A Phase 1 Trial of CIML NK Cell Infusion for Myeloid Disease Relapse After Hematopoietic Cell Transplantation

1. Inclusion Criteria: 1.1 Relapse or post-transplant persistence of AML, MDS (including JMML) or MPN (CMML, myelofibrosis or MDS/MPN). Disease relapse or persistence will be defined as any measurable disease by morphology, flow-cytometry, validated tests for minimal residual disease or disease-defining mutations in the bone marrow, or non-immune privileged extramedullary sites. 1.2 Persistence of disease within 4 weeks before planned NK cell infusion and at least 2 weeks after completion of immune suppression taper as long as it is \> 2 months after stem cell transplantation for both adult and pediatric patients. If 2 weeks after completion of the immune suppression taper is still within 2 months of the most recent stem cell transplant, then chemotherapy with Fludarabine/Cyclophosphamide would need to start no earlier than at least 2 months after the transplant. For adults, disease persistence after a second transplant is allowed as long as the most recent transplant was a haploidentical or HLA matched stem cell transplant. In the pediatric cohort, disease persistence or recurrence after a second transplant is allowed as long as the most recent transplant was a haploidentical or matched related donor SCT. 1.3 Available original donor (same donor as used for the most recent haploidentical or HLA matched stem cell transplant for adults, or for the most recent matched related donor or related haploidentical donor for pediatrics) that is willing and eligible for non-mobilized collection. 1.4 Age ≥12 years. 1.5 ECOG performance status ≤2. For For patients in the pediatric cohort, this corresponds to a Lansky (patients \<16 years) or Karnofsky (≥16years) performance status of ≥50. 1.6 T cell chimerism ≥20% donor-derived within the 4 weeks prior to cell infusion. 1.7 Patient with ≤80% bone marrow involvement within 4 weeks prior to cell infusion. Medications like hydroxyurea, decitabine or cytarabine are allowed to control rising blasts between study enrollment and cell infusion. 1.8 No systemic corticosteroid therapy for GVHD (≤ 5mg of prednisone or equivalent dose of systemic steroids for non-GVHD, non-autoimmune indications are allowed) for at least 4 weeks prior to cell infusion. Patients on systemic GVHD prophylaxis medications such as tacrolimus or sirolimus need to be off these medications for at least 4 weeks prior to cell infusion. 1.9 No other systemic medications/treatments (e.g. ECP) for GVHD for at least 4 weeks prior to cell infusion. 1.10 Ability of the patient or legal guardian to understand and the willingness to sign a written informed consent document. 1.11 Adequate organ function within 2 weeks of NK cell infusion 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 * Serum creatinine ≤2.0mg/dL * O2 saturation: ≥90% on room air * LVEF \>40%. If there is no clinical evidence of a change in cardiovascular function from the time of pre-transplantation ECHO, then there is no need to repeat it. Otherwise, an ECHO will need to be repeated within 2 weeks of NK cell infusion. 1.12 Negative pregnancy test for women of childbearing potential only. 1.13 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, for the duration of study participation, and 4 months after the last IL-2 dose administration. 2. Exclusion Criteria: 2.1 Extramedullary relapse involving immuno-privileged sites (e.g. CNS, testes, eyes). Other sites of extramedullary relapse (e.g. leukemia cutis, granulocytic sarcoma) are acceptable. 2.2 Participants who have had investigational agents within 4 weeks prior to cell infusion (6 weeks for nitrosoureas or mitomycin C), or immunotherapy within 8 weeks prior, or those who have not recovered from adverse events due to agents administered more than 4 weeks prior or standard chemotherapy administered more than 14 days ago. Use of hydroxyurea, hypomethylating agents, low-dose cytarabine or venetoclax to control counts within 4 weeks prior to cell infusion is permitted with study PI approval but would need to be stopped 1 day prior to administration of Fludarabine and Cyclophosphamide preceding the NK cell infusion (provided that there are no ongoing AEs attributed to these agents that would preclude start of lymphodepletion in the view of the investigator). Patients on standard of care FLT-3, IDH1, and IDH2 inhibitors can stay on this treatment. Therapy with BCR-ABL inhibitors or bcl-2 inhibitors must be stopped 2 weeks before NK cell infusion and may be resumed after the end of the DLT period. 2.3 Prior history of Donor Lymphocyte Infusion (DLI) within 8 weeks of CIML NK infusion. DLI that was given before this time period and that did not result in any GVHD requiring systemic treatment is not an exclusion criterion. 2.4 Prior history of severe (grade 3 or 4) acute GVHD, or ongoing active GVHD requiring systemic treatment. 2.5 Solid organ transplant recipient. Prior allogeneic HLA matched or mismatched stem cell transplant is allowed in the pediatric cohort. Prior HLA matched related donor or HLA matched unrelated donor stem cell transplant is allowed in the adult cohort. 2.6 History of allergic reactions attributed to compounds of similar chemical or biologic composition to IL-2 or other agents used in study. 2.7 Autoimmune disease: Patients wi