The goal of the studies detailed in Project I is to improve the outcome of allogeneic hematopoietic cell transplantation for hematologic malignancy. The specific disease entities that we will focus on are acute leukemia and myelodysplasia. The improvement in outcome will be achieved by an integrated investigational approach designed to address the following parameters that impact on outcome; (i) disease relapse, (ii) the incidence and severity of acute and chronic graft-versus-host disease, (iii) the development of CMV-associated disease, and (iv) toxicities directly attributable to the preparative regimen. By conducting clinical and laboratory-based studies designed to minimize the incidence and/or the severity of each of these parameters, significant improvement in the outcome of allogeneic transplantation for patients with acute leukemia and myelodysplasia can be achieved. To this end, we propose five specific aims focused on the four parameters listed above within this project entitled """"""""Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancy"""""""". The specific of Project I will be realized in the context of a series of Phase I, II and III clinical trials conducted at City of Hope, in collaboration with the BMT programs of Stanford and the Fred Hutchinson Cancer Research and the Southwest Oncology Group. The five specific aims of Project I are: 1) To determine the significance of minimal residual disease detection by molecular assays on subsequent clinical disease relapse, 2) To pilot adoptive T cell therapy targeting CD19 as a strategy to eradicate molecular post-transplant relapse, 3) To improve the efficacy of chemo- prophylaxis of acute and chronic graft-versus-host disease, 4) To delineate optimal pharmacological prophylaxis of cytomegalovirus infection and pilot novel donor/recipient immunization approaches, and 5) To explore novel preparative regimens with optimized anti-tumor activity and minimized end organ toxicities. Project I will serve as a clinical resource for experimental Projects III and VI and will be supported by Cores A, B, C, D, E and F.
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