Inclusion Criteria:

* Patients with a diagnosis of AML, acute biphenotypic leukemia, or high risk MDS (\>= 10% blasts or International Prognostic Scoring System \[IPSS\] \>= intermediate-2) will be eligible; patients with CML in myeloid blast phase are also eligible
* For frontline cohorts (1 or 4): no prior potentially curative therapy for leukemia; prior therapy with hydroxyurea, hematopoietic growth factors, azacytidine, decitabine, tretinoin (ATRA), or a total dose of cytarabine up to 2 g (for emergency use for stabilization) is allowed; patients deemed able to receive venetoclax (ie. insurance clearance) will be assigned to frontline cohort 4; patients with secondary AML who have been treated for their antecedent myeloid neoplasm will be enrolled into the separate secondary AML cohort
* For salvage cohort: patients with previously treated, relapsed or refractory AML, acute biphenotypic leukemia, or CML in myeloid blast phase are eligible
* Bilirubin =\< 2 mg/dL
* Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =\< 3 x upper limit of normal (ULN) or \< 5 x ULN if related to leukemic involvement
* Creatinine =\<1.5 x ULN
* Known cardiac ejection fraction of \>= 45% within the past 6 months
* Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2
* A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial
* Patient must have the ability to understand the requirements of the study and signed informed consent a signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol

Exclusion Criteria:

* Pregnant women are excluded from this study because the agents used in this study have the potential for teratogenic or abortifacient effects; because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding should also be avoided
* Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (New York Heart Association \[NYHA\] class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Patient with documented hypersensitivity to any of the components of the chemotherapy program
* Men and women of childbearing potential who do not practice contraception; women of childbearing potential and men must agree to use contraception prior to study entry and for the duration of study participation