Background: Allogeneic transplantation (allo-HCT) is an effective treatment for many patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). With HCT the long term disease free survival (DFS) rate is approximately 60% for patients transplanted in first remission. After relapse, the rate falls to approximately 40% if the patients are in remission at the time of HCT. However, many patients present with refractory chemo-resistant disease, relapse during or shortly after induction therapy, or develop complicating comorbidities due to prolonged induction. For most such relapse-refractory (R/R) AML patients, allo-HCT is not an option. These patients have a dire prognosis with only 5-10% long term DFS. Natural Killer (NK) cells are cytotoxic lymphocytes that are able to identify tumors and exert an anti-tumor effect in an MHC-I independent manner. However, NK cells from patients with cancer can be dysfunctional and reduced in number. To overcome that, NK cells expanded ex vivo to yield high numbers of cells could provide a cellular therapeutic option for cancer patients, including patients with AML/MDS. The therapeutic potential of ex vivo membrane-bound IL-21 expanded NK cells (FC21-NK) from a haploidentical donor has been established in patients with poor prognosis AML/MDS undergoing a haploidentical HCT. Besides obtaining sufficient cell numbers, having them readily available for patients is another major obstacle for adoptive NK cell immunotherapy. Patients with aggressive disease need prompt intervention yet the manufacture of patient-specific NK cells exceeds three weeks. As NK alloreactivity plays a critical role in mediating anti-tumor effects, we identified KIR and HLA-mismatched 'ideal' donors (selected through "Be The Match Biotherapies"). Using lymphocytes from these donors, we have established a third-party NK cell bank to ensure readily-available immune cell therapies that allows scalable, affordable mass-production of large numbers of NK cells suitable for banking & immediate 'off-the-shelf' administration to a broad population of recipients. This trial is to determine the safety of FC21 expanded Off-the-shelf (OTS), Third-party donor-derived NK cells for relapsed/refractory AML patients. Methods: This phase 1 study follows a 3+3 design to investigate the safety of FC21-expanded, third-party, OTS NK cells for treatment of patients with primary refractory or relapsed AML or myelodysplastic syndrome. Active GvHD is excluding. Patients aged ≥18 or ≤80 years are enrolled into two cohorts: those 60 yrs or Disclosures Vasu: Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees. Bhatnagar:KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Blachly:AbbVie, AstraZeneca, KITE Pharma: Consultancy. O'Donnell:Kiadis Pharma: Other: Licensing of intellectual property. Lee:Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.