Inclusion Criteria:

* Diagnosis of MDS or chronic myelomonocytic leukemia (CMML) according to World Health Organization (WHO)
* Patients are either not eligible for or choose not to proceed with a stem cell transplant at the time of enrollment
* MDS and CMML classified by International Prognostic Scoring System (IPSS) as intermediate-2/high risk with excess blasts \> 5%, or with 10-19% bone marrow blasts
* No response following at least 4 cycles of therapy or relapse after initial CR, partial response (PR), or HI or progression after any number of cycles of either azacitidine, decitabine, guadecitabine or ASTX727 (oral decitabine) as single agents or in combination with other investigational agents
* Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study
* Total bilirubin \< 3 mg/dL (will allow less than 5 x upper limit of normal \[ULN\] if Gilbert's at investigator's discretion)
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 3 x ULN
* Serum creatinine clearance \> 30 mL/min and no end/stage renal disease
* Hydroxyurea for control of leukocytosis or use of hematopoietic growth factors (eg, granulocyte-colony stimulating factor \[G-CSF\], granulocyte-macrophage colony-stimulating factor \[GM-CSF\], procrit, aranesp, thrombopoietins) is allowed at any time prior to or during study if considered to be in the best interest of the patient

Exclusion Criteria:

* New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) \< 50 by echocardiogram or multigated acquisition (MUGA) scan
* History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias
* Uncontrolled infection not adequately responding to appropriate antibiotics
* Female patients who are pregnant or lactating
* Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives \[birth control pills\], contraceptive injections, intrauterine devices \[IUD\], double-barrier method \[spermicidal jelly or foam with condoms or diaphragm\], contraceptive patch, or surgical sterilization) throughout the study
* Female patients with reproductive potential who have a positive urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening
* Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy (within 14 days of initiating study treatment)
* Prior cumulative anthracycline exposure of \> 550 mg/m\^2 daunorubicin or equivalent, or \> 400 mg/m\^2 in patients who received radiation therapy to the mediastinum