Guadecitabine in Treating Patients With Higher-Risk Myelodysplastic Syndromes

Inclusion Criteria: * Patients with higher risk MDS (International Prognostic Scoring System \[IPSS\] int-2 or high; or \>= 10% blasts as defined by World Health Organization \[WHO\]) * No prior intensive chemotherapy or high-dose cytarabine (\>= 1 g/m\^2) * Prior biologic therapies (=\< 1 cycle of prior decitabine or azacitidine), targeted therapies, or single agent chemotherapy is allowed * Off chemotherapy for 2 weeks prior to entering this study with no toxic effects of that therapy, unless there is evidence of rapidly progressive disease * Hydroxyurea is permitted for control of counts prior to treatment * Hematopoietic growth factors are allowed * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * Serum creatinine =\< 1.5 mg/dL * Serum bilirubin =\< 1.5 x upper limit of normal (ULN) * Aspartate transaminase (AST) or alanine transaminase (ALT) =\< 2.5 x ULN * Alkaline phosphatase =\< 2.5 x ULN * Provide signed written informed consent * Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent * Female patients of childbearing potential must have a negative pregnancy test within 2 weeks prior to entering this study * Women who are able to become pregnant and men who can father a child must use birth control while on study and for at least 8 weeks after your last dose of study drug(s); acceptable birth control includes a condom or a diaphragm with spermicidal jelly; and birth control methods that are taken by mouth, injected, or implanted; if you are already using birth control, you must check with the study staff to make sure that it is considered one of the acceptable forms to use in this study Exclusion Criteria: * Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol * Use of investigational agents within 30 days or any anticancer therapy within 2 weeks prior to entering this study with the exception of hydroxyurea; the patient must have recovered from all acute toxicities from any previous therapy * Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment * Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) * Pregnant or lactating patients * Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results * Any concurrent malignancy * Exceptions * Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed * Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed