New combo aims to wipe out hidden leukemia cells

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: * COHORT A: Participants must meet diagnostic criteria for either B-cell acute lymphoblastic leukemia (ALL) with KMT2A-translocation or acute leukemia with ambiguous lineage (ALAL) with KMT2A-translocation * COHORT A: Participants must have KMT2A-translocation documented locally by conventional cytogenetics, fluorescence in situ hybridization (FISH) or molecular studies such as next generation sequencing (NGS) * COHORT A: Participants must have achieved morphological first complete remission (CR1) after induction cycle (s) as defined bone marrow lymphoblasts \< 5% * COHORT A: Participants must have either known trackable clone(s) by clonoSEQ that was identified at initial diagnosis, or a banked diagnostic sample, which can include clinical samples from the treating institution, available that can be used to identify trackable clone(s) * Participants must not be known not to have trackable clones by clonoSEQ * Participants must not be known already to have MRD-negativity by clonoSEQ prior to enrollment * COHORT A: Participants must have evidence of CD19 expression at any level in ALL or ALAL documented locally by flow cytometry or immunohistochemistry in bone marrow or peripheral blood at the time of initial diagnosis. Immunophenotyping of the blood or marrow lymphoblasts must be performed to determine lineage. Appropriate marker studies including CD19 (B cell) must be performed. If a bone marrow aspirate cannot be obtained despite an attempt (dry tap), appropriate Immunohistochemistry (IHC) testing, including CD19, must be performed on the bone marrow biopsy to determine lineage * COHORT A: Participants must have Philadelphia-chromosome negative ALL or ALAL * COHORT A: Participants must not have known lymphoid blast crisis arising from chronic myeloid leukemia (CML) or have received previous tyrosine kinase inhibitor (TKI) therapy for their chronic myeloid leukemia (CML) * COHORT B: Participants must meet diagnostic criteria for either newly diagnosed with acute lymphoblastic leukemia (ALL) or acute leukemia with ambiguous lineage (ALAL) * Participants with either B or T-cell subtypes of ALL are permitted on Cohort B * Participants must have KMT2A-translocation documented locally by conventional cytogenetics, fluorescence in situ hybridization (FISH) or molecular studies such as next generation sequencing (NGS) * COHORT B: Participants must have Philadelphia-chromosome negative ALL or ALAL * COHORT B: Participants must not have known lymphoid blast crisis arising from CML or have received previous TKI therapy for their chronic myeloid leukemia (CML) * COHORT A: Participants ≥ 18 years may have received 1 to 3 cycles of induction/consolidation before entering the study. It is encouraged to enroll participants immediately after completing the first induction cycle if the patient achieves morphological CR. For pediatric patients \< 18 years of age, enrollment must occur after induction therapy * COHORT A: Participants must discontinue strong cytochrome P450 (CYP)3A4 inhibitors or strong or moderate inducers, except corticosteroids, within 14 days prior to registration * COHORT A: Participants must have recovered from any prior major surgery adverse effects at least 14 days prior to registration, to the satisfaction of the local investigator * Note: Central venous access placement is not considered major surgery for the purposes of this protocol * COHORT A: Participants must not be receiving any oral or intravenous systemic immunosuppressive therapy with the exception of induction/consolidation chemotherapy for the treatment of their current ALL or ALAL. Participants may receive up to 10 mg per day of prednisone or prednisone equivalent for adrenal insufficiency or other indications * COHORT A: Participants must not have received a prior allogeneic hematopoietic stem cell transplant * COHORT A: Participants must not have received prior blinatumomab, menin inhibitors, chimeric antigen receptor (CAR)-T therapy, or anti-CD19 antibodies * COHORT B: Participants must not have received prior systemic therapy for ALL or ALAL, with the exception of hydroxyurea, steroid, retinoic acid, intrathecal chemotherapy, or induction chemotherapy as defined below * Participants who have been started on the study regimen backbone (i.e. induction therapy) before consenting and then are found to have the KMT2Ar and are eligible for the study, can be enrolled on the study as long as revumenib treatment can be started by day 8 of induction therapy * COHORT B: Participants must discontinue strong CYP3A4 inhibitors or strong or moderate inducers, except corticosteroids, within 14 days prior to registration * COHORT B: Participants must have recovered from any prior major surgery adverse effects at least 14 days prior to registration, to the satisfaction of the local investigator * Note: Central venous access placement is not considered major surgery for the purposes of this protocol * COHORT B: Participants must not be receiving any systemic oral or intravenous immunosuppressive therapy with the exception of induction chemotherapy or corticosteroid for the treatment of their current ALL or ALAL * COHORT B: Participants must not have received a prior allogeneic hematopoietic stem cell transplant * COHORT A: Participant must be ≥ 1 years old at the time of registration. There is no upper age limit * COHORT A: Participant must have Zubrod/Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or Lansky/Karnofsky performance status scores of 50-100 * COHORT A: Participants must have a complete medical history and physical exam within 28 days prior to registration * COHORT A: Glomerular filtration rate (GFR) ≥ 50 ml/min/1.73 m\^2 (within 14 days prior to registration) * COHORT A: Absolute neutrophil count ≥ 1 x 10\^3/uL (within 14 days prior to registration) * COHORT A: Platelets ≥ 100 x 10\^3/uL (within 14 days prior to registration) * COHORT A: Direct bilirubin ≤ 2.0 mg/dL (34.2 micromoles/L) (within 14 days prior to registration) * Note: Participants with history of Gilbert's disease must have direct bilirubin ≤ 5 x institutional upper limit of normal (ULN) * COHORT A: Alanine aminotransferase (ALT) ≤ 5 x institutional ULN (within 14 days prior to registration) * COHORT A: Participants ≥ 18 years must have a calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault formula. This specimen must have been drawn and processed within 14 days prior to registration * COHORT A: Adequate renal function for participants \< 18 years of age is defined as: * A GFR ≥ 50 mL/min/1.73 m\^2, as determined by one of the following methods: * Estimated GFR (eGFR) ≥ 50 mL/min/1.73 m\^2 "Bedside" Schwartz formula (2009) * Measured GFR ≥ 50 mL/min/1.73 m\^2 (any age). If measured GFR is used, it must be performed using direct measurement with a nuclear blood sampling method or small molecule clearance method (iothalamate or other molecule per institutional standard) * COHORT A: Participants must have adequate cardiac function. Participants must have cardiac ejection fraction ≥ 50% by MUGA or 2 dimensional (2-D) echocardiogram or shortening fraction (SF) ≥ 27% by echocardiogram within 90 days prior to registration. