CIML NK Cells With Venetoclax for AML

Inclusion Criteria for Trial Enrollment (Registration Visit): * Diagnosis of AML or MDS/AML (10-19% blasts) by 2022 ELN criteria. Historical test results (either peripheral blood or bone marrow) can be used to establish this diagnosis. * Age ≥ 18 years old * At time of screening patient has received any prior lines of therapy including prior chemotherapy and any prior stem cell transplant, provided that the stem cell transplant is \> 6 months ago with no ongoing need for immunosuppressive therapy for active graft-versus-host disease. * Presence of molecular risk factors for relapse as defined by any of the following present at any time during a participant's history of AML: * 2022 ELN adverse risk karyotype: t(6;9)(p23.3;q34.1)/DEK::NUP214; t(v;11q23.3)/KMT2A-rearranged; t(9;22)(q34.1;q11.2)/BCR::ABL1; t(8;16)(p11.2;p13.3)/KAT6A::CREBBP; inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/ GATA2, MECOM(EVI1), t(3q26.2;v)/MECOM(EVI1)-rearranged; -5 or del(5q); -7; Complex karyotype, monosomal karyotype * 2022 ELN adverse risk mutations: Any one of the following mutations: Mutated TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2 * Additional mutations associated with acquired resistance to venetoclax: Mutated NRAS, KRAS, FLT3 ITD/TKD * ECOG performance status ≤2 (see Appendix A) * Participants must meet the following organ function as defined below: * Direct bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then \< 3 x ULN) * AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN * creatinine clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula * oxygen saturation ≥ 90% on room air * left ventricular ejection fraction ≥ 40% * Negative pregnancy test for women of childbearing potential only. * The effects of CIML NK cells and IL-2 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and until 4 months after the last IL-2 dose administration. * Participants with current symptoms of cardiac disease should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better. * Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. * Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged) * Subjects must be able to swallow pills. * No laboratory evidence of ongoing hemolysis in the opinion of investigator (demonstration of hemolysis should include a haptoglobin level that is below assay). Exclusion Criteria for Trial Enrollment (Registration visit) * Participants are excluded if they received prior allogeneic stem cell transplant ≤ 6 months ago or require immunosuppressive therapy for active GVHD, received prior donor lymphocyte infusion (DLI) ≤ 2 months ago, or received prior organ transplant or donor lymphocyte infusion (DLI), CAR-T cell or NK cell therapy at any time. * Persisting Grade \> 2 non hematologic toxicity related to prior therapy is excluded; however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable. * Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease requiring any steroids \>\> the equivalent dose of 10 mg of prednisone or other immunosuppressive therapies at the time of this registration visit (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's Granulomatosis\]) and motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Patients with Hashimoto's thyroiditis are eligible to go on study. * Pregnant women are excluded from this study because of the unknown teratogenic risk of CIML NK cells and IL-2 and with the potential for teratogenic or abortifacient effects by Flu/Cy chemotherapy regimen. Breastfeeding should also be discontinued if the mother is treated on this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CIML NK cells and IL-2. * HIV-positive participants are ineligible because of the potential for pharmacokinetic interactions with anti-retroviral agents used in this study. In addition, these participants are at increased risk of lethal infections when treated with marrow suppressive therapy. * Individuals with active uncontrolled hepatitis B or C are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after conditioning therapy. Hepatitis B and C testing should be performed as needed. * Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1. History of other malignancy and have had complete remission of disease for at least 2 years; 2. Diagnosed and treated within the past 2 years for: nonmetastatic melanoma, surgically resected (not needing systemic chemotherapy) squamous cell carcinoma of skin and nonmetastatic prostate cancer not needing systemic chemotherapy. * History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to IL-2 or other agents used in study. * Participants who are receiving any other investigational agents for AML, MDS/AML, or GVHD. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Prior history of Grade 2 or higher hemolytic anemia (≥ 2g decrease in hemoglobin plus laboratory evidence of hemolysis) from any cause. Inclusion Criteria to Start Investigational Treatment Plan (On Treatment visit) * Patient was eligible for protocol per section 3.1. * Participants must undergo a repeat bone marrow biopsy at Visit #2 to determine one of two scenarios below. * MRD+ remission: Repeat bone marrow biopsy at this time shows a complete remission (CR) or complete remission with incomplete count recovery (CRi) or morphologic leukemia free state (MLFS) (\< 5% blasts) but with presence of measurable residual disease (MRD+). MRD can be determined by either flow cytometry, next generation sequencing or PCR. Patients with only persistent DNMTA, TET2 or ASXL1 mutations will not qualify as MRD+ as these DTA mutations without other comutations are associated with clonal hematopoiesis. Any prior treatment history is permitted. OR * Relapsed/refractory oligoblastic AML (5-19% blasts): Repeat bone marrow biopsy at this time shows 5-19% residual myeloblasts in the bone marrow by either bone marrow aspirate or core biopsy. Additionally, the participant must fulfill one of the following criterion for relapsed/refractory disease. 