Testing the Effects of Novel Therapeutics for Newly Diagnosed, Untreated Patients With High-Risk Acute Myeloid Leukemia (A MyeloMATCH Treatment Trial)

Inclusion Criteria:

• STEP 1 REGISTRATION:

• Participants must have been registered to Master Screening and Re-Assessment Protocol, MYELOMATCH, prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox, prior to registration to this study.

• Note: Pre-enrollment/diagnosis labs must have already been performed under MYELOMATCH

• Participants must have newly diagnosed, untreated acute myeloid leukemia (AML) per World Health Organization (WHO) criteria

• Participants must have high-risk (adverse) AML per European LeukemiaNet (ELN) 2017 criteria

• Participants with therapy-related AML (t-AML), or with AML evolving from an antecedent hematologic disorder (such as myeloproliferative neoplasm), or AML with myelodysplasia-related changes (AML-MRC) are eligible

• Acute promyelocytic leukemia is excluded

• Participants with favorable or intermediate risk disease are excluded

• Participants with FLT3 mutations (ITD or TKD) are excluded

• Participants with t(9;22) translocation are excluded

• A single dose of intrathecal chemotherapy is allowed prior to study entry

• Prior anthracycline therapy is allowed but must not exceed a cumulative lifetime dose of 200 mg/m^2 daunorubicin or equivalent. Prior hypomethylating agent (HMA) exposure is allowed, as long as not for AML diagnosis

• Participants must not have received or be currently receiving any prior therapy for acute myeloid leukemia. Hydroxyurea to control the white blood cells (WBC) is allowed prior to registration and initiation of protocol-defined therapy. All trans retinoic acid (ATRA) given until a diagnosis of acute promyelocytic leukemia is ruled out is also allowed.

• Participants must not be receiving or planning to receive any other investigational agents before completing protocol therapy

• Participants must be between 18 and 59 years of age

• Participants must have Zubrod performance status =< 3 as determined by a history and physical (H&P) completed within 14 days prior to registration

• Participants must have a complete medical history and physical exam within 7 days prior to registration

• Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications

• Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at time of registration and have undetectable HIV viral load within 6 months prior to registration

• Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days prior to registration and be on suppressive therapy, if indicated

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration

• The following tests must be performed within 14 days prior to registration to establish baseline values:

• Complete blood count (CBC)/differential/platelets

• Total bilirubin

• Lactate dehydrogenase (LDH)

• Albumin

• Glucose

• Fibrinogen

• Participants must have adequate kidney function as evidenced by creatinine clearance >= 30mL/min (by Cockcroft Gault) within 28 days prior to registration

• Participants must have adequate liver function as evidenced by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN) within 28 days prior to registration

• Total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the participant has a history of Gilbert's disease) within 28 days prior to registration

• Participants must have adequate cardiac function as determined by echocardiography or MUGA scan with an ejection fraction >= 50% within 28 days prior to registration

• Participants with a prior or concurrent malignancy whose natural history (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. No concurrent therapies for such malignancy are allowed with the exception of hormonal therapy

• Participants with known history of Wilson's disease or other known copper-metabolism disorder are excluded

• Participants must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use 2 contraception methods. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods (e.g., hormonal contraceptives [examples include birth control pills, vaginal rings, or patches] associated with inhibition of ovulation for at least 1 month prior to taking study drug), "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. A barrier method should be used during this study along with hormonal contraceptives from initial study drug administration to 30 days after the last dose of study drug as drug-drug interaction with venetoclax is unknown

• Participants must have agreed to have specimens submitted for translational medicine (MRD) under the myeloMATCH MSRP and specimens must be submitted

• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines

• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system