To assess safety and tolerability at increasing dose levels of IO-202 in successive cohorts of participants with AML with monocytic differentiation and CMML in order to estimate the maximum tolerated dose (MTD) or maximum administered dose (MAD) and select the recommended Phase 2 dose (RP2D)

This is a Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Intravenously Administered IO-202 and IO-202 + Azacitidine ± Venetoclax in Acute Myeloid Leukemia (AML) Patients with Monocytic Differentiation and in Chronic Myelomonocytic Leukemia (CMML) Patients

Inclusion Criteria:

1. Patients must be ≥18.

2. For the Part 1 Dose-Escalation Phase, patients must be diagnosed with the following:

   1. Relapsed or refractory AML with myelomonocytic or monoblastic/monocytic differentiation according to the World Health Organization 2016 criteria and has failed treatment with available therapies known to be active for AML.
   2. Relapsed or refractory CMML and has failed treatment with available therapies known to be active for CMML

3. Part 2 Expansion Phase:

   1. Relapsed or refractory LILRB4high AML with myelomonocytic or monoblastic/monocytic differentiation and has failed treatment with available therapies known to be active for AML.
   2. Hypomethylating-agent naive CMML regardless of LILRB4 expression levels.
   3. Newly diagnosed high LILRB4 expression monocytic AML patients considered to be ineligible for standard induction therapy.

4. Patients must be amenable to serial BM aspirates/biopsies and peripheral blood sampling during the study.

5. Patients must be able to understand and willing to sign an informed consent. A legally authorized representative may consent.

6. Patients must have an ECOG performance status of 0 to 2

7. Patients must have adequate hepatic function

8. Patients must have adequate renal function

9. Patients must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer.

10. Patients must be off systemic calcineurin inhibitors for at least 4 weeks prior to study drug treatment.

11. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy.

Exclusion Criteria:

1. Patients who have previously received a monoclonal antibody therapy targeting LILRB4.
2. Patients who have undergone HSCT within 60 days of the first dose of IO-202.
3. Patients who received systemic anti-cancer therapy or radiotherapy <7 days prior to their first day of study drug administration (Hydroxyurea or leukapheresis is allowed up to 24 hours prior to the first dose.
4. Patients who received an investigational agent <7 days prior to their first day of study drug administration.
5. Patients for whom potentially curative anti-cancer therapy is available.
6. Patients who are pregnant or breastfeeding.
7. Patients with uncontrolled, active infection.
8. Patients with known hypersensitivity to any of the components of the IO-202 formulation.
9. Patients with known pulmonary lesions and/or history of pneumonitis or interstitial lung disease.
10. Active known malignancy.
11. Patients with New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF) or left ventricular ejection fraction (LVEF) <40%.
12. Ongoing cardiac dysrhythmias Grade 2 or higher per of NCI CTCAE, Version 5.0, Grade ≥2.
13. Known or suspected hypersensitivity to recombinant proteins.
14. Known active bacterial, viral, and/or fungal infection.
15. Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol.
16. Patients with clinical signs and/or symptoms suggesting active, uncontrolled central nervous system (CNS) leukemia or known active, uncontrolled CNS leukemia.
17. Patients with immediately life-threatening, severe complications of leukemia.
18. Donor Lymphocyte Infusion within 30 days prior to first IO-202 administration.
19. Current active treatment in another interventional therapeutic clinical study.
20. Chronic systemic corticosteroid treatment with a dose of >10 mg prednisone/day or dose equivalent.
21. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
22. Acute Promyelocytic Leukemia patients or patients with known Philadelphia chromosome (Ph+) positive AML or chronic myelogenous leukemia (CML) blast crisis.
23. Hyperleukocytosis (leukocytes ≥25 x 10e9/L) at first dose of IO-202.