The purpose of this research study is to look at how safe and useful a drug called azacitidine in combination with a drug called venetoclax, is in people with accelerated or blast phase BRC-ABL negative myeloproliferative neoplasms.

All participants in this study will receive azacitidine and venetoclax.

This study will be done in multiple stages:

Safety Run-In Period - 7 participants will receive the study drugs to ensure that the combination is safe and tolerable.

Stage 1 - About 15 participants will receive the study drugs and will be evaluated to see whether they respond to the study drugs.

Stage 2 - If enough participants in Stage 1 respond to the study drugs, then Stage 2 will begin. During this stage, an additional 25 participants will take part in the study to further see if participants respond to the study drugs.

Inclusion Criteria:

• Ability to voluntarily provide written informed consent.
• Documented diagnosis per World Health Organization (WHO) 2016 criteria of BCR-ABL negative myeloproliferative neoplasms (MPN).
• Documented MPN transformation to accelerated phase (AP) or blast phase (BP) without prior blast reduction therapy for their AP/BP disease.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Adequate organ function.
• Must practice at least one reliable method of birth-control starting at least on cycle 1 day 1 until at least 90 days after the last dose of study drug.
• Female participants of childbearing potential must have a negative serum pregnancy test within 14 days prior to cycle 1 day 1.

Exclusion Criteria:

• History of allogeneic stem cell transplant for MPN.
• Previous treatment with venetoclax, navitoclax, azacytidine or other hypomethylating agents (HMA).
• White blood cell count >25 x 10^9/L.
• Current enrollment in another interventional study.
• Presence of any active uncontrolled infection such as bacterial or fungal infections progressing despite adequate antimicrobial treatment.
• Myocardial infarction in the preceding 3 months.
• Active human immunodeficiency virus (HIV), hepatitis B (HBV), hepatitis C (HCV) infection.
• History of active malignancy in the previous 2 years.
• Any psychiatric illness or social circumstances or significant co-morbid conditions that may compromise study participation.
• Pregnant or breastfeeding women.
• Patients with known central nervous system (CNS) involvement with acute myeloid leukemia (AML) or CNS extramedullary hematopoiesis.
• Patients with t (15;17)
• Patients who have received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
• Active COVID-19 infection.
• History of prior blast-reduction therapy for AP/BP-MPN.
• Preceding history MDS, chronic myelomonocytic leukemia (CMML), and other myelodysplastic syndromes (MDS)/MPN overlap syndromes.