Hematologic malignancies are important causes of morbidity and mortality in adults. These diseases affect primarily patients over the age of 50, and results of conventional therapy are unsatisfactory. Allogeneic stem cell transplantation has been effective in obtaining long-term disease control in many patients with these disorders including those in whom initial therapy has failed. Allografting has traditionally been limited to younger patients in good medical condition because of the high rates of graft versus host disease (GVHD) and non-relapse mortality associated with increasing age and decreasing performance status. Strategies to decrease morbidity and mortality related to allografting in older patients have included reductions in the intensity of the preparative regimens. In this grant application we propose to determine whether unrelated donor transplantation using a reduced intensity conditioning will result in lower rates of acute GVHD and non relapse mortality and better outcomes in older patients (45 to 65 years of age) with myeloid leukemias when compared to a conventional myeloablative protocol, and whether this reduction in non relapse mortality is secondary to lower levels of inflammatory cytokines (IL-1,IL-2,IFN-gamma, TNF-alpha, IL-6, IL-10, and IL12) in patients receiving a reduced intensity conditioning than in patients receiving conventional myeloablative transplants. Within this application we will also determine the relevance of lineage specific chimerism using existing cell sorting and chimerism determination techniques, and correlate degree of chimerism of specific myeloid, lymphoid, and stem cell subsets with engraftment, relapse, and GVHD. The ultimate goal of this study is to optimize transplant strategies for each patient population by defining the best preparative regimen associated with the lowest toxicities and best long term outcomes.
