This phase I trial studies the side effects of donor natural killer (NK) cell therapy in treating patients with acute myeloid leukemia that has come back (recurrent) or has not responded to treatment (refractory). Natural killer cells are a type of immune cell. Immunotherapy with genetically modified NK cells from donors may induce changes in the body's immune system and may interfere with the ability of cancer cells to grow and spread.

PRIMARY OBJECTIVE:

I. To determine the safety of adoptive NK cell therapy using membrane-bound interleukin-21 (mbIL21)-expanded, off-the-shelf, third-party donor-derived NK cells in patients with relapsed/refractory acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. Estimate the complete response (CR, CR with incomplete hematologic recovery [CRi] & morphologic leukemia-free state [MLFS]).

II. Estimate the median relapse free survival. III. Estimate the median time to neutrophil and platelet count recovery. IV. Estimate the median duration of remission. V. Estimate the incidence of infectious complications. VI. Estimate percentage of patients receiving this regimen who are rendered transplant-eligible.

CORRELATIVE OBJECTIVES:

I. Determine the persistence of ex-vivo expanded, off-the-shelf, third-party NK cells.

II. Characterize in vivo expansion of third-party NK cells and if it differs based on the conditioning regimen as defined by NK chimerism assay.

III. Determine the immunophenotype and function of expanded cells. IV. Chimerism analysis in patients who have had post-transplant relapses.

OUTLINE: This is a dose-escalation study of membrane-bound interleukin-21-expanded haploidentical natural killer cells.

INDUCTION: Patients receive fludarabine intravenously (IV) and cytarabine IV on days -6 to -2 in the absence of disease progression or unacceptable toxicity.

COHORT II: Patients who are >= 60 years old, unable/unwilling to tolerate intensive chemotherapy, or disease insensitive to cytarabine (tp53, TET2 mutations) receive fludarabine IV on days -5 to -2 and decitabine IV on days -6 to -2 in the absence of disease progression or unacceptable toxicity.

All patients receive membrane-bound interleukin-21-expanded haploidentical natural killer cells via infusion on days 0, 2, 4, 7, 9, and 11.

After completion of study treatment, patients are followed up to day 56.

Inclusion Criteria:

Patient Inclusion Criteria for Induction Phase

• Primary Relapsed AML including
• Relapsed AML after allogeneic stem cells
• Isolated CNS or extramedullary disease (Note: a response monitoring plan must be developed a priori for subjects with extramedullary disease)
• 1-3 prior lines of therapy which includes chemotherapy, hypomethylating agents, venetoclax or targeted therapy.
• Patient weight ≥ 42 kg
• Performance status: Karnofsky or Lansky Performance Scale (PS) greater or equal to 70, or, ECOG score 0-2.
• Renal function: Serum creatinine ≤ 2 mg/dl and/or creatinine clearance greater or equal than 40 cc/min.
• Pulmonary function: FEV1, FVC and DLCO ≥ 50% of expected, corrected for hemoglobin.
• Liver function: Total bilirubin ≤ 2 mg/dl or ≤ 2.5 x ULN for age (unless Gilbert's syndrome) and SGPT (ALT) ≤ 2.5 x ULN for age.
• Cardiac function: left ventricular ejection fraction ≥ 40%.
• CNS: Patients with seizure disorder are eligible if seizures well controlled.
• Negative serum test to rule out pregnancy within 2 weeks prior to enrollment in females of childbearing potential (non-childbearing potential defined as premenarchal, greater than one year post-menopausal, or surgically sterilized).
• Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator.
• Ability to understand and willingness to sign the written informed consent document.
• Negative serology for human immunodeficiency virus (HIV).
• Patients on hydrocortisone for adrenal insufficiency or on inhaled or topical steroids are eligible.

Maintenance Phase: Patients that complete induction therapy and who achieve a CR/CRi/PR within the designated follow-up period and who are ineligible, unable or unwilling to undergo HSCT; these patients will not receive fludarabine or cytarabine.

Exclusion Criteria for Induction Phase:

• Investigational therapies in the 3 weeks prior to beginning treatment on this protocol.
• Patients receiving any concurrent therapy including but not limited to chemotherapy, targeted therapy, radiation therapy, or immunotherapy for R/R AML.
• Any comorbidities that in the opinion of the investigator will preclude receiving fludarabine or cytarabine.
• Uncontrolled infection, defined as an infection which has not resolved spontaneously or does not show evidence of significant resolution after initiating appropriate therapy. Asymptomatic viremia such as CMV, HPV, BK virus, HCV, HBV etc. is NOT considered as an exclusion criteria.
• Uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease.
• Active GVHD
• Prednisone dose is > 20 mg/day or >0.25mg/kg, whichever is higher will be excluded.
• Patients with donor-specific antibodies with MFI > 5000 will be ineligible
• Maintenance Phase: Patients must continue to meet exclusion criteria as defined in Section 4.4.