Inclusion Criteria:

1. Must be ≥ 18 years of age at the time of signing the Informed Consent Form (ICF); must voluntarily sign an ICF; and must be willing and able to meet all study requirements.
2. Must have morphologically confirmed diagnosis of MDS/MPN, excluding JMML, in accordance with WHO (2016) diagnostic criteria (Appendix 1, Section 12.1).
3. Treatment-naïve patients (patients who have had no prior disease-modifying therapy) may enroll in any AM-001 Arm that is open to accrual in phase 1 or phase 2. Treatment-naïve patients may have received recombinant erythropoietin, danazol, hydroxyurea or anagrelide, which are not considered to be disease-modifying therapy for the purpose of this study.

4. After an appropriate wash-out period, patients who have failed (or were intolerant to) prior therapy with a regimen(s) containing a DNMTi may enroll in any Arm in phase 1b or any Arm which has met the criterion of the first Simon's Stage and are open to accrual in the second Simon's Stage in phase 2 (Error! Reference source not found.). Except in the first stage of the phase 2, there are no limits on number of prior therapies if the patient meets all other eligibility criteria. Previously treated patients include:

   • Patients treated with DNMTi therapy prior to enrollment in AM-001 who failed to achieve a complete remission, per the MDS/MPN IWG response criteria, after at least 4 cycles of DNMTi therapy
   • Patients enrolled in AM-001, or patients treated off-study with a regimen containing a DNMTi, who have definitive disease progression as defined in the protocol after at least 2 cycles of the prior therapy-this includes patients who fail to achieve a response with clearly progressive disease and patients who achieve an initial response who then lose that response;
   • Patients enrolled in AM-001 who have stable disease as best response at the second response evaluation after 6 cycles of the prior AM-001 therapy;
   • Patients treated on AM-001 who had and recovered from an adverse event that precludes further therapy on that Arm; after recovery from a toxicity that is likely to be related to ASTX727, enrollment in another AM-001 may occur provided that dose modifications are made as appropriate.
5. Must be willing to undergo bone marrow biopsy with aspiration during screening and bone marrow aspiration with tissue collection for disease assessment and correlative studies periodically throughout the trial.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
7. Life expectancy of at least 3 months, as assessed by the treating physician.
8. For previously treated patients, recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia.

9. Must have adequate hepatic and renal function during screening as demonstrated by:

   • ALT (SGPT) and AST (SGOT) ≤ 3x the institutional upper limit of normal (ULN);
   • Total bilirubin ≤ 1.5x ULN or ≤ 2x ULN, if upon judgment of the treating investigator the elevated bilirubin is due to extramedullary hematopoiesis related to the underlying MDS/MPN or to Gilbert's disease;
   • Calculated creatinine clearance (CrCl) ≥60 mL/min. For dose modification purposes in Arm B, CrCl should be calculated using the Cockcroft-Gault equation. For patients with renal impairment entering Arm B (ASTX727 + ruxolitinib), specific dose modifications per the section 6.5.4 will apply.

Exclusion Criteria:

1. Patients should be excluded from any treatment Arm that includes a novel targeted agent to which they have had previous exposure. Novel targeted agents in this study currently include itacitinib (INCB039110) and ruxolitinib (RUX) only, currently. Patients who have had prior exposure to ASTX727 therapy are not excluded, provided they meet all other eligibility criteria.
2. Prior receipt of any investigational study drug, including treatment on any prior AM-001 Arm, within 30 days or 5 half-lives (whichever is shorter) before receiving the first dose of study drug in an Arm of AM-001, except if approved by the medical monitor.
3. Prior receipt of any systemic antineoplastic therapy, including but not limited to prior DNMTi therapy, standard induction or cytotoxic chemotherapy (excluding hydroxyurea), or approved targeted agent within 21 days or 5 half-lives (whichever is shorter) before receiving the first dose of study drug in an Arm of AM-001.
4. Known hypersensitivity to decitabine and ruxolitinib.
5. Transformation to acute myeloid leukemia (e.g., >20% myeloid blasts in bone marrow or >20% circulating blasts in peripheral blood).
6. Organ transplant recipients including allogeneic hematopoietic stem cell transplant.
7. History of clinically significant or uncontrolled cardiac disease, including recent history (within 6 months) of unstable angina, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, or clinically significant uncontrolled arrhythmia. Patients with history of atrial tachycardia and/or bradycardia that is well-controlled with medical management and/or pacemaker for at least 1 month before the first dose of study drug will be allowed.
8. History of thromboemobolic events (such as deep vein thrombosis, pulmonary embolism, stroke, myocardial infraction) in the 6 months prior to study entry.
9. Active HBV or HCV. Participants with positive total HBc antibody or positive HCV antibody must have negative viral load for HBV and HCV at screening.
10. Known HIV seropositive status. For participants with unknown HIV status, HIV testing will be performed at screening.
11. History of abnormal electrocardiogram (ECG) or presence of abnormal screening ECG that, in the investigator's opinion, is clinically significant and contraindicated for clinical study. Corrected QT interval (QTc), as corrected by Fredericia, on screening ECG >500 milliseconds is excluded, unless there is concomitant right bundle branch block (RBBB) or concomitant left bundle branch block (LBBB) with a pacemaker.
12. Any known contraindications to the use of ASTX727.
13. Any sign of active and clinically significant bleeding.
14. Other active malignancy, not including localized non-melanoma skin cancer, cervical carcinoma in situ, breast ductal carcinoma in situ of the breast, or localized prostate cancer controlled with hormone therapy. Patients with history of other cancers should be free of disease without ongoing anti-neoplastic therapy for at least 2 years.
15. Receipt of wide-field radiotherapy (including therapeutic radioisotopes) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study medications; or has not recovered from side effects of such therapy.
16. Patients who require continuation of a prohibited concomitant medication (Section 6.6) for which no alternative therapy or allowable substitute is available.
17. Active, uncontrolled infection. Patients with infection that is under control with active treatment are eligible.
18. Major surgery requiring general anesthesia within 4 weeks prior to starting study treatment. (Placement of a central line or port-a-catheter is acceptable within this time frame and does not exclude the patient.)
19. Women who are pregnant or lactating.
20. Subjects who expect to conceive or father children within the projected duration of the study and/or who are unwilling to use highly effective methods of contraception throughout the duration of the study, starting with the screening visit through the end of treatment visit. For women of child-bearing potential (WOCBP), a negative urine pregnancy test at screening and immediately prior to initiating treatment on any AM-001 treatment Arm (Cycle 1 Day 1) is required.
21. Any concurrent serious or unstable medical or psychiatric condition that in the investigator's opinion would jeopardize the patient's ability to provide informed consent or to comply with the protocol.
22. Any psychological, familial, geographical or sociological condition that in the investigator's opinion would jeopardize the patient's ability to comply with the protocol.