• PATIENTS WHO ARE SCHEDULED TO UNDERGO HEMATOPOIETIC CELL TRANSPLANTATION (HCT) OR THOSE WHO HAVE UNDERGONE HCT: Documented informed consent of the participant and/or legally authorized representative

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Agreement to allow the use of archival tissue from diagnostic tumor biopsies; if unavailable, exceptions may be granted with study principal investigator (PI) approval

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participant is willing and able to adhere to the study visit schedule and other protocol requirements

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Age: \>= 2 years

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Have a date for transplant within the next 4 weeks or have received transplant within the last 4 months

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participant was diagnosed with an acute leukemia as defined by the World Health Organization (WHO) 5th edition criteria for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or acute leukemia with ambiguous lineage

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participant must meet one of the following disease characteristics:

‣ Confirmed NPM1m AML with at least one of the following additional characteristics

• FLT3-ITD co-mutation

∙ Pre-transplant MRD+ disease by flow cytometry or real time polymerase chain reaction (qPCR)

∙ Requires more than one AML induction regimen to acquire complete response (CR)1

∙ In second or later complete remission

⁃ Confirmed KMT2Ar acute leukemia obtained by fluorescence in situ hybridization (11q23 MLL-break apart fluorescence in situ hybridization \[FISH\]) or next-generation sequencing (NGS)

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Any donor (sibling, unrelated, mismatched related/unrelated, cord and haploidentical) or graft source (peripheral blood \[PB\] stem cell or bone marrow \[BM\]) will be included

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Conditioning regimen: investigator's choice based on center guidelines

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: GVHD prophylaxis: investigator's choice based on center guidelines

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Patients receiving menin inhibitors prior to alloHCT are eligible

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Negative serum pregnancy test for female patients of childbearing potential who have already undergone alloHCT

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: If a female of childbearing potential, must be willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose

• PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: If male of childbearing potential, must agree to use barrier contraception from the time of enrollment through 120 days following the last study drug dose

‣ Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

• PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Participant has an Eastern Cooperative Oncology Group (ECOG) =\< 2 or Karnofsky Performance Status (KPS) \>= 70, or a Lansky Performance Score of \>= 70 (if aged \< 18 years)

• PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Participant must be eligible for alloHCT by City of Hope (COH) standard operating procedure (SOP) guidelines

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Patients should be in complete remission (CR) by day + 30 (± 7 days) post-HCT BM biopsy

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: No evidence of active or uncontrolled infection at the time of start of revumenib therapy

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant has an ECOG =\< 2 or KPS \>= 70, or Lansky Performance Score of \>= 70 if aged \< 18 years

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: No active grade 2-4 acute GVHD (prednisone dose of =\< 0.5 mg/kg daily is allowed)

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Hemoglobin (Hgb) \>= 9. Transfusion or growth factors are not allowed to achieve these levels

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Platelets \>= 75 thousand (k). Transfusion or growth factors are not allowed to achieve these levels

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Patients must be fully engrafted after HCT, defined as absolute neutrophil count (ANC) \>= 500 for 3 days. Patients may NOT be given granulocyte colony-stimulating factor (GCSF) to meet eligibility criteria; however, they may receive GCSF after start of treatment

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: No morphologic evidence of relapse post-HCT (pre-HCT MRD+ is)

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant is between day + 50 and + 150 after first alloHCT with no morphologic evidence of relapse post-HCT

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Total bilirubin =\< 1.5 x upper limit of normal (ULN) (unless considered to be due to Gilbert's syndrome)

‣ Note: Participants who are \< 75 years of age may have a bilirubin of =\< 3.0 x ULN. Patients with abnormal liver function tests (LFTs) in the context of active GVHD will not be included

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Aspartate aminotransferase (AST) =\< 2.5 x ULN

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Alanine aminotransferase (ALT) =\< 2.5 x ULN

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: QTc using Fridericia's correction (QTcF) =\< 450 msec (males) or =\< 470 msec (females)

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Ejection fraction (EF) of \>= 50% by echocardiogram or multigated acquisition (MUGA) scan

• CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Creatinine clearance of \>= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula