Cladribine, Idarubicin, Cytarabine, and Venetoclax in Treating Patients With Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndrome, or Blastic Phase Chronic Myeloid Leukemia

Inclusion Criteria:

1. Patients with a diagnosis of AML, Acute Biphenotypic Leukemia, or high risk MDS (>/= 10% blasts or IPSS >/= intermediate-2) will be eligible. Patients with CML inMyeloid Blast Phase are also eligible.

2. For Frontline cohort (1 or 4): No prior potentially-curative therapy for leukemia.Prior therapy with hydroxyurea, hematopoietic growth factors, azacytidine,decitabine, ATRA, or a total dose of cytarabine up to 2g (for emergency use forstabilization) is allowed. Patients deemed able to receive venetoclax (ie. insuranceclearance) will be assigned to Frontline cohort 4. Patients with secondary AMLwhohave been treated for their antecedent myeloid neoplasm will be enrolled into theseparate Secondary AML cohort.

3. For Salvage cohort: Patients with previously treated, relapsed or refractory AML,Acute Biphenotypic Leukemia, or CML in Myeloid Blast Phase are eligible.

4. Age </= 65 years.

5. Adequate organ function as defined below:

• liver function (bilirubin < 2mg/dL, AST and/or ALT <3 x ULN - or <5 x ULN ifrelated to leukemic involvement)

• kidney function (creatinine < 1.5 x ULN ).

• known cardiac ejection fraction of > or = 45% within the past 6 months

6. ECOG performance status of ≤ 2.

7. A negative urine pregnancy test is required within 1 week for all women ofchildbearing potential prior to enrolling on this trial.

8. Patient must have the ability to understand the requirements of the study and signedinformed consent. A signed informed consent by the patient is required prior totheir enrollment on the protocol.

Exclusion Criteria:

1. Pregnant women are excluded from this study because the agents used in this studyhave the potential for teratogenic or abortifacient effects. Because there is apotential risk for adverse events in nursing infants secondary to treatment of themother with the chemotherapy agents, breastfeeding should also be avoided.

2. Uncontrolled intercurrent illness including, but not limited to active uncontrolledinfection, symptomatic congestive heart failure (NYHA Class III or IV), unstableangina pectoris, clinically significant cardiac arrhythmia, or psychiatricillness/social situations that would limit compliance with study requirements.

3. Patient with documented hypersensitivity to any of the components of thechemotherapy program.

4. Men and women of childbearing potential who do not practice contraception. Women ofchildbearing potential and men must agree to use contraception prior to study entryand for the duration of study participation.