Testing the Use of Combination Therapy in Patients With Persistent Low Level Acute Myeloid Leukemia (AML) Following Initial Treatment

Inclusion Criteria:

* Patient must be ≥ 18 and ≤ 59 years of age.
* Patient must have ECOG performance status 0-2
* Patient must have morphologically documented AML or secondary AML \[from prior conditions such as myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN)\] or therapy related AML (t-AML), as defined by World Health Organization (WHO) criteria
* Patient must have completed induction chemotherapy in a myeloMATCH Young Adult Tier-1 protocol. Patient may have received prior hypomethylating agents (HMAs). Patient may have received prior azacitidine + venetoclax.
* Patient must have been assigned to this protocol by myeloMATCH MSRP/MATCHBOX/. Patients thereby assigned will have attained complete remission (CR) or CR with partial hematologic recovery (CRh) (defined as CR with (ANC) ≥ 500/mcL and/or platelets \> 50/mcL) with detectable MRD at time of assignment. MRD is defined as \>0.1% flow cytometry on bone marrow (BM) biopsy as assessed by MDNet. The definition of CR or CRh may be made ± 2 weeks from BM biopsy
* Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible.
* Patient must have recovered (i.e.: resolved to \< grade 2) from adverse events related to prior anti-cancer therapy at the time of randomization with the exception of alopecia
* Patient must have adequate organ and marrow function as defined below (these labs must be obtained ≤ 7 days prior to protocol randomization):

Absolute neutrophil count (ANC) ≥ 500/mcL ANC:\_\_\_\_\_\_\_\_\_\_ Date of Test:\_\_\_\_\_\_\_\_\_\_ Platelets ≥ 50,000/mcL Platelets:\_\_\_\_\_\_\_\_\_\_ Date of Test:\_\_\_\_\_\_\_\_\_\_ Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) Total Bilirubin:\_\_\_\_\_\_\_\_\_\_ Institutional ULN:\_\_\_\_\_\_\_\_\_ Date of Test:\_\_\_\_\_\_\_\_\_\_ AST(SGOT)/ALT(SGPT) ≤ 3.0 × institutional ULN AST:\_\_\_\_\_\_\_ Institutional ULN:\_\_\_\_\_\_\_\_\_ Date of Test:\_\_\_\_\_\_\_ ALT: \_\_\_\_\_\_\_Institutional ULN:\_\_\_\_\_\_\_\_\_ Creatinine ≤ 1.5 x institutional ULN Creatinine \_\_\_\_\_\_\_\_\_\_\_\_\_\_Date of Test:\_\_\_\_\_\_\_\_ OR

≥ 50 mL/min/1.73 m2

* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial.
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Patients must be able to swallow oral tablets and be free of GI absorption issues.

Exclusion Criteria:

* Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.

All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy.

A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Patient of child bearing potential? \_\_\_\_\_\_ (Yes or No) Date of blood test or urine study: \_\_\_\_\_\_\_\_\_\_\_

* Patients of childbearing potential and/or sexually active patients must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and continue for 6 months after the last dose of daunorubicin + cytrarabine liposome, 6 months after the last dose of azacitidine for patients of childbearing potential, 3 months after the last dose of azacitidine for male patients, and for 30 days after the last dose of venetoclax. Patient must also abstain from nursing an infant for 2 weeks after the last dose of daunorubicin + cytrarabine liposome and for 1 week after the last dose of azacitidine.
* Patients must not have FLT3 TKD or ITD mutation. Patients with this mutation, will be excluded from this study because myeloMATCH plans separate studies in tier-2 for those patients
* Patient must not be receiving any other investigational agents at the time of randomization.
* Patient must not have history of allergic reactions attributed to compounds of similar chemical or biologic composition to cytarabine, azacitidine, venetoclax or Daunorubicin and Cytarabine liposome
* Patients must not have uncontrolled intercurrent illness including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or serious chronic gastrointestinal conditions associated with diarrhea