This grant application seeks to renew our status as a Core Clinical Center and member of the Steering Committee of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The City of Hope Hematopoietic Cell Transplantation Program has focused its efforts over the last 35 years on the development of Phase I, II and III clinical trials leading to Improvements in hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancy. In addition to developing laboratory-based translational research trials, our program has conducted prospective clinical trials in areas such as reduction of relapse, graft-versus-host disease and CMV infection. During our 10 years as a member of the BMT CTN, we have participated in the development of clinical trials focused on important questions confronting HCT patients, several of which were derived from early phase studies conducted in our program. Myelodysplasia is an incurable hematologic malignancy for which limited progress has been made in extending progression-free survival. Historically, allogeneic transplantation has been the only curative approach, but was generally restricted to younger patients eligible for fully ablative allogeneic transplantation. Given that the vast majority of MDS patients are over 60, treatment options have been primarily palliative. With the advent of reduced intensity conditioning (RIC) allogeneic HCT, many centers, including our own, have developed trials focused on addressing the problem of myelodysplasia in older patients. Phase II trials conducted at our own and other institutions suggest that patients into their 60's have the opportunity for a potential curative approach through RIC. We propose to the BMT CTN, a biologically allocated Phase III trial comparing hypomethylating therapy versus reduced intensity allogeneic transplantation in patients over the age of 60 with high IPSS scores. All patients will receive the same induction therapy with either azacytidine or decitabine, while a donor search, either in the family or through unrelated donor registries, is pursued. Those patients with an allogeneic donor will proceed to transplantation, while those without a donor will continue on with hypomethylating therapy until progression or development of leukemia. This trial will help define the role of allogeneic transplantation in curing MDS, and characterize the short- and long-term complications in this unique patient population. Patients as well as health care underwriters would benefit from this trial, and patients with Medicare benefits would be eligible for participation. This proposal represents a national effort on behalf of the BMT CTN to extend transplantation for treatment of MDS to those older patients with no other curative options. RELEVANCE City of Hope, as part of the Blood and Marrow Transplant Clinical Trials Network, proposes to continue leadership in the development and execution of prospective clinical trials addressing key issues in hematopoietic cell transplantation. We also propose a national trial to determine the efficacy of reduced intensity allogeneic transplantation in curing older patients with high risk myelodysplasia, in comparison to modern hypomethylating therapy with azacytidine or decitabine. This study addresses an important health care issue, particularly for patients entering the seventh decade of life who have no other curative options.