1. Relapsed disease: Defined as the appearance of 5% or greater myeloblasts in the bone marrow or peripheral blood after achieving a CR, CRh, or CRi. There are no stipulations on prior therapies. 2. Refractory disease: Defined as failure to achieve a CR, CRh, or CRi after ≥ 1 cycle of intensive chemotherapy with a cytarabine-containing regimen (e.g., 7+3, MEC, HIDAC, reinduction chemotherapy such as 5+2, etc.), ≥ 2 cycles of Ven/HMA or a targeted therapy (for FLT3, IDH1/2, NPM1, or KMT2Ar), or ≥ 4 cycles of HMA monotherapy. So long as these criteria are met, participants with relapsed/refractory AML may have received any bridging therapy between Visit #1 and Visit #2 per clinicians' discretion. * Confirmed haploidentical or fully HLA-matched related donor that is willing and eligible for non-mobilized collection must be confirmed by the time of Visit #2. Search for this donor should have commenced after Visit #1 and be completed during the time in between Visit #1 and Visit #2 (see Textbox 1). * ECOG performance status ≤2 (see Appendix A) * Participants must meet the following laboratory and organ function as defined below: * Direct bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then \< 3 x ULN) * AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN * creatinine clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula * oxygen saturation ≥ 90% on room air * No significant change in clinical status that would, in the opinion of the investigator, increase the risk of adverse events associated with CIML NK infusion, (e.g., symptomatic congestive heart failure, unstable angina, cardiac arrhythmia) * Negative pregnancy test for women of childbearing potential only. * Subjects must be able to swallow pills. Exclusion Criteria to Start Investigational Treatment Plan (On Treatment visit) * No live vaccines within the last 6 months. * No ongoing or active infections. * Moderate/strong inhibitors of CYP3A except of antifungal medications (such as posaconazole, voriconazole) which the patient is on and the dose of venetoclax has already been adjusted. These are excluded as moderate/strong inhibitors of CYP3A induce higher drug levels of venetoclax which in turns carry the risk of CIML NK cell elimination. * The presence of donor-specific antibodies (DSAs) with mean fluorescence intensity (MFI) \>1000 using a standard assay in subjects who do not receive a desensitization protocol prior to and during stem cell transplant. Criteria to Receive Lymphodepletion on Day -5 * Adequate organ function within 24 hours of lymphodepletion as defined below: * Direct bilirubin: ≤ 1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then \< 3 x ULN) * AST (SGOT)/ALT (SGPT): ≤ 3 x institutional ULN * No significant change in clinical status that would, in the opinion of the investigator, increase the risk of adverse events associated with lymphodepletion, (e.g., significant hypoxemia, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia) * No evidence of active, uncontrolled infection. Patients receiving antibiotics for an infection may be treated if they have clinically responded to antibiotics. These cases should be reviewed with the study PI before proceeding. * No live vaccines within the last 6 months Criteria to Receive CIML NK Infusion * Adequate organ function within 24 hours of NK cell infusion as defined below: * Direct bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then \< 3 x ULN) * AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN * Creatinine clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula * No Grade ≥3 non-hematologic toxicities of cyclophosphamide and fludarabine conditioning (except for Grade 3 nausea, vomiting, diarrhea, or constipation). * No significant change in clinical status that would, in the opinion of the investigator, increase the risk of adverse events associated with CIML NK infusion, (e.g., significant hypoxemia, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia) * No evidence of active, uncontrolled infection. Patients receiving antibiotics for an infection may be treated if they have clinically responded to antibiotics. These cases should be reviewed with the study PI before proceeding. * No systemic steroid therapy (oral or IV) of \> 10mg prednisone or equivalent dose of other steroid agent on the day of NK cell infusion If any of the above criteria are noted at these time points, please discuss with PI the benefits/risks of proceeding with the CIML infusion and document rationale for course of action taken in study regulatory binder. However, patient may still receive CIML NK infusion if relevant parameters are reviewed and both PI and IND holder agree with proceeding. If inclusion/exclusion criteria are not met on planned day of CIML NK cell infusion, the NK cell infusion may be delayed for up to 24 hours to enable inclusion criteria to be met. Criteria to Receive Venetoclax * Adequate organ function within 24 hours of venetoclax initiation as defined below: * Total bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then \< 3 x ULN) * AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN * No Grade ≥3 non-hematologic toxicities of cyclophosphamide and fludarabine conditioning (except for Grade 3 nausea, vomiting, diarrhea, or constipation). * No significant change in clinical status that would, in the opinion of the investigator, increase the risk of adverse events associated with venetoclax administration, (e.g., significant hypoxemia, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, severe ongoing tumor lysis syndrome) * No evidence of active, uncontrolled infection. Patients receiving antibiotics for an infection may be treated if they have clinically responded to antibiotics. These cases should be reviewed with the study PI before proceeding. * No live vaccines within the last 6 months