WEE1 Inhibitor AZD1775 With or Without Cytarabine in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

Inclusion Criteria:

* Patient population (histological or cytologically confirmed diagnosis):

  * Untreated elderly (\> 60 years) AML if in the intermediate and poor-risk cytogenetic group and not candidates (as judged by treating doctor of medicine \[MD\]) for or willing to undergo standard induction therapy (i.e. elderly unfavorable cytogenetic AML) or any untreated AML age \> 65 years

    * Note: previous therapy with a hypomethylating agent (HMA) for a diagnosis of MDS is allowed
  * Relapsed or refractory AML (\>= 18 years)
  * Any MDS (\>= 18 years) having failed or been intolerant to prior hypomethylating agent (HMA) treatment

    * Failure is defined as any disease progression while on HMA, relapse after HMA treatment or no response after 4 cycles of 5-Azacitidine or decitabine
    * Patients with isolated 5q-/5q- syndrome must have failed, not tolerated, or lenalidomide in addition to having failed or been intolerant to HMA treatment

      * Note: patients with chronic myelomonocytic leukemia (CMML) and MDS/myeloproliferative neoplasms (MPN) overlap are allowed if meeting other study eligibility criteria
      * Note: for all patient groups, therapy as part of a plan as a bridge to transplant is allowed
* Total bilirubin =\< 1.5 mg/dL (except Gilbert's syndrome or known hemolysis or leukemic infiltration)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x upper limit normal (ULN) or \< 5 x ULN if organ involvement
* Alkaline phosphatase \< 5 x ULN
* Serum creatinine =\< 2 x ULN or 24 hour creatinine (Cr) clearance \> 30 ml/min
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
* Ability to provide informed written consent and be able to adhere to the study visit schedule and other protocol requirements
* Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
* Willing to provide blood and bone marrow aspirate samples for correlative research purposes
* Negative serum pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only
* Men and women must be willing to use appropriate contraception throughout study and for 6 months after
* Male patients who are sexually active with a female partner of childbearing potential must be either surgically sterilized or agree to use barrier contraception (ie, condoms) for the duration of study participation, and for 90 days after the final dose of study drug; cessation of birth control after this point should be discussed with a responsible physician
* Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are \> 60 days from stem cell infusion, have graft-versus-host disease (GVHD) =\< grade 1 and are off immunosuppressive agents for \> 28 days at time of registration

Exclusion Criteria:

* Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, known positive for active infectious hepatitis, type A, B or C (past infection allowed), or psychiatric illness/social situations that would limit compliance with study requirements; Note: ongoing infection controlled on antibiotics/antifungal/antiviral medications are allowed
* Any of the following prior therapies:

  * Cytotoxic chemotherapy =\<14 days prior to registration
  * Immunotherapy =\< 14 days prior to registration
  * Biologic therapy (i.e. antibody therapies) =\< 14 days prior to registration
  * Radiation therapy =\<14 days prior to registration
  * Targeted therapies (i.e. kinase inhibitors, =\< 7 days or 5 half-life's whichever is shorter)

    • For steroids or other non-cytotoxics given for blast count control, patient must be off for \> 24 hours (hrs) before starting therapy; NOTE: hydroxyurea (HU) is allowed for blast count control throughout study
  * Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =\< 14 days prior to registration
* Active uncontrolled central nervous system (CNS) leukemia; NOTE: positive (cyto)pathology is allowed and patient can receive intrathecal chemotherapy
* Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; NOTE: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
* Any previous treatment with AZD1775 or allergic reactions to excipients of AZD1775
* Acute promyelocytic leukemia (APL, M3) unless failed regimens that included tretinoin, arsenic trioxide, anthracyclines and cytarabine and currently NOT candidates for stem cell transplantation
* Major surgery =\< 28 days prior to registration
* Clinically significant heart disease, including the following:

  * Active severe angina pectoris within 3 months prior to registration
  * Acute myocardial infarction within 3 months prior to registration
  * New York Heart Association classification IV cardiovascular disease or symptomatic class III disease

    * Note: patients with any of the above may be allowed after discussion amongst the investigators including the principal investigator
* Any of the following:

  * Pregnant women
  * Nursing women
  * Men or women of childbearing potential who are unwilling to employ adequate contraception
* Subject has had prescription or non-prescription drugs or other products known to be sensitive cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued two weeks prior (alternatively 5 half lives if T1/2 is known) prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug

  * NOTE: co-administration of aprepitant or fosaprepitant during this study is prohibited
  * Note: individual drugs exerting CYP interactions may be continued on a case by case basis if felt essential for patient management, after discussions and discretion of the treating physician
  * The preferred azole anti-fungal medication is fluconazole (alternatively posaconazole) which can be given during treatment with AZD1775 at the treating physician's discretion, however with dose reductions of AZD1775 by 25-75% (i.e. from AZD1775 200mg to 150 or 100mg)
* Patients may not be on an inhibitor of breast cancer resistance protein (BCRP)

  * NOTE: AZD1775 is an inhibitor of breast cancer resistance protein (BCRP); the use of statins including atorvastatin which are substrates for BCRP are therefore prohibited and patients should be moved on to non-BCRP alternatives
* Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville oranges, pummelos, and exotic citrus fruits from 7 days prior to the dose of study medication and during the entire study; NOTE: orange juice is allowed
* Corrected QT interval (QTc) \> 470 msec (as calculated per institutional standards) at study entry or congenital long QT syndrome