This study is being done to evaluate if the combination of ASTX727 and venetoclax works better than ASTX727 alone at decreasing the signs and symptoms of bone marrow cancer, known as myelodysplastic/myeloproliferative neoplasm (MDS/MPN).

We are doing this study because we want to find out if this approach is better or worse than the usual approach for bone marrow cancer called chronic myelomonocytic leukemia (CMML) or a less common form called non-CMML MDS/MPN. The usual approach is defined as care most people get.

ASTX727 (a combination of cedazuridine and decitabine) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic myelomonocytic leukemia (CMML), but is not approved for non-CMML MDS/MPN. The combination of decitabine and venetoclax is an FDA approved regimen for the treatment of another related disease called acute myeloid leukemia (AML). ASTX727 given in combination with venetoclax is not approved for CMML or non-CMML MDS/MPN.

Participants will be randomly assigned to receive either ASTX727 alone or the combination of ASTX727 and venetoclax. Randomization means there is an equal chance of being assigned to either treatment group.

One group will receive ASTX727 orally once daily on days 1-5 of each cycle and venetoclax orally on days 1-14 of each cycle. Cycles repeat every 28 days until there is disease progression or unacceptable side effects.

The other group receive ASTX727 orally on days 1-5 of each cycle. Cycles repeat every 28 days until there is disease progression or unacceptable side effects. Patients who do not have response to treatment may cross over to the combination treatment arm.

All participants will undergo bone marrow biopsy and aspiration and collection of blood samples throughout the study and undergo buccal swab sample collection at screening.

After completing treatment, participants will continue to be followed by the study team every 3 months for 2 years after treatment. After that, they will check in every 6 months for 3 years.