Testing the Use of an IDH1 Inhibitor, Olutasidenib, in Acute Myeloid Leukemia Added to ASTX727 and Venetoclax; in High-Risk MDS Added to ASTX727; and Alone in Low Risk MDS (A MyeloMATCH Treatment Substudy)

Inclusion Criteria:

* Patient must be enrolled on the MYELOMATCH Master Screening and Reassessment Protocol (MSRP), determined to have an IDH1-R132 mutation and assigned to this trial via MATCHBox
* REGISTRATION ELIGIBILITY CRITERIA (STEP 1):
* Documentation of IDH1 mutated MDS or AML
* COHORT A: Age ≥ 60 years or adults ˂ 60 and ≥ 18 who in the opinion of the treating physician are not candidates for intensive, cytarabine-based induction based on clinical status (i.e., performance status), organ dysfunction, or disease biology with a morphologically confirmed diagnosis of AML with ≥ 20% myeloblasts in the bone marrow or peripheral blood
* COHORT B: Age ≥ 18 years with treatment-naïve HR-MDS with an IPSS-R score ≥ 4.0 at time of enrollment
* COHORT C: Age ≥ 18 years with LR-MDS with an IPSS-R score ≤ 3.5 at time of enrollment and either:

  * RBC-TD anemia (≥ 2 units/8 weeks in the 16 weeks prior to registration) who have failed or are ineligible to erythropoiesis-stimulating agents (ESA) therapy
  * Presence of either neutropenia (\< 1 x 10\^9/L) or thrombocytopenia (\< 100 x 10\^9/L) for use as frontline therapy or after failure of prior therapies, including growth factors. Patient must be hypomethylating agent (HMA)-naïve
* No prior therapy excluding:

  * Cohort A: hydroxyurea and all-trans retinoic acid (ATRA) for AML
  * Cohort B: ESAs (erythropoiesis-stimulating agents) and/or TGF-β inhibitors for HR-MDS
  * Cohort C: ESAs (erythropoiesis-stimulating agents, TGF-β inhibitors, telomerase inhibitors, and/or G-CSF for LR-MDS)
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 3
* Creatinine clearance ≥ 30 mL/min (using the Cockcroft-Gault equation)
* Total bilirubin ≤ 3 x upper limit of normal (ULN)

  * Unless the increase is due to Gilbert's disease as determined per physician discretion/institutional practice
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3 x upper limit of normal (ULN)
* Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effect on the developing fetus and newborn are unknown

  * Therefore, for women of childbearing potential only, a negative pregnancy test must be done ≤ 7 days prior to registration. (Cohorts B and C only)
* 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 with known HIV infection on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration 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 known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. A corrected QT interval \< 480 msec (calculated using the Fridericia's formula \[QTcF\]) excluding patients with a right bundle branch block (RBBB) after approval of the principal investigator (PI)
* No known medical condition causing an inability to swallow, tolerate oral medications and must have no known malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or small bowel resection) that may significantly alter the absorption of the study drugs
* RE-REGISTRATION ELIGIBILITY CRITERIA FOR COHORT B, ARM 3 (STEP 2): Patients on the ASTX727 monotherapy arm (Cohort B-Arm 3) that do not achieve a CR (complete response), CRL (CR with limited count recovery), or CRh (CR with partial count recovery) after completing 6 cycles of study treatment
* RE-REGISTRATION ELIGIBILITY CRITERIA FOR COHORT B, ARM 3 (STEP 2): ECOG Performance Status ≤ 3
* RE-REGISTRATION ELIGIBILITY CRITERIA FOR COHORT B, ARM 3 (STEP 2): Creatinine clearance ≥ 30 mL/min (using the Cockcroft-Gault equation)
* RE-REGISTRATION ELIGIBILITY CRITERIA FOR COHORT B, ARM 3 (STEP 2): Total bilirubin ≤ 3 x upper limit of normal (ULN)

  * Unless the increase is due to Gilbert's disease as determined per physician discretion/institutional practice
* RE-REGISTRATION ELIGIBILITY CRITERIA FOR COHORT B, ARM 3 (STEP 2): AST (SGOT)/ALT (SGPT) ≤ 3 x upper limit of normal (ULN)