Milademetan Tosylate and Low-Dose Cytarabine With or Without Venetoclax in Treating Participants With Recurrent or Refractory Acute Myeloid Leukemia

This phase I/II trial studies the side effects and best dose of milademetan tosylate and to see how well it works with cytarabine with or without ventoclax in treating participants with acute myeloid leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Milademetan tosylate and ventoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known if giving milademetan tosylate and low-dose cytarabine with or without ventoclax will work better in treating participants with recurrent or refractory acute myeloid leukemia.

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study.

If you are enrolled in Phase 1, the dose of DS-3032b you receive will depend on when you join this study.

If you are enrolled in Phase 2, you will receive DS-3032b at the highest dose that was tolerated in Phase 1.

All participants will receive LDAC at a fixed dose (meaning the dose will not change). If you are assigned to receive it, your dose of venetoclax will not change either. However, if needed because you have side effects, your dose may be adjusted.

Up to 58 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of acute myeloid leukemia (AML) by World Health Organization (WHO) 2016 criteria. Patients will be divided into 2 arms during the phase 2 portion:

  * Arm A: Subjects must have newly diagnosed AML
  * Arm B: Subjects must have refractory or relapsed AML
* TP53 wild-type status on molecular testing performed within the last 3 months
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 3
* Creatinine clearance \>= 60 mL/min, as calculated using the modified Cockcroft-Gault equation OR creatinine =\< 1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 3 x ULN
* Bilirubin =\< 1.5 x ULN, unless resulting from hemolysis, Gilbert's disease or considered to be due to leukemic involvement
* No gastrointestinal issues to interfere with oral medication absorption
* No active uncontrolled infection or comorbidity that would interfere with therapy or place patient at increased risk
* Subject (male and female) of childbearing/reproductive potential must agree to use double-barrier contraceptive measures or avoid intercourse during the study and for 90 days after the last dose of study drug
* Subject must sign and date an Institutional Review Board-approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study-specific procedures or tests
* Able and willing to provide bone marrow biopsies/aspirates as requested by the protocol
* Willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at screening
* Use of hydroxyurea is allowed prior to and during the first cycle of study treatment. 1-2 doses of cytarabine are also permitted if needed for cytoreduction prior to initiating study treatment

Exclusion Criteria:

* Patient with t(15;17) karyotypic abnormality or a diagnosis of acute promyelocytic leukemia
* Patient with other malignancy that contains a non-synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening
* Prior treatment with an MDM2 inhibitor
* Presence of central nervous system involvement of leukemia. History of prior leptomeningeal leukemia/disease that has fully resolved is eligible
* A second concurrent primary malignancy that has required systemic anti-neoplastic treatment within the previous 6 months, except for localized cancers that have apparently been cured, for example non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast
* Any condition that would preclude adequate absorption of DS-3032b, including refractory vomiting, malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease (GVHD) affecting the gut
* Any active uncontrolled infection, known human immunodeficiency virus infection, or active hepatitis B or C infection
* Any concomitant medical condition that would in the opinion of the investigator increase the risk of toxicity
* Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5, grade =\< 1 or baseline. Subjects with chronic grade 2 toxicities may be eligible per discretion of the investigator and sponsor (e.g., grade 2 chemotherapy-induced neuropathy)
* Patient having received hematopoietic stem cell transplantation (HSCT) within 60 days of the first dose of DS-3032b, is on immuno-suppressive therapy post-HSCT at the time of screening, or has clinically significant GVHD (use of topical steroids for ongoing skin GVHD will be permitted)
* Prolongation of corrected QT interval using Fridericia's method (QTcF) at rest, where the mean QTcF interval is \>= 450 ms for males or \>= 470 ms for females based on electrocardiograms (ECGs). Patients with right bundle branch block (RBBB) will be eligible after discussion with principal investigator (PI)
* Pregnant or breastfeeding
* Substance abuse or medical, psychological, or social conditions that, in the opinion of the investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results