Inclusion Criteria:

• Able to understand and comply with the study procedures, understand the risks involved in the study, and provide legally effective informed consent before the first study-specific procedure.
• Men or women ≥ 18 years with IPSS low-risk or Int-1 MDS (all subjects). Subjects must have had at least 1 of the following disease-related criteria during the 8 weeks before randomization:
  • RBC transfusion dependence of 2 or more units of RBCs or Hb of < 8.5 g/dL in at least 2 blood counts prior to randomization;
  • ANC of <0.5 ×10^9 /L in at least 2 blood counts prior to randomization;
  • Platelet counts of < 50×10^9 /L in at least 2 blood counts prior to randomization.
• ECOG performance status of 0 to 2.
• Adequate organ function defined as follows:
  • Hepatic: Total or direct bilirubin ≤ 2 × upper limit of normal (ULN); aspartate aminotransferase/ serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 5 × ULN;
  • Renal: serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance or glomerular filtration rate ≥ 50 mL/min.
• Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]*; CTFG 2020) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice 2 highly effective contraceptive measures of birth control (as described below) and must agree not to become pregnant for 6 months after completing treatment; men with female partners of child-bearing potential must agree to practice 2 highly effective contraceptive measures of birth control and must agree not to father a child while receiving treatment with ASTX727 and for at least 3 months after completing treatment. Contraceptive measures which may be considered highly effective comprise combined hormonal contraception (oral, vaginal, or transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence, and surgically successful vasectomy. Abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of birth control.

*A woman is considered of childbearing potential (i.e., fertile) following menarche and until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.

Exclusion Criteria:

• Treatment with any investigational drug or therapy within 2 weeks before study treatment, or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant AEs from previous treatment.
• Prior treatment with azacitidine, decitabine, or guadecitabine.
• Treatments for MDS, including erythropoietins, colony-stimulating factors (CSFs), thrombopoietins, chemotherapy, and immunosuppression including calcineurin inhibitors, glucocorticoids, etc., must be concluded 1 month prior to study treatment.
• Diagnosis of CMML.
• Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
• Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the subject to high risk of noncompliance with the protocol.
• Life-threatening illness, medical condition or organ system dysfunction, or other reasons including laboratory abnormalities, which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ASTX727 LD, or compromise the integrity of the study outcomes.
• Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject has been disease free for at least 1 year.
• Known active infection with human immunodeficiency virus or hepatitis viruses.