The purpose of this study is to assess how bleximenib and Venetoclax (VEN)+ Azacitidine (AZA) works as compared to placebo and VEN+AZA alone for the treatment of participants with newly diagnosed Acute Myeloid Leukemia (AML) with a mutation in the NPM1 or KMT2A gene.
Be 18 years of age or older at the time of informed consent
Previously untreated lysine N-methyltransferase 2A gene rearranged (KMT2Ar) or nucleophosmin 1 gene mutated (NPM1m) acute myeloid leukemia (AML) with greater than or equal to (> or =) 10% bone marrow blasts per 2022 international Consensus Classification criteria
Ineligible for intensive chemotherapy based on the following criteria: a) >= 75 years of age and ineligible per physician's discretion, with Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, b) >=18 to <75 years of age with >= 1 of the following comorbidities: i) ECOG performance status of 2, ii) Severe cardiac disorder, iii) Severe pulmonary disorder, iv) Renal impairment, v) Moderate hepatic impairment vi) Comorbidity that, in the investigator's opinion, makes the participant unsuitable for intensive chemotherapy, which must be documented before enrollment as defined in the protocol. Ineligibility for intensive chemotherapy should be explicitly approved by a multidisciplinary team in countries in which this process is standard of care
Participants must have adequate hepatic and renal function
Diagnosis of acute promyelocytic leukemia (APL)
Known active leukemic involvement of the central nervous system (CNS)
Recipient of solid organ transplant
Any cardiac disorders such as heart attack, uncontrolled/unstable chest pain, congestive heart failure, uncontrolled or symptomatic irregular heartbeat, blockage of a blood vessel to brain, or transient ischemic (decreased oxygen in tissue) attack within 6 months of randomization
Parallel
Bleximenib
DrugBleximenib will be administered orally.
Venetoclax (VEN)
DrugVEN will be administered orally.
Azacitidine (AZA)
DrugAZA will be administered intravenously or subcutaneously.
Placebo
DrugPlacebo will be administered orally.
Percentage of Participants who Achieve Complete Remission (CR)
CR is defined as Bone marrow blasts less than (\<) 5 percent (%); Absence of circulating blasts; Absence of extramedullary disease; Absolute neutrophil count (ANC) greater than or equal to (\>=) 1.0 \* 10\^9/Liter (1,000/microliter \[mcL\]); Platelet count \>= 100 \* 10\^9/L (100,000/mcL).
Overall Survival (OS)
Overall survival time is defined as the time duration from the date of randomization to death due to any cause.
Event-free survival (EFS)
EFS is defined as the time from randomization to treatment failure, relapse, or death due to any cause, whichever occurs first.
Duration of CR
Duration of CR will be estimated among responders from the date of initial documentation of CR, to the date of first documented evidence of relapse, or death due to any cause, whichever occurs first, respectively.
Time to CR
Time to CR is defined as time from randomization to first documented response.
Rate of CR Without Measurable Residual Disease (MRD-)
Rate of CR MRD- is defined as percentage of participants who have achieved CR without MRD.
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