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 av…