Study of Biomarker-Based Treatment of Acute Myeloid Leukemia

Inclusion Criteria (IC): * Adults, age ≥60 yrs at diagnosis unless in a specific known cytogenetic \& genomic group for which treatment in Group A, B, or C is allowed by the substudy where age 18+ is allowed. Patients \<60 yrs who are screened but do not fall w/in the cytogenetic \& genomic open substudies would still be followed on the M1 Master Protocol (MP) \& not considered screen fails * Patients must be able to understand \& provide written informed consent * Group A: Patients must have previously untreated AML according to WHO classification w/ no prior treatment other than hydroxyurea. Patients w/ myeloid malignancies \[eg, myelodysplastic syndrome (MDS) or other disease\], will be allowed to enroll to this group. For previously untreated subjects w/ ≥20% blasts in bone marrow or blood only: Prior therapy for MDS, myeloproliferative syndromes (MPD), or aplastic anemia is permitted. For select group, patients who cannot wait or choose not to wait for results of genomic testing, will be allowed to enroll to select substudies that allow enrollment \& treatment of all patients regardless of their genomic mutations or cytogenetics. For this group, genomic samples will be collected to be analyzed retrospectively after patients' enrollment * Group B: Patients must have relapsed or refractory AML according to WHO classification. For study purposes, refractory AML is defined as failure to ever achieve a complete response (CR) or recurrence of AML w/in 6 months of achieving CR; relapsed AML is defined as all others w/ disease after prior remission. For select genomic aberrations specified in substudies, patients ≥18 yrs may be allowed to enroll in this portion of the study. Patients w/ relapsed or refractory myeloid malignancies (eg, MDS or other diseases) will be allowed to enroll to this group * Group C: For select sites not part of Beat AML core sites. These sites will only participate in select substudies. Patients in this group will enroll under the Beat AML M1 MP w/ the intent to enroll into these select substudies \& following screening on Beat M1 MP, they will come off M1 MP Exclusion Criteria (EC): * Acute promyelocytic leukemia (APL) * Clinically active CNS involvement by AML. A patient may be considered eligible if CNS leukemia is showing response to treatment at study entry \& should continue to receive intrathecal therapy as clinical indicated. Patients who require or are undergoing craniospinal irradiation of disease control are not eligible for participation * Signs of leukostasis requiring urgent therapy * Disseminated intravascular coagulopathy (DIC) w/ active bleeding or signs of thrombosis * Patients w/ psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol (including failure to collect genomics samples for screening), or complying w/ study treatment \& follow-up * Any other significant medical condition, including psychiatric illness or lab abnormality, that would preclude patient participation in the trial or would confound interpretation of trial results S17 - IC 1. Age ≥60 yrs at diagnosis w/ untreated AML according to International Consensus Classification (ICC) 2022 \& have NPM1 mutated or KMT2A rearrangement disease \& are not candidates for or do not wish to pursue intensive chemotherapy 2. Patients must be able to understand \& provide written informed consent 3. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 4. Aspartate aminotransferase (AST) \<5 x upper limit of normal (ULN), alanine aminotransferase (ALT) \<5 x ULN, \& total bilirubin \<2 x ULN (except for patients w/ known or suspected Gilbert's syndrome \& w/ direct bilirubin w/in normal range) for the local lab 5. Adequate renal function as defined by calculated creatinine clearance ≥60 mL/min for the local lab 6. Females must be non-childbearing, postmenopausal, surgically sterile or meet certain criteria if of childbearing potential. Males must adhere to criteria if w/ females of childbearing potential 7. Patients must have previously untreated AML w/ no prior treatment other than hydroxyurea. No chemotherapy for AML outside of hydroxyurea for treatment of leukostasis or ATRA for initially suspected APL (that is ruled out) is allowed as well as 1 dose of intrathecal chemotherapy for suspected CNS involvement (that is ruled out) is allowed. Prior therapy for MDS allowed except for hypomethylating agents 8. If patient has co-morbid illness or malignancy, life expectancy attributed to this must be \>2 yrs S17 - EC 1. Isolated myeloid sarcoma (must have blood or marrow involvement w/ AML) 2. APL (FAB M3) 3. Favorable risk cytogenetics (Core Binding Factor AML) 4. Active CNS involvement by AML 5. Signs of leukostasis requiring urgent therapy 6. WBC ≥25,000/μl (WBC \<25,000/μl to begin therapy, Hydroxyurea may be used to obtain this level) 7. Willing \& able to receive intensive chemotherapy 8. DIC w/ active bleeding or signs of thrombosis 9. Patients w/ psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or complying w/ study treatment \& follow-up 10. Any significant medical condition, including psychiatric illness or lab abnormality, that would preclude the patient participating in the trial or would confound trial result interpretation 11. Known active HIV, active hepatitis B or C infections 12. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (CHF), unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction (MI) as presentation of AML, New York Heart Association (NYHA) Class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients w/ medical comorbidities that will preclude safety evaluation of the combination should not be enrolled 13