Background: Myeloablative allogeneic hematopoietic cell transplantation (AHCT) is potentially curative for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but toxicities of conditioning limit its use in older or frail patients. Non-myeloablative (NMA) conditioning achieves better tolerability, at the expense of higher rates of relapse. We have developed a first-in-class monoclonal antibody (mAb), JSP191, which inhibits stem cell factor binding to CD117 (c-Kit), thereby depleting normal and MDS/AML disease-initiating hematopoietic stem cells (HSC). In pre-clinical models, anti-CD117 mAbs potently synergize with low dose total body radiation (TBI) to deplete HSC and facilitate donor cell engraftment. We reasoned that adding JSP191 to a standard NMA conditioning of 2 Gy TBI and fludarabine (Flu) would be safe and result in depletion of measurable residual disease (MRD) in older adults with high-risk MDS/AML entering AHCT. Methods: We report on the first 6 enrolled subjects in our Phase 1 trial (NCT#04429191) of JSP191/TBI/Flu as AHCT conditioning in MDS/AML patients, ≥ 60 years, with MRD detected by cytogenetics (cyto), difference from normal flow cytometry (flow), and/or next-generation sequencing (NGS). Primary endpoints are safety and tolerability of JSP191/TBI/Flu and JSP191 pharmacokinetics. Secondary endpoints include engraftment, donor chimerism, MRD clearance, GVHD, NRM, EFS, and OS at 1 year. JSP191 at 0.6 mg/kg was administered intravenously; serum concentration of JSP191 was used to confirm timing to begin Flu at 30 mg/m²/day x 3 days [Transplant Day (TD)-4, -3, -2] and TBI 2 Gy on TD0. Peripheral blood grafts from HLA-matched related or unrelated donors were administered on TD0 (10-13 days after JSP191). GVHD prophylaxis was tacrolimus, sirolimus, and mycophenolate mofetil. Results: All subjects are still on trial, and there have been no infusion toxicities and no JSP191-related serious adverse events. All subjects engrafted with neutrophil recovery TD+19 to TD+26, and showed ≥94% donor myeloid chimerism in the blood at TD+28. All 3 evaluable subjects with TD+90 follow up showed complete donor (≥95%) total and myeloid chimerism and MRD elimination (Table). Conclusions: These early results are the first to demonstrate that JSP191/TBI/Flu is safe, well-tolerated, and capable of clearing MDS/AML MRD in older adults undergoing NMA AHCT. Clinical trial information: NCT04429191