Navitoclax, Venetoclax, and Decitabine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Previously Treated With Venetoclax

Prior treatment

• Hematopoietic stem cell transplant within 100 days prior to day 1 of protocol therapy
• Chemotherapy, radiation therapy, biological therapy, or immunotherapy within 14 days or 5 half-lives, whichever is shorter, prior to day 1 of protocol therapy with the following exceptions:
  • Subjects will be allowed to have been on venetoclax at screening and remain on it through treatment start.
  • Hydroxyurea is allowed prior to treatment and through cycle 1 for control of rapidly progressing leukemia
• Strong or moderate CYP3A4 inducers within 14 days prior to day 1 of protocol therapy
• Grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit consumed within 3 days prior to the first dose of study drug
• Immunosuppressants (steroids =\< 10 mg/day of oral prednisone or equivalent is allowed) within the last 28 days
• Must not have received or planning to receive live vaccine while being on study or 4 weeks before and after completion of treatment
• Active/uncontrolled HIV infection, acquired immunodeficiency syndrome (AIDS), or currently taking contraindicated medications for HIV control

Other illness

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Active graft-versus-host-disease (GVHD)
• Active central nervous system (CNS) disease
• No measurable disease in the bone marrow
• Gastrointestinal disorder that interferes with oral drug absorption such as malabsorption syndrome
• Clinically significant cardiac morbidities (class III/IV cardiovascular disability according to the New York Heart Association classification, arrhythmia not stable on medical management, acute cardiovascular ischemic event within 6 months of enrollment, etc.)
• Clinically significant uncontrolled illness
• Active infection requiring antibiotics
• Diagnosis of Gilbert's disease
• Any other active malignancy at time of enrollment. Exceptions include basal/squamous cell carcinoma, in situ adequately treated breast and uterine cancer
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures

Lab values

• Herbal medications known to affect platelet function within 14 days of therapy initiation

Other

• Hematopoietic growth factors in the last 14 days
• Active diarrhea
• Females only: Pregnant or breastfeeding
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

• Documented informed consent of the participant and/or legally authorized representative
• For participants under the age of 18 years, documentation of adolescent assent by the participant and consent of both parents or guardian
• Adults aged \>= 18 years
• Adolescent patients aged \>= 16 years and \< 18 years weighing at least 45 kg who have no other standard-of-care option for treatment
• Eastern Cooperative Oncology Group (ECOG) =\< 2
• Patients with histologically confirmed AML, according to World Health Organization (WHO) criteria, with refractory/relapsed (R/R) disease following a venetoclax-containing regimen who are ineligible for therapies known to be effective for treatment of their AML.
  • Patients with extramedullary disease may be included if they also have marrow involvement
  • Patients with acute promyelocytic leukemia (APL) will not be eligible
• Fully recovered from the acute toxic effects (except alopecia) to =\< grade 1 of prior anti-cancer therapy
• Ability to swallow pills
• Absolute neutrophil count (ANC) \>= 750/mm\^3 (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
  • NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement
• White blood cell (WBC) =\< 25 x 10\^9/L prior to initiation of study therapy. Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be required (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
• Platelets \>= 75,000/mm\^3
  • NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
• Total bilirubin =\< 1.5 X upper limit of normal (ULN) (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
• Aspartate aminotransferase (AST) =\< 3.0 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
• Alanine aminotransferase (ALT) =\< 3.0 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
• Creatinine clearance of \>= 45 ml/min per 24-hour urine test or the Cockcroft-Gault formula (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
• If in the absence of anticoagulants: International normalized ratio (INR) OR prothrombin (PT) =\< 1.5 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
• If in the absence of anticoagulants: Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
• Left ventricular ejection fraction (LVEF) \>= 50%
  • Note: To be performed within 28 days prior to day 1 of protocol therapy
• Corrected QT interval (QTc) =\< 480 ms
  • Note: To be performed within 28 days prior to day 1 of protocol therapy
• Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (RPR) (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
  • If positive, Hepatitis C RNA quantitation must be performed
• Meets other institutional and federal requirements for infectious disease titer requirements
  • Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy
• Women of child-bearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months (males) and 6 months (females) after the last dose of protocol therapy
  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)