Inclusion Criteria:

1. Adults: ≥18 years of age
2. Diagnosis of either:

1. Newly diagnosed or relapsed/refractory AML who have received at least 2 cycles of azacitidine and venetoclax
2. Relapsed/ refractory (R/R) MDS who have received at least 2 prior cycles of azacitidine and venetoclax or single agent hypomethylating agent for at least 4 cycles
3. Relapsed/refractory (R/R) MDS/MPN overlap syndromes like CMML who have received at least 2 prior cycles of azacitidine and venetoclax or single agent hypomethylating agent for at least 4 cycles
3. For patients with targetable mutations (IDH1, IDH2, KMT2A, or FLT3): Receipt of and/or decision not to receive associated inhibitor.
4. Patients with R/R MDS or R/R MDS/MPN overlap syndromes must have at least one of the following:

1\) Bone marrow blasts \>5% and higher than previous evaluation by at least 5% 2) Progression to AML (≥20% blasts) 3) Appearance of previously absent leukemic blasts in peripheral blood 4) Absolute neutrophil count \<1 x 109/L and 50% below best unsupported on-study value 5) Platelet count \<100 x 109/L and 50% below best unsupported on-study value 6) Hemoglobin \<11g/dL, and ≥2 g/dL reduction from best unsupported on-study value 7) Increase of the volume of transfused red blood cells by more than 30% in an 8-week period 8) Increase of the number of transfused platelet units by more than 30% in an 8-week period In the case of criteria 4-8 above, no reasonable alternative explanation such as drug toxicity should be identified.

5\. Patients with AML must have:

1. Persistent or recurrent MRD positivity defined by presence of blasts ≥5% and \<20% AND/OR disease detected by multiparametric flow cytometry (MFC) at a level of ≥0.1%, AND/OR persistent genomic mutations other than those found most with CHIP (DNMT3A, ASXL1, TET2) AND/OR persistent cytogenetic abnormalities related to underlying myeloid neoplasm
2. Residual blasts must be positive for CD33 expression at any level
3. Myeloblasts must be \<20%

6\. Left Ventricular Ejection Fraction (LVEF) ≥ 45% at rest (MUGA or echocardiogram)

7\. Performance status ≤ 2 (ECOG Scale)

8\. Females of childbearing potential and males must agree to use an effective method for contraception for the duration of the treatment with study drug plus 90 days (duration of sperm turnover). Males must also abstain from sperm donations during study treatment and for at least 90 days after the last dose of study drug.

9\. Ability to provide informed consent and provision of written informed consent In order to be eligible to participate in the dose expansion portion of this study, an individual must meet all criteria that apply to the R/R MDS or R/R AML population (Newly diagnosed patients and patients with MDS/MPN overlap syndromes are not eligible for the expansion phase of the study).

In order to be eligible to participate in the dose expansion portion of this study, an individual must meet all criteria that apply to the R/R MDS or R/R AML population (Newly diagnosed patients and patients with MDS/MPN overlap syndromes are not eligible for the expansion phase of the study).

Exclusion Criteria:

1. Pregnancy or lactation
2. Prior treatment with anti-CD33 therapy
3. Patients who are being actively considered for stem cell transplant. This does not exclude patients that may be eligible for stem cell transplant at some future (undetermined) date.
4. Clinically significant organ dysfunction, defined as any of the following:

* AST or ALT \>3x the upper limit of normal (ULN)
* Total bilirubin \>1.5x the ULN, unless due to ongoing hemolysis or Gilbert's syndrome, in which case \> 3.0 mg/dL
* Absolute lymphocyte count (ALC) \< 300 lymphocytes/microliter
* Creatinine clearance \<30 mL/min
* Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of clinical improvement despite antimicrobial treatment).
5. Patients that are platelet refractory with a platelet level of \<30,000 platelets/microliter
6. Known human immunodeficiency virus (HIV) with detectable viral load.
7. Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection

a. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.
8. Patients with a prior or concurrent malignancy whose natural history or treatment is anticipated to interfere with the safety or efficacy assessment of the investigational regimen (according to the treating investigator).
9. Treatment with any antileukemic agents or chemotherapy (other than hypomethylating agents or venetoclax) agents in the last 7 days or 5 half-lives (whichever is sooner) before study entry.
10. Known allergy to hypomethylating agents