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better * COHORT A: Participants ≥ 18 years of age with a known history of human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration * COHORT A: Participants ≥ 18 years of age with a known history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated * COHORT A: Participants ≥ 18 years of age with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated * COHORT A: Participants must not have prolonged Fridericia's formula-corrected QT interval (QTcf) defined as \> 450 msec on screening electrocardiogram (EKG) prior to registration * COHORT A: Participants must not have relapsed or refractory disease in the bone marrow (≥ 5% blasts) or extramedullary sites involvement * COHORT A: Participants must not have systemic fungal, bacterial, viral or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) as determined by the local investigator * COHORT A: Participants must not have clinically significant autoimmune disease * COHORT A: Participants must be able to take oral medications and comply with the oral regimen Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications. Administration via nasogastric/gastrostomy (NG/G)-tube is acceptable as long as oral solution is used * COHORT A: Participants must not have uncontrolled intercurrent illness including, but not limited to: * Active central nervous system status 3 (CNS3) or CNS2 (CNS leukemia) * Note: Participants with CNS1 or who had prior CNS2 or CNS3 are eligible if this has cleared and have become CNS-1 * Currently requiring supplemental oxygen (more than 2 liters per minute), mechanical ventilation, vasopressors * COHORT A: Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen * COHORT A: Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 24 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen * Note: Participants of childbearing potential must have a negative pregnancy test within 7 days prior to starting treatment * COHORT B: Participant must be ≥ 55 years old at the time of registration * COHORT B: Participant must have Zubrod/ECOG performance status of 0-2 * COHORT B: Participants must have a complete medical history and physical exam within 28 days prior to registration * COHORT B: GFR ≥ 50 ml/min/1.73 m\^2 (within 14 days prior to registration) * COHORT B: Direct bilirubin ≤ 2.0 mg/dL (34.2 micromoles/L) (within 14 days prior to registration) * Note: Participants with history of Gilbert's disease or elevated bilirubin is related to underlying leukemia must have direct bilirubin ≤ 5 x institutional ULN * COHORT B: ALT ≤ 5 x institutional ULN unless abnormal liver tests are related to underlying leukemia (within 14 days prior to registration) * COHORT B: Participants must have a calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault formula. This specimen must have been drawn and processed within 14 days prior to registration * COHORT B: Participants must have adequate cardiac function. Participants must have cardiac ejection fraction ≥ 50% by MUGA or 2-D echocardiogram within 28 days prior to registration. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better * COHORT B: Participants with a known history human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration * COHORT B: Participants with a known history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated * COHORT B: Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated * COHORT B: Participants must have a lumbar puncture to determine CNS involvement of ALL within 14 days prior to registration. Intrathecal cytarabine and/or methotrexate administered prior to study registration may count as the first dose of intrathecal therapy required as part of protocol therapy * COHORT B: Participants must not have an active uncontrolled infection * COHORT B: Participants must not have prolonged QTcf defined as \> 450 msec participants on screening EKG prior to registration * COHORT B: Participants must not have known clinical signs of bulk central nervous system involvement (CNS3c), such as facial palsy, brain/eye involvement or hypothalamic syndrome * COHORT B: Participants must be able to take oral medications and comply with the oral regimen Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications. Administration via NG/G-tube is acceptable as long as oral solution is used * COHORT B: Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen * COHORT B: Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 24 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen * Note: Participants of childbearing potential must have a negative pregnancy test within 7 days prior to starting treatment * ALL COHORTS: Participants must be offered the opportunity to participate in specimen collection submitted for translational medicine work. With participant consent, specimens must be collected and submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System * NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system * Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines * For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations * This trial will use a slot reservation system to enroll the feasibility and safety run-in portions of the study for Cohort A and Cohort B. Patients planning to enroll at this portion of the study must first have a slot reserved in advance of the registration. All site staff will use OPEN to create a slot reservation