Inclusion Criteria:

* Understand and voluntarily sign an informed consent form
* Diagnosis of any of the following:

* Newly diagnosed (or untreated) AML with poor-risk cytogenetics, poor-risk molecular, or secondary AML (i.e. therapy-related or evolved from antecedent hematologic malignancy
* Newly diagnosed (or untreated) myeloid blast phase of myeloproliferative neoplasm (MPN) (including myeloid blast phase of chronic myeloid leukemia \[CML\])
* Newly diagnosed (or untreated) high-risk, very-high risk or secondary MDS
* Newly diagnosed (or untreated) MDS/MPN (regardless of cytogenetic/molecular status)
* Relapsed and/or refractory AML, MDS, MDS/MPN, myeloid blast phase of MPN (including myeloid blast phase of CML) who are either salvage 1 or salvage 2
* Patients on non-investigational regimens or on investigational new drug (IND)-exempt MD Anderson studies (for hematologic malignancies) of approved drugs are also eligible
* Patients on IND studies (for hematologic malignancies) utilizing Food and Drug Administration (FDA) approved commercially available drugs are eligible
* Investigational agents that are not used for treatment of the leukemia per se (e.g. anti-infective prophylaxis or therapy) will be allowed. Other supportive care studies are allowed, even if under an IND
* Newly diagnosed MDS or AML, as well as MDS/MPN, myeloid blast phase of MPN (including myeloid blast phase of CML), patients can enroll on this study after start of non-investigational induction therapy, but must be within first 3 cycles of therapy and benefiting from their front-line therapy. Patients with relapsed and/or refractory AML, MDS, MDS/MPN, myeloid blast phase of MPN (including myeloid blast phase of CML) who are either salvage 1 or salvage 2 are eligible for these salvage cohorts if they are within the first 3 cycles of salvage 1 or salvage 2 therapy
* Transformed and untreated AML transformed from previously treated MDS, myeloproliferative neoplasm (MPN) or other types of secondary AML are allowed. Myeloid blast phase of MPN and chronic myeloid leukemia (CML) are allowed
* Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2 at study entry
* Serum creatinine =\< 1.5 mg/dL (unless due to leukemia or other hematologic malignancy)
* Total bilirubin =\< 2.0 x upper limit of normal (ULN), unless the patient has Gilbert's (unless due to leukemia or other hematologic malignancy)
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.0 x ULN (unless due to leukemia or other hematologic malignancy)
* Women of childbearing potential (WCBP) must have a negative urine pregnancy test within 7 days and must either commit to continued abstinence from heterosexual intercourse or adopting at least one highly effective method of contraception. These methods include intra-uterine device, tubal ligation, partner's vasectomy, and hormonal birth control pills. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential
* Extramedullary disease is allowed as long as it can be measured and followed for response

Exclusion Criteria:

* Nursing and pregnant females. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
* Uncontrolled inter-current illness including, but not limited to, uncontrolled active infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements or which judged by the investigator, places the patient at unacceptable risk
* Acute Promyelocytic leukemia (APL)