ABSTRACT The University of Michigan Consortium brings together physician scientists from the two major cancer centers in the State of Michigan: the University of Michigan in Ann Arbor and the Karmanos Cancer Institute in Detroit. In addition, both the University of Michigan (U-M) and the Karmanos Cancer Institute (KCI) are affiliated with pediatric hospitals—U-M with Mott Children’s Hospital and KCI with the Children’s Hospital of Michigan (CHM). The U-M Consortium has been a strong supporter of BMT CTN Network activities throughout the current grant cycle, with more than 300 subjects (and counting) enrolled into CTN trials since 2017. The U-M Consortium will have an emphasis on non-malignant blood disorders, with more than 2,000 patients with hemoglobinopathies and immunologic disorders currently being followed. The organizational structure pairs hematologists with transplant physicians who have expertise in these conditions. The Consortium has deep experience in translating early-phase clinical trials to multicenter studies, has comprehensive biorepositories as foundations for its programs, and has a team of physician-scientists (Dr. Greg Yanik, Dr. Sung Won Choi, Dr. Joseph Uberti, and Dr. John Magenau) with an established track record of academic success. This research proposal examines a new paradigm in bone marrow transplantation, focusing on inhibition of epigenetic pathways as a potential mechanism both to prevent transplant-related organ toxicity and to mitigate graft versus host disease (GVHD). The role of histone deacetylase inhibitors has been an area of intense research at U-M for the past two decades, with pre-clinical studies at both cancer centers having led to five multicenter clinical trials over this period. NIH- funded clinical trials using a histone deacetylase inhibitor (Vorinostat) have been performed in recipients of reduced and myeloablative conditioning, in a variety of donor cell sources (sibling, unrelated, haplo-identical) and in both adults and pediatric patients. The proposed project will study the role of epigenetic modifiers in patients undergoing transplant for non-malignant blood disorders, including those with hemoglobinopathies or immune-hematologic disorders. The study will use a novel composite endpoint: one-year GVHD-free, event-free survival, with events defined as death due to any cause, graft rejection/failure, or second HCT, whichever occurs first. GVHD will be defined as grade III-IV acute GVHD or chronic GVHD requiring systemic immune suppression. Secondary endpoints include overall survival, primary and secondary graft failure, chimerism and infectious events. This trial will not only mitigate the severity of GVHD in patients with non-malignant blood disorders, but also advance the understanding of the biology of epigenetic modifiers in HCT. The U-M Consortium is committed to the scientific agenda of the BMT CTN and fully anticipates that this research strategy will provide new insights into reducing...