Project Abstract Our program has focused on the translation of transplantation biology from the laboratory to the clinic to improve the outcome of blood and marrow transplantation (BMT). The development of high-dose post-transplant cyclophosphamide (PTCy) to modulate graft-versus-host disease (GVHD) is a prime example of our group’s successful translational research. PTCy allows safe mismatched alloBMT with results similar to those seen with matched donors, as well as permits virtually anyone in need of BMT to undergo the procedure. The median age of patients diagnosed with most hematologic malignancies is 65 or older. Refinements over the years to allogeneic BMT, including the use of reduced intensity conditioning (RIC) regimens and newer GVHD prophylaxis platforms, allow patients at least up to age 80 to undergo the procedure. Accordingly, the median age of patients enrolled on the recent large, multi-institutional trial undertaken by the BMT CTN that established PTCy-based GVHD prophylaxis as the new standard of care, was 66. Nevertheless, transplant-related toxicities are higher in older patients, especially those over 70, and traditional pretransplant risk assessment tools such as Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) do not predict risk as well in older patients receiving RIC conditioning. Thus, improving BMT outcomes in older patients is critically important. Our preliminary data suggest clonal hematopoiesis (CH) in older BMT recipients with lymphoid malignancies (to exclude myeloid MRD masquerading as CH) is associated with significantly increased non-relapse mortality (NRM) despite subsequent replacement by healthy donor hematopoiesis. Accordingly, older patients without CH have the same NRM as younger patients. Detection of CH may add important prognostic information to current risk stratification strategies for older patients. We would like to confirm these findings in a larger, independent cohort of older recipients and include myeloid malignancies. Moreover, it may be possible to ameliorate the effects of CH. Our specific objectives as a Core Clinical Center are to: 1) participate in multicenter trials through the BMT CTN, 2) validate CH as a predictor of poor clinical outcomes in a large cohort of older alloBMT patients, and 3) if the role of CH is confirmed, propose a clinical trial to address CH.