This is a multi-institutional Phase I/II study of an allogeneic KIR-HLA mismatched NK cell infusion (AdaptNK) and a short course of subcutaneous interleukin-2 (IL-2) administered after lymphodepleting chemotherapy [cyclophosphamide (CY)/fludarabine (FLU)] in patients with relapsed or refractory acute myelogenous leukemia (AML). AdaptNK is a natural killer (NK) cell product that is enriched for NK cells with an "adaptive", or human cytomegalovirus (CMV)-induced, phenotype.

Inclusion Criteria:

• 18-74 years with Karnofsky score ≥ 70%
• 75 years and older: KPS ≥ 70%, HCT-CI < 5 (excluding history of solid tumor), AND not frail by Fried frailty criteria (see Appendix III)
• HLA type C1/C1 or C2/C2

Note: For easy determination, the definition of HLA-C ligand group assigments is included below:

HLA-C1 group alleles are defined as HLA-C01, C03, C07, C08, C12, C14, C16 HLA-C2 group alleles are defined as HLA-C02, C04, C05, C06, C15, C17, C18

• adequate liver, renal, pulmonary and cardiac function
• ability to be off glucocorticoids and other immunosuppressive medications indicated for acute or chronic GVHD for at least 28 days prior to the AdaptNK cell infusion
• There must be sufficient time between the most recent therapy and the screening bone marrow as delineated below:
• anti-leukemic systemic cytotoxic chemotherapy - 2 weeks
• Targeted anti-leukemic agents (FLT-3, IDH, menin inhibitors) - 3 half-lives of the medication
• Radiotherapy - 1 week
• donor lymphocyte infusions - 6 weeks
• hematopoietic growth factors (filgrastim, TPO agonists, EPO) - 1 week
• biologic therapy (monoclonal antibodies, T-cell engagers) - 2 weeks
• Immune effector cellular therapy - 4 weeks
• Intrathecal chemotherapy for treatment of active CNS leukemia - there must be at least two CSF samples negative for leukemia separated by one week before enrollment.
• WBC shall be < 25,000 before infusion. Hydroxyurea is permitted until day -3 to control excess blast proliferation. No other systemic treatment is allowed after the screening bone marrow is performed for inclusion in protocol
• All prior treatment related toxicities should have resolved to ≤ grade 1 prior to study enrollment
• agrees to use of adequate contraception from study enrollment to 4 months after cell infusion
• voluntary written consent

Exclusion Criteria:

• Myeloid neoplasms with known or strongly suspected germline background, except DDX41, TP53, or RUNX1.
• Acute promyelocytic leukemia (APL)
• myocardial infarction (MI) within previous 6 months of study enrollment
• pregnant or breastfeeding
• Active CNS involvement with AML
• new or progressive pulmonary infiltrates
• active autoimmune disease requiring immunosuppressive therapy
• Preexisting inflammatory disease requiring immunosuppressive therapy
• history of severe asthma and currently on chronic systemic medications
• HIV-1/2 positivity or hepatitis C/B
• active systemic infections requiring anti-infective treatment
• received any investigational agent within the 14 days before the start of study treatment (1st dose of fludarabine)
• Patients with second malignancies are excluded if they have required systemic cytotoxic chemotherapy within 1 year or if they are not in remission
• Exception: patients that are on stable dosing of hormonal therapy (e.g. aromatase inhibitor or antiandrogen therapy) for active breast or prostate cancer for 1 year are eligible.
• Patients with excised basal cell or squamous cell carcinoma of the skin are eligible.
• Patients with excised carcinoma in situ of the cervix or breast are eligible.
• Patients with untreated T1a or T1b prostate cancer are eligible.