Pacritinib With Aza for Upfront Myelodysplastic Syndrome

Inclusion Criteria: * Individuals must meet all of the following inclusion criteria to be eligible to participate in the study: 1. Patients must have histologic evidence of intermediate to high-risk myelodysplastic syndrome defined as having an IPSS-M score of moderate low, moderate high, high or very high risk. This will be assessed based on evaluations performed prior to screening for trial. Of note, the most recent evaluation pre-trial may be used which does not have to necessarily be at diagnosis. 2. Subjects must have recovered from the toxic effects of any prior chemotherapy to ≤ Grade 1 (except alopecia). 3. Required screening visit laboratory values: CrCL ≥45; total bilirubin \<2xULN except for patients with known Gilbert's disease; SGPT (ALT) ≤2xULN, PTT ≤1.5xULN. 4. Negative pregnancy test for women with child-bearing potential at screening visit. 5. Initial screening baseline QTc ≤480ms. 6. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing. 7. Patients must have an absolute neutrophil count of ≥750 to enroll in study, this must be achieved without the addition of growth factor medication. Exclusion Criteria: * An individual who meets any of the following criteria will be excluded from participation in this study: 1. Any prior exposure to a hypomethylating agent (azacitidine or decitabine) 2. Any prior exposure to JAK2 inhibitor therapy (ie ruxolitinib or prior pacritinib therapy) 3. Any exposure within the past seven days of initiation of study treatment to a strong CYP3A inhibitor/inducer. 4. Subjects must not be receiving any chemotherapy agents (except hydroxyurea) within the past thirty days. 5. Subjects must not be receiving growth factors (erythropoietin mimetics, granulocyte stimulating factor mimetics, thrombopoietin mimetics) for two weeks prior to enrollment bone marrow. Subjects may not receive growth factors for the duration of this study. 6. Subjects with a "currently active" second malignancy, other than curatively treated non-melanoma skin cancer, carcinoma in situ of the cervix, resected incidental prostate cancer (staged pT2 with Gleason Score ≤ 6 and postoperative PSA \<0.5 ng/mL), or other adequately treated carcinoma-in-situ are eligible. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 1 year. 7. Subjects with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure (NYHA class 2), myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible. 8. Bleeding event grade \>=2 (CTCAE 5.0) within prior three months unless provoked (e.g., by surgery or trauma) 9. Use of anticoagulant or antiplatelet agents within fourteen days prior to day one with the exception of low dose aspirin (81mg daily). 10. Subjects with other severe concurrent disease which in the judgment of the investigator would make the patient inappropriate for entry into this study are ineligible. 11. Active or uncontrolled diarrhea or constipation. 12. Subjects must not have evidence of active disease in the CNS. 13. Subjects must not have received any investigational agents within fourteen days or five half-lives (whichever is longer) of study entry. 14. Subjects must not be pregnant or breastfeeding. Pregnancy tests must be obtained for all females of child-bearing potential. Pregnant or lactating patients are ineligible for this study due to the unknown human fetal or teratogenic toxicities of pacritinib. Males or women of childbearing potential may not participate unless they have agreed to use a highly effective contraceptive method (defined in section 10.4.4). 15. Subjects who have uncontrolled infection are not eligible. Patients must have any active infections under control. Fungal disease must be stable for at least two weeks before study entry. 16. Subjects with bacteremia must have documented negative blood cultures prior to study entry. 17. Subjects who are currently candidates for allogeneic transplantation, have a suitable donor, and are willing to undergo transplantation prior to study start. 18. Subjects who cannot hold a medication, over the counter, or supplemental product that in the investigator's opinion may put the patient at increased harm.