8-Chloroadenosine in Combination With Venetoclax for the Treatment of Patients With Relapsed/Refractory Acute Myeloid Leukemia

This phase I trial tests the safety, side effects, and best dose of a new 8-chloroadenosine in combination with venetoclax in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). 8-Chloroadenosine may help block the formation of growths that may become cancer. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving 8-chloroadenosine in combination with venetoclax may help prevent the disease from coming back in patients with acute myeloid leukemia.

Inclusion Criteria: * Documented informed consent of the participant and/or legally authorized representative. * Age: \>= 18 years. * Eastern Cooperative Oncology Group (ECOG) =\< 2. * Life expectancy \> 3 months. * Patients with histologically confirmed acute myeloid leukemia (AML), according to World Health Organization (WHO) criteria, with relapsed/refractory disease. * Patients must have any one of the following treatment history criteria: * Relapsed AML * Failed at least 1 line of salvage therapy or * Untreated relapse and are not candidates for allogeneic hematopoietic stem cell transplantation (alloHCT) * De novo AML * have not achieved complete response (CR) after 2 lines of therapy or * refractory to frontline therapy and not eligible for alloHCT * AML evolving from myelodysplastic syndrome (MDS) or myeloproliferative disorder who have failed hypomethylating agents (HMA) or induction chemotherapy * Patients who have relapsed after allo-HCT are eligible if they are at least 3 months after HCT, do not have active graft versus host disease (GVHD) and are off immunosuppression except for maintenance dose of steroids (prednisone 10 mg/day or less). * Male subjects must agree to not donate sperm while taking protocol therapy through at least 90 days after the last dose. * White blood cell (WBC) =\< 25 x 10\^9/L prior to initiation of venetoclax. Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be required. * Total bilirubin =\< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease). * Aspartate aminotransferase (AST) =\< 2.5 x ULN. * Alanine aminotransferase (ALT) =\< 2.5 x ULN. * Creatinine clearance of \>= 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula. * QTc =\< 480 ms. * Women of childbearing 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. * 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 6 months (females) and 3 months (males) 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). Exclusion Criteria: * Current or planned use of other investigational agents, antineoplastic, biological, chemotherapy, or radiation therapy during the study treatment period, or within 2 weeks prior to day 1 of protocol therapy, with the following exception: * Hydroxyurea which may be continued through cycle 1. * Expected to undergo HCT within 120 days of enrollment. * Current or planned use of agents that prolong or suspected to prolong QTc. * Received strong or moderate CYP3A inducers or St. John's Wort within 7 days prior to day 1 of protocol therapy. * Received strong or moderate CYP3A inhibitors, or consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to day 1 of protocol therapy. * P-glycoprotein (P-gp) inhibitors within 7 days prior to day 1 of protocol therapy. * Narrow therapeutic index P-gp substrates within 7 days prior to day 1 of protocol therapy. * Acute promyelocytic leukemia. * Active central nervous system (CNS) leukemia. * Active fungal infection or bacterial sepsis. * Class III/IV cardiovascular disability according to the New York Heart Association classification. * Participants with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of enrollment. Subjects with controlled, asymptomatic atrial fibrillation can enroll. * History of acute cardiovascular ischemic event, i.e., myocardial infarction or unstable angina within 6 months of enrollment. * History of unexplained syncope, significant histories of CAD (requiring revascularization by percutaneous coronary intervention \[PCI\] or coronary artery bypass grafting \[CABG\]), cardiomyopathy (ejection fraction \[EF\] \< 50%). * Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy). * Unable to swallow capsules, has a partial or small bowel obstruction, or has a gastrointestinal condition resulting in a malabsorptive syndrome (e.g. small bowel resection with malabsorption). * Active peptic ulcer disease. * Other active malignancy except for localized skin cancer, bladder, prostate, breast or cervical carcinoma in situ. * Females only: Pregnant or breastfeeding. * 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. * 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).