Venetoclax in Combination With Cladribine and Cytarabine Alternating With Azacitidine Plus Venetoclax for the Treatment of Newly Diagnosed Monocytic AML and Active Signaling Mutated AML

PRIMARY OBJECTIVE: I. Assess efficacy of the investigational treatment based on disease remission. SECONDARY OBJECTIVES: I. Assess efficacy of the investigational treatment based on clinical response. II. Assess any-cause survival after treatment. III. Assess survival in the absence of treatment failure, hematologic relapse, or progressive disease. IV. Assess duration of response, based on morphological assessments. V. Assess the safety and tolerability of the regimen. EXPLORATORY OBJECTIVES: I. Assess response based on measurable residual disease (MRD). II. Identify markers of clonal or clinical response and resistance to treatment. III. Assess participant quality of life (QoL) using Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO CTCAE). OUTLINE: INDUCTION: Patients receive cladribine intravenously (IV) over 1-2 hours on days 1-5, cytarabine subcutaneously (SC) twice daily (BID) or once daily (QD) on days 1-10, and venetoclax orally (PO) on days 1-21 of cycle 1. RE-INDUCTION: Patients with \> 5% blasts after cycle 1 receive cladribine IV over 1-2 hours on days 1-5, cytarabine SC BID or QDon days 1-10, and venetoclax PO QD on days 1-21 of cycle 2. REMISSION AFTER INDUCTION: Patients who achieve complete remission (CR)/CR with partial hematologic recovery/CR with incomplete blood count recovery/morphologic leukemia-free state (MLFS) after cycle 1 of induction, receive cladribine IV over 1-2 hours on days 1-3, cytarabine SC BID or QD on days 1-10 and venetoclax PO QD on days 1-21 of cycle 2. CONTINUING THERAPY: Patients who achieve MLFS receive venetoclax PO QD on days 1-21 and azacitidine IV or SC QD on days 1-7 for 2 cycles then cladribine IV over 1-2 hours on days 1-3, cytarabine SQ BID or QD on days 1-10 and venetoclax PO QD on days 1-21 for 2 cycles. Cycles repeat every 28 days and continue to alternate every 2 cycles for up to cycle 18 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) as clinically indicated on study. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the study. At completion of study treatment, patients are followed up for 2 years.