Inclusion Criteria:

* Diagnosis of myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) including chronic myelomonocytic leukemia (CMML) according to World Health Organization (WHO)
* For hypomethylating agent naive patients: int-2 or higher by International Prognostic Scoring System (IPSS) or \> 5% bone marrow blasts if MDS or dysplastic CMML (white blood cell \[WBC\] \< 13 x 10\^9/L). Patients with proliferative (WBC \>= 13 x 10\^9/L) CMML or MDS/MPN, or those with dysplastic CMML with high-risk molecular features (mutations in ASXL1, TP53 or more than 3 mutations) are also eligible independently of IPSS risk score or bone marrow blast percentage
* For patients with prior hypomethylating agent therapy: no response after 6 cycles of azacitidine, decitabine, guadecitabine or ASTX727 or relapse or progression after any number of cycles
* Detectable FLT3-ITD mutation in bone marrow and/or peripheral blood, or presence of CBL exon 8 or 9 deletions or point mutations
* Serum creatinine =\< 2 x upper limit of normal (ULN)
* Total bilirubin \< 2 x ULN (will allow less than 5 x ULN if Gilbert's 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 (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:

* Uncontrolled infection not adequately responding to appropriate antibiotics
* Screening electrocardiogram (ECG) with a corrected QT interval by Fridericia's formula (QTcF) \> 450 msec. The QTcF interval will be calculated by Fridericia's correction factor (QTcF). The QTcF will be derived from the average QTcF in triplicate. Patients are excluded if they have QTcF \> 450. Subjects with prolonged QTcF interval in the setting of RBBB (right bundle branch block) may participate upon review and approval by the principal investigator and following evaluation by cardiology consult
* Patients with congenital long QT syndrome
* History or presence of sustained ventricular tachycardia requiring medical intervention
* Any history of clinically significant ventricular fibrillation or torsades de pointes
* Known history of second- or third-degree heart block (may be eligible if the patient currently has a pacemaker)
* Sustained heart rate of \< 50/minute on screening ECG
* Right bundle branch block + left anterior hemiblock (bifascicular block)
* Complete left bundle branch block
* Atrial fibrillation documented within 2 weeks prior to first dose of study drug
* 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
* Patients who are actively taking a strong CYP3A4 inducing medication
* Patients who require treatment with concomitant drugs that prolong QT/corrected QT (QTc) interval or strong CYP3A4 inhibitors with the exception of antibiotics, antifungals, and antivirals that are used as standard of care to prevent or treat infections, antiemetics (such as ondansetron) and other such drugs that are considered absolutely essential for the care of the subject or if the Investigator believes that beginning therapy with a potentially QTc-prolonging medication (such as anti-emetic) is vital to an individual subject's care while on study
* 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 \[spermidical jelly or foam with condoms or diaphragm\], 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 HCG) pregnancy test at screening
* Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy
* 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