PROJECT SUMMARY This grant application seeks to renew our status as a Core Clinical Center (CCC) and member of the Steering Committee of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The City of Hope (COH) Hematopoietic Cell Transplantation (HCT) Program has focused its efforts over the last 50 years on the development of Phase I, II and III clinical trials leading to improvements in HCT for the treatment of hematologic malignancy and non-malignant disorders. 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 (GVHD), and CMV infection. During our 20 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. This proposal summarizes COH CCC capabilities for BMT CTN, our operational and scientific approaches, and our work in clinical trials both in our own institution and in collaborations with the BMT CTN. As part of this application, we also propose a concept for “a Phase 2, platform clinical trial of post-HCT maintenance therapeutics in patients undergoing allogeneic HCT for treatment of TP53-mutated AML or MDS”. The outcomes of AML/MDS with TP53 mutation is dismal, and development of effective therapeutic approach is a true unmet need. HCT is the only potentially curative therapy for high-risk AML/MDS, including those with TP53-mutated diseases, but only a small fraction of patients receives HCT, primarily due to advanced age, poor performance status, and uncontrolled disease. Even after HCT, TP53-mutated MDS/AML are associated with low survival rates primarily due to a very high incidence of relapse. The primary objective of our platform trial is to evaluate the efficacy of different maintenance therapies for TP53-mutated AML/MDS as measured by 1-year progression-free survival (PFS). The first arm to be tested will be magrolimab (MAGRO) and azacitidine (AZA). To further improve HCT outcomes in these high-risk patients, we propose to capture a subset of patients before HCT and incorporate a multidisciplinary team intervention aimed at detoxifying HCT by recording valid measures of functional recovery and creating a paradigm for safer application of allogeneic HCT and proceeding to post-HCT maintenance. This trial is based on the unmet need in the field as recognized at the BMT CTN SOSS 2021 and based on the experience and expertise at COH investigating MAGRO/AZA as post-HCT maintenance therapy (NCT05823480, PI. Al Malki) and assessment of frailty/resiliency in HCT candidates with a multidisciplinary approach to optimize care of these patients at older age or inform clinical condition (NCT04914338, PI. Artz). Moreover, broad collaborations on correlative science will significantly advance our understanding of this hi...