To learn if revumenib (also known as SNDX-5613) can help to control leukemias associated with an increase in expression of HOX genes.

Primary Objectives

• To assess the efficacy of revumenib in leukemias associated with upregulation of HOX genes.

Secondary Objectives

• To assess rates of measurable residual disease (MRD) clearance, as assessed by multiparameter flow cytometry in participants who respond to treatment.
• To assess rates of cytogenetic remissions in participants with baseline cytogenetic abnormalities at diagnosis.
• To assess event-free survival (EFS), duration of response (DOR), and overall survival (OS) in participants with leukemia associated with upregulation of HOX following treatment with revumenib.

Exploratory Objectives

• To evaluate molecular and cellular markers that may be predictive of antitumor activity and/or resistance
• To evaluate HOX/MEIS1 expression as a biomarker of response.
• To assess the rate of mutations in the MEN1 gene as a mechanism of resistance.

Inclusion Criteria:

1. Age ≥ 12 years with weight ≥ 40Kg.

2. ECOG performance status of ≤ 2.

3. Relapsed or refractory acute leukemia, of either myeloid, lymphoid or mixed lineages, with genetic alterations associated with upregulation of HOX, as specified below:

   Alteration/Mutation - Cytogenetics KMT2A-PTD = Normal karyotype; NPM1