Patients older than fifty years comprise the majority of patients with hematologic malignancies that can not be cured with chemotherapy alone. Due to the advent of less toxic reduced intensity conditioning regimens (RIT), these older patients represent the fastest growing group of patients receiving unrelated donor hematopoietic cell transplant (URD). This population of patients generally poorly tolerates graft-versus-host disease (GVHD) and standard treatment with high-dose steroids. Thus new treatments are needed for GVHD, the most serious complication of allogeneic bone marrow transplantation (BMT). Current pharmacological agents for GVHD prevention and treatment primarily target one of the essential effectors for GVHD, donor T cells. Other key elements for GVHD, and therefore potential therapeutic targets, are inflammatory cytokines and regulatory T cells (Tregs). Extensive experimental data developed by our team support the conduct of translational clinical trials to test agents that act upon these additional GVHD mechanisms. First, we have demonstrated that the inflammatory cytokine, TNF1 is strongly correlated with GVHD. We have also shown in clinical trials that TNF- inhibition with etanercept is safe and may have clinical efficacy for GVHD. Second, strong experimental data demonstrates that Tregs exert an inhibitory effect on GVHD. We have shown that extracorporeal photopheresis (ECP) induces Tregs in experimental models of GVHD and our team, as well as others, has data suggesting that ECP may have clinical efficacy in GVHD prevention and treatment. In this project we will perform a unique clinical trial that combines these two therapies for GVHD prevention. A further advance in GVHD, the individualization of treatment, is presently hampered because GVHD can not be predicted precisely, the diagnosis is often hard to establish, and patients whose GVHD is likely to be resistant to therapy can not be identified. One of the first GVHD biomarker panels with predictive and diagnostic power was recently identified by our team. The clinical and laboratory data generated by this project is essential to design and execute a large clinical trial that will (1) definitively test this novel approach to GVHD prevention and (2) incorporate GVHD biomarkers. The Specific Aims are: 1. To conduct a phase II GVHD prevention trial using standard GVHD prophylaxis augmented by the TNF- inhibitor, etanercept, and regulatory T-cell (Treg) induction, by extracorporeal photopheresis (ECP) in unrelated donor (URD) reduced intensity transplantation (RIT). 2. To correlate cellular and plasma biomarkers of GVHD with clinical outcomes on the above trial. (End of Abstract) PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, GVHD. Strategies that mitigate GVHD will allow for better harnessing of this effective therapeutic modality to treat many patients with hematological cancers.