Trial of Revumenib Plus FLA Chemotherapy for Children With Relapsed or Refractory NUP98-rearranged AML."

Inclusion Criteria: Age Patients must be \> 1 year and \< 22 years of age at time of enrollment. Diagnosis Patients must have NUP98-r AML (according to WHO Classification of Hematolymphoid Tumors (5th Edition)) that is either refractory to or is in first relapse following initial therapy. Documentation of prior known NUP98-r AML is sufficient. Definition of relapsed disease: * Recurrent disease with ≥ 5% leukemic blasts by morphology in the bone marrow after having achieved morphologic remission (morph-CR). Patients who have received any other re-induction therapy following relapse will not be eligible. * Morph-CR is defined as attainment of an M1 bone marrow (\< 5% morphologic leukemic blasts) no evidence of circulating leukemic blasts or extramedullary disease and with recovery of peripheral blood counts (ANC ≥ 500/µL and platelet count ≥ 50,000/µL). Definition of primary refractory disease: Refractory disease with ≥ 5% leukemic blasts by morphology in the bone marrow after one attempt at remission induction, which may consist of up to two different therapy courses (e.g., COG AAML1831 de novo therapy including Induction I and Induction II). Patients must not have received more than one remission induction remission attempt. White Blood Cell Count: White blood cell count must be \<25,000 cells/uL at the time of enrollment on the study. Cytoreduction with leukapheresis, hydroxyurea, and/or cytarabine (up to a total dose of 500 mg/m\^2) prior to enrollment is allowed. Performance Level Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2 (\> 50 Lansky or Karnofsky score). Use Karnofsky for patients \> 16 years of age and Lansky for patients ≤ 16 years of age (Appendix I). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. CNS Disease Patients may have status of CNS1, CNS2, or asymptomatic CNS3 disease. Patients with symptomatic CNS 3 disease are ineligible. HIV-Infection HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial, provided antiretroviral therapy does not have clinically significant drug-drug interactions with revumenib. Prior Therapy: Patients must have recovered from all prior treatment-related toxicities to grade ≤1 or the patient's baseline and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. 1. Cytotoxic Chemotherapy: Must not have received within 14 days of entry onto this study, except for hydroxyurea or cytarabine NOTE: Cytoreduction with hydroxyurea and cytarabine (up to a total dose of 500 mg/m2) must be discontinued prior to the start of protocol therapy. 2. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before enrollment. Any toxicity related to prior antibody therapy must be recovered to Grade ≤ 1. 3. Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors). 4. Hematopoietic Growth Factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or ≥ 7 days for short acting growth factor. 5. Radiation Therapy (RT): * 14 days have elapsed for local palliative RT (small port); * ≥ 84 days must have elapsed if prior craniospinal RT or if 50% radiation of pelvis; * ≥ 42 days must have elapsed if other substantial BM radiation. 6. Stem Cell Infusions: * ≥ 84 days since allogeneic (non-autologous) bone marrow or stem cell transplant (with or without TBI) or boost infusion (any stem cell product; not including DLI); * No evidence of graft versus host disease (GVHD). 7. Cellular Therapy: ≥ 28 days after the completion of DLI (donor lymphocyte infusion) or any type of cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.). NOTE: Potential subjects who have received an intervention intended to treat their primary malignancy which does not fall into one of the above categories will require a minimum 30 day washout from that intervention and the patient must be discussed with the Study Chair or designee who may determine a longer washout period as necessary. NOTE: Intrathecal chemotherapy: No waiting period is required for patients having received any combination of intrathecal therapy (cytarabine, methotrexate, and/or corticosteroids). Organ Function Requirements Adequate Renal Function Defined as: Patient must have a calculated creatinine clearance or radioisotope GFR ≥ 60ml/min/1.73m2. Adequate Liver Function Defined as: * Total bilirubin (sum of conjugated + unconjugated) ≤ 1.5x institutional upper limit of normal for age (unless attributable to leukemic involvement), and * SGPT (ALT) and SGOT (ALT) must be ≤3x institutional upper limit of normal. Patients with ALT and AST ≥ 3x ULN attributable to leukemic involvement of the liver are eligible as long as both are ≤5x ULN. Adequate Cardiac Function at Screening, Defined as: * Ejection fraction (EF) of ≥ 50% or if EF unavailable, shortening fraction (SF) ≥ 28% by echocardiogram. AND * Corrected QT (using Fridericia's correction \[QTcF\]) interval \< 450 msecs. See Appendix II for directions on calculating QTcF. NOTE: There are no specific electrolyte parameters for eligibility. However, it should be noted that, to limit QTc prolongation risk, patients must maintain adequate potassium and magnesium levels to initiate and continue revumenib on protocol therapy. See section 4.1.2.1 for electrolyte monitoring. . Reproductive Function * Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 72 hours prior to enrollment. * Female patients with infants must agree not to breastfeed their infants while on this study and for one week after the last revumenib dose. * Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for up to 4 months (16 weeks) after the last dose of revumenib. Exclusion Criteria: Isolated Extramedullary Disease: Patients with isolated extramedullary disease are ineligible. Prior diagnosis of acute lymphoblastic leukemia: Patients experiencing lineage switch to AML will not be eligible for this study. CNS3 Disease with clinical signs or neurologic symptoms suggestive of CNS leukemia at time of relapse, such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome. Infection: Patients with documented active, uncontrolled infection at the time of study enrollment. Patients are excluded if they have: * Positive blood culture within 48 hours of study enrollment; * Fever above 38.2⁰C within 48 hours of study enrollment with clinical signs of infection. NOTE: Fever that is determined to be due to tumor burden does NOT exclude patients if there are documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability. * A positive fungal culture within 30 days of study enrollment. * Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic prophylaxis therapy to prevent infections does not exclude patients. Cardiac: Patients with a history of congenital prolonged QT syndrome, congestive heart failure, or uncontrolled arrhythmia in the past 6 months prior to study enrollment. Gastrointestinal issues: Patients with gastrointestinal issues of the upper gastrointestinal tract that might affect oral drug absorption. Prior menin inhibitor therapy Patients with active GVHD are ineligible to enroll. Patients who are receiving systemic cyclosporine, tacrolimus, or other agents to prevent or treat either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible to enroll on the trial. Patients must be off calcineurin inhibitors for at least 4 weeks to be eligible. Concomitant Medications CYP3A4 Inhibitors/Inducers: Systemically administered moderate or strong CYP3A4 inducers or strong CYP3A4 inhibitors should be discontinued for at least 5 half-lives or 7 days prior to enrollment (whichever is later) with the following exceptions: itraconazole, ketoconazole, posaconazole, or voriconazole. Corticosteroids: Patients who are receiving systemic corticosteroids are not eligible except when given as physiologic dosing (prednisone equivalent of ≤ 10 mg/day if ≥18 years and ≤ 10 mg/m2/day for patients \< 18 years is allowed). Investigational Drugs: Patients who are receiving another investigational drug (for a time frame less than the 5 half-life periods of the respective investigational drug) are not eligible. QTc Prolonging Agents: Medications with a known risk of Torsades de Pointes (TdP) are prohibited, with the exception of drugs that are used as standard supportive therapies (listed below). Medications with a possible or conditional risk of TdP are allowed. Consult CredibleMeds® at https://crediblemeds.org/ for risk classifications. Medications with a known risk of TdP used as standard supportive therapies that are allowed for concomitant use: azithromycin, ciprofloxacin, fluconazole, levofloxacin, methadone (allowed if chronic, scheduled use \> 2 weeks prior to revumenib initiation; do not initiate methadone during protocol treatment), ondansetron, pentamidine, and propofol. See Appendix II for Cardiac Monitoring Guidelines Patients with a contraindication or unable to tolerate at least one of the following medications utilized for antifungal prophylaxis: itraconazole, ketoconazole, posaconazole, or voriconazole. Patients will be excluded if they have a known allergy to any of the drugs used in the study. Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results. Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded. Patients with cirrhosis based on PELD and Child-Pugh scoring systems with moderate to severe hepatotoxicity are excluded.