High dose chemoradiotherapy with allogeneic hematopoietic transplantation is an effective treatment for AML. This approach was conceived as a strategy to produce marrow ablation, but recent data indicates that the immune mediated graft-vs-leukemia effect is also important. Relapse of leukemia remains a major problem. In this project we evaluate a number of innovative approaches designed to improve the outcome of allogeneic transplantation. This includes evaluation of decitabine as a novel agent for preparative regimens with allogeneic peripheral blood progenitor cell transplants in matched siblings. The recent promising results with donor lymphocyte infusions suggests that achieving engraftment of donor peripheral blood cells after standard dose chemotherapy for induction of graft-vs-leukemia might also be beneficial. This will be studied in older patients who have a matched sibling donor with primary endpoints of analysis being engraftment, GVHD and remission duration. Allogeneic transplants have been less successful in adult patients who lack an HLA identical sibling; we examine two innovative approaches to achieve engraftment without GVHD in this setting. Prevention of GVHD in patients receiving allogeneic transplant will be studied using thymidine kinase transduced donor lymphocytes (suicidal lymphocytes) which can be ablate by ganciclovir treatment. For mismatched related donor transplants we are evaluating CD34 selected marrow plus peripheral blood progenitors, providing a large progenitor cell dose and depleted of aIloreactive T-cells. For unrelated donor or mismatched transplants, we will study an innovative T-cell depletion method, using a system to retain graft facilitating cells to enhance engraftment while still preventing GVHD. For patients who relapse, we reported the unique observation that G-CSF treatment can reinduce remissions; we further examine the efficacy of this approach and attempt to define its mechanism. We also will study whether retinoic acid which downregulates bcl-2 and enhances apoptosis, will enhance the therapeutic effect. Lastly we will examine the presence of minimal residual AML in patients after transplantation therapies. This project interacts extensively with the other clinical projects within this proposal.
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