Cytokine Modulation Strategy in Clinical Allogeneic BMT

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AIIogeneic bone marrow transplantation (BMT) is the treatment of choice for a number of malignant and non-malignant disorders. When family donors are not available, successful BMT may be accomplished using volunteer, unrelated donors (URD). Early mortality following URD BMT remains unacceptably high and limits the successful application of this procedure. Acute g raft-versus-host disease (GVHD) and idiopathic pneumonia syndrome (IPS) are the two most significant complications following URD BMT and contribute to approximately 80% of non-relapse mortality by day 100. A significant body of experimental data has demonstrated that inflammatory cytokines including tumor necrosis factor (TNFalpha are significant contributors to GVHD and IPS. We have recently successfully completed two pilot trials using one such agent, etanercept, a soluble, dimeric TNalpha binding protein to treat patients with either acute GVHD or IPS. This translational research proposal will test our central hypothesis: That neutralization of TNFalpha will significantly reduce the rate of acute GVHD and day 100-mortality after URD BMT. The specific aims of Project 3 are: Aim1: To conduct a phase II clinical trial using etanercept in combination with standard G VHD prophylaxis in recipients of full intensity URD BMT. Aim2: To develop biologic and genetic predictive markers of outcomes after URD BMT. Aim3: To determine the role of TNFalpha in dendritic cell activation and keratinocyte apoptosis that occurs in GVHD skin. Aim4: To conduct a phase 1/11trial to determine the safety of the HDAC inhibitor, ITF2357, when given with standard GVHD prophylaxis after full intensity URD BMT.