ALLO STEM CELL TRANSPLANT. FOR HIGH RISK HEMOTOLOGIC CA

University Of Maryland Baltimore, Baltimore MD

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Abstract

The curability of hematologic cancer patients undergoing allogeneic stem cell transplantation (allo-SCT) is severely compromised by non-relapse mortality (NRM currently intrinsic, even in relatively healthy patients with HLA-matched donors. Moreover, NRM is increased in other, less optimal situations, severely limiting the potential of this otherwise highly-curative procedure. The events that lead to NRM (usually regimen-related toxicity [RRT] and acute graft-vs-host disease (aGVHD) are mediated by oxidant stress that lead to upregulation of proinflammatory cytokines (esp. TNFalpha, IL-beta, IL-6 and interferon gamma). Therefore, the central focus of this application is to test the hypothesis that eliminating strong oxidant stresses, such as are produced by certain elements of "routine" allo-SCT, especially total body irradiation (TBI) and cyclophosphamide (CY) from the (pre-transplant) conditioning regimen, will decrease the pre-and post-transplant release of these proinflammatory cytokines, adhesion molecules and nitric oxide, that create an "inflammatory environment" which actually hinders engraftment and acts on host and allogeneic donor cells to exaggerate their responses, leading to the signs of inflammation and apoptosis characteristic of RRT and aGVHD. We further hypothesize that engraftment of allogeneic stem cells and a reduced incidence and severity of aGVHD can occur when the total oxidant stress of the conditioning regimen is reduced. We will evaluate this hypothesis in a clinical trial using agents that are less likely to provoke these cytokines, namely busulfan (or, when busulfan can not be utilized, melphalan) and T10B9 (MEDI-500), a TCRalpha/beta monoclonal antibody in patients selected as requiring allo-SCT for optimal therapy but with an excessive risk of NRM of so doing. MEDI-500 will also be continued post allo-SCT to decrease the incidence and severity of aGVHD; other routine measures will be utilized as well. We will measure engraftment, both indirectly and by molecular techniques on sorted cell populations, the rate and severity of non-relapse mortality due to various problems as well as the kinetics of immunoreconstitution. In addition, the degree of oxidant stress, activation of the NF-kappabeta, and circulating levels of inflammatory factors will be compared (admittedly in a non-definitive fashion) with the outcome measures.