Leukemia Clinical Trials

• 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).

• 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.

∙ 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.

‣ 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.