Seclidemstat and Azacitidine for the Treatment of Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

Inclusion Criteria: * Age \>= 18 years as myelodysplastic syndrome (MDS) is a very rare disease in the pediatric setting * Diagnosis of MDS or chronic myelomonocytic leukemia (CMML) according to World Health Organization (WHO) and: * MDS with int-1, int-2, or high risk by International Prognostic Scoring System (IPSS), or CMML-1/CMML-2 , myeloproliferative CMML (white blood cell \[WBC\] \>= 13 x 10\^9/L) or CMML-0 with high-risk molecular features (known mutations in ASXL1, SETBP1, RUNX1, NRAS, TP53 or more than 3 mutations). * No response after 6 cycles of azacitidine, decitabine, guadecitabine, ASTX030 or ASTX727 or relapse or progression after any number of cycles * Serum creatinine =\< 1.5 x upper limit of normal (ULN) OR creatinine clearance \>= 50 ml/min for patients with creatinine levels \> 1.5 x ULN * Adequate hepatic function with total bilirubin \< 2 x ULN (will allow less than 5 x ULN if Gilbert's syndrome at investigator's discretion) * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 3 x ULN * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * 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 * Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors (e.g., 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: * Uncontrolled infection not adequately responding to appropriate antibiotics * 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 * Baseline corrected QT interval by Fridericia formula (QTcF) (Fridericia) \>= 450 msecs and long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome * Currently receiving any of the following substances and cannot be discontinued 14 days for CYP inhibitors prior to cycle 1 day 1: * Moderate or strong inhibitors or inducers of major CYP isoenzymes, including grapefruit, grapefruit hybrids, pomelos, star fruit and Seville oranges * Moderate or strong inhibitors or inducers of major drug transporters * Substrates of CYP3A4/5 with a narrow therapeutic index * 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 do not have a negative urine or blood beta-human chorionic gonadotropin (beta human chorionic gonadotropin \[HCG\]) pregnancy test at screening * Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy * Evidence of graft versus host disease or prior allogeneic (allo)-stem cell transplantation within 6 months of cycle 1 day 1 or receiving immunosuppressants following a stem-cell procedure * Patients known to be positive for hepatitis B surface antigen expression or with active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months). Patients with history of human immunodeficiency virus (HIV) disease are also excluded from the study