid leukemia
- recurrent adult Burkitt lymphoma
- recurrent adult diffuse large cell lymphoma
- recurrent adult diffuse mixed cell lymphoma
- recurrent adult diffuse small cleaved cell lymphoma
- recurrent adult Hodgkin lymphoma
- recurrent adult immunoblastic large cell lymphoma
- recurrent adult lymphoblastic lymphoma
- recurrent adult T-cell leukemia/lymphoma
- recurrent cutaneous T-cell non-Hodgkin lymphoma
- recurrent grade 1 follicular lymphoma
- recurrent grade 2 follicular lymphoma
- recurrent grade 3 follicular lymphoma
- recurrent mantle cell lymphoma
- recurrent marginal zone lymphoma
- recurrent small lymphocytic lymphoma
- recurrent adult acute lymphoblastic leukemia
- extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
- nodal marginal zone B-cell lymphoma
- splenic marginal zone lymphoma
- adult nasal type extranodal NK/T-cell lymphoma
- stage III adult Hodgkin lymphoma
- stage IV adult Hodgkin lymphoma
- stage III adult T-cell leukemia/lymphoma
- stage IV adult T-cell leukemia/lymphoma
- stage III adult Burkitt lymphoma
- stage IV adult Burkitt lymphoma
- stage III adult diffuse large cell lymphoma
- stage IV adult diffuse large cell lymphoma
- stage III adult diffuse mixed cell lymphoma
- stage IV adult diffuse mixed cell lymphoma
- stage III adult immunoblastic large cell lymphoma
- stage IV adult immunoblastic large cell lymphoma
- stage III adult lymphoblastic lymphoma
- stage IV adult lymphoblastic lymphoma
- stage III grade 1 follicular lymphoma
- stage III grade 2 follicular lymphoma
- stage III grade 3 follicular lymphoma
- stage IV grade 1 follicular lymphoma
- stage IV grade 2 follicular lymphoma
- stage IV grade 3 follicular lymphoma
- stage III mantle cell lymphoma
- stage IV mantle cell lymphoma
- stage III marginal zone lymphoma
- stage IV marginal zone lymphoma
- stage III small lymphocytic lymphoma
- stage IV small lymphocytic lymphoma
- stage III adult diffuse small cleaved cell lymphoma
- stage IV adult diffuse small cleaved cell lymphoma
- adult acute lymphoblastic leukemia in remission
- adult acute myeloid leukemia in remission
- atypical chronic myeloid leukemia
- noncontiguous stage II adult Burkitt lymphoma
- noncontiguous stage II adult diffuse large cell lymphoma
- noncontiguous stage II adult diffuse mixed cell lymphoma
- noncontiguous stage II adult diffuse small cleaved cell lymphoma
- noncontiguous stage II adult immunoblastic large cell lymphoma
- noncontiguous stage II adult lymphoblastic lymphoma
- noncontiguous stage II grade 1 follicular lymphoma
- noncontiguous stage II grade 2 follicular lymphoma
- noncontiguous stage II grade 3 follicular lymphoma
- noncontiguous stage II mantle cell lymphoma
- noncontiguous stage II marginal zone lymphoma
- noncontiguous stage II small lymphocytic lymphoma
- refractory hairy cell leukemia
- stage I multiple myeloma
- stage II multiple myeloma
- Primary Myelofibrosis
- Neoplasms
- Graft vs Host Disease
- Leukemia
- Lymphoma
- Lymphoma, Non-Hodgkin
- Multiple Myeloma
- Neoplasms, Plasma Cell
- Plasmacytoma
- Myelodysplastic Syndromes
- Preleukemia
- Myeloproliferative Disorders
- Lymphoma, Large-Cell, Immunoblastic
- Myelodysplastic-Myeloproliferative Diseases
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