Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation With a Conditioning Regimen of Targeted Busulfan, Cyclophosphamide, and Thymoglobulin
- 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.
- 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.
- 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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Transplantation-related mortality at 100 days post-transplantation
Marcel Devetten, MD
University of Nebraska
United States: Institutional Review Board