This is a single-arm, multi-center Phase II trial using IL-15 super-agonist complex (N-803 formerly known as Alt-803) maintenance after allogeneic hematopoietic cell transplant (alloHCT) for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS).

Inclusion Criteria:

1. Diagnosis of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) for whom an allogeneic hematopoietic stem cell transplant using a reduced intensity conditioning is planned or has been performed and patient is prior to day 60 post-transplant.

2. Able to begin study treatment between day +42 and day +60 after the transplant and meets the following transplant related requirements:

   • Sustained neutrophil (ANC > 1000/mcL) and platelet (> 30,000/mcL) engraftment
   • >50% donor myeloid and lymphoid chimerism blood or bone marrow on most recent bone marrow (BM) evaluation
   • No evidence of recurrent disease on most recent bone marrow evaluation (day 21 or 28 post-transplant is acceptable)
   • No morphologic evidence of relapse (< 5% bone marrow blasts) on most recent BM evaluation (Day 21 or 28 post-transplant is acceptable)
   • Being followed in the outpatient setting (not an inpatient)
   • No plan of giving other anti-cancer treatment directed at diseases under study (i.e. maintenance therapy [e.g. sorafenib for FLT3m+ AML or hypomethylating therapy], additional therapy for MRD)

3. If acute GVHD is present it must be clinically improving on topical steroids and/or on low dose systemic steroids (≤ 0.3 mg/kg/day prednisone) and with clinical stability for at least 1 week prior to determination of eligibility. GVHD prophylaxis will be continued per individual institutional standard practice

4. One of the following donor graft sources used for the transplant:

   • Group 1: sibling donor
   • Group 2: haploidentical donor [with post-transplant cyclophosphamide]
   • Group 3: unrelated donor
   • Group 4: unrelated umbilical cord blood

5. Karnofsky performance status ≥ 70%

6. Adequate organ function within 14 days of study enrollment defined as:

   • Renal: serum creatinine: ≤ 2.0 mg/dL
   • Hepatic: SGOT ≤ 3 x upper limit of institutional normal (ULN)

7. Sexually active females of child-bearing potential and males with partners of child bearing potential must agree to use effective contraception during therapy and for 4 months after completion of therapy.

8. Voluntary written consent prior to the performance of any research related procedures

Exclusion Criteria:

1. Prior N-803 (previously known as ALT-803)
2. Pregnant or breastfeeding - N-803 is an investigational agent. Women of child bearing potential must have a negative pregnancy test at screening.
3. Class II or greater New York Heart Association Functional Classification criteria or serious cardiac arrhythmias likely to increase the risk of cardiac complications of cytokine therapy (e.g. ventricular tachycardia, frequent ventricular ectopy, or supraventricular tachyarrhythmia requiring chronic therapy)
4. Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a QTc interval > 500 milliseconds)
5. Active uncontrolled bacterial, fungal, or viral infections - all prior infections must have resolved following optimal therapy and must be afebrile for at least 24 hours at time of enrollment.
6. Active autoimmune disease requiring immunosuppressive therapy (GVHD prophylaxis is permitted per institutional practice)
7. History of severe asthma and currently on chronic medications (mild asthma requiring inhaled steroids only is eligible)
8. Received any investigational agent within the 14 days before the start of study treatment (1st dose of N-803)

12 months