Trial of Cladribine and Low-Dose Cytarabine (LoDAC) Alternating With Decitabine vs. Hypomethylating Agents (HMA) Plus Venetoclax as Frontline Therapy for AML or High-Grade MDS in Patients Unfit for Intensive Induction

Inclusion Criteria:

* Age \> 60 years.

  * Adults \< 60 years are eligible if deemed unfit for intensive induction by their treating physician (or choose to receive a non-intensive regimen due to patient's preference)
* Diagnosis of treatment-naive AML (excluding acute promyelocytic leukemia treated with hydroxyurea) or high grade MDS defined as \>10% marrow blasts or R-IPSS of intermediate 2 risk or higher with \> 10% bone marrow blasts, and 1 or more of the following:

  * Circulating blasts in peripheral blood
  * Rapidly declining blood counts over the past 8 weeks, as determined by treating investigator
  * Transfusion dependence
  * Adverse cytogenetic changes or molecular mutations with high risk of rapid progression to AML, as determined by treating investigator
  * Significant B-symptoms attributed to MDS (weight loss, fatigue, unexplained fever, night sweats)
  * Evidence of clonal evolution with emergence of new cytogenetic changes or new mutations compared to previous bone marrow biopsy.
* White blood cell count \< 25 K/uL. Cytoreduction with hydroxyurea is allowed prior to enrollment to obtain white blood cell count \< 25 K/uL.
* Subjects of childbearing potential (SOCBP) must have a negative pregnancy test and agree to use of an adequate method of contraception to avoid pregnancy throughout the study and for at least 4 months after the last dose of study drug. Prior to study enrollment, subjects of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 4 months following the last dose of study drug.

Exclusion Criteria:

* Participants with acute promyelocytic leukemia (APML, APL, AML-M3)
* Patient with active central nervous system leukemia
* Karnofsky performance status \< 50 at screening

  * Karnofsky performance status of 40-50 is allowed to proceed on study if the patient had a performance status of 50-100 at screening and the decline to 40 is deemed definitely related to disease (AML/MDS).
* Patients with AML with molecular mutations with FDA approved targeted therapies in the first line setting.

  * This includes FLT3 ITD/TKD + AML, IDH1+ AML. (Note: IDH2+ AML has targeted therapy approved in relapsed setting only; FDA approval for first line setting is pending and will be excluded once approval is obtained).
* Subjects with familial AML/MDS syndromes and those with inherited DNA repair syndromes like Fanconi Anemia
* Concurrent illness that in the opinion of the Investigator would pose an undue risk to the subject participating in this clinical study.
* Severe kidney impairment CrCL \< 10 mL/min (per Cockcroft Gault equation) or dialysis-depended renal failure
* Class III-IV NYHA heart failure
* Child-Pugh class C liver cirrhosis
* Known seropositivity or active viral infection with human immunodeficiency virus (HIV), hepatis B virus (HBV), or hepatitis C virus (HCV) unless fully treated and negative by PCR. Patients who are seropositive because of HBV vaccine are eligible.
* Subjects with uncontrolled life-threatening infections

  * Subjects with fever (temperature \> 38.3 C) thought to be related to AML/MDS are eligible
* History of allergic reaction to hypomethylating agents (decitabine, azacitidine), venetoclax, cladribine, or cytarabine.
* Active solid tumor malignancy requiring treatment within previous 2 years.

  * Patients with prior history of malignancy who completed treatment \> 2 years prior to baseline are eligible to enroll if there is currently no evidence of disease and all toxicities of prior treatments are resolved.
* Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.
* Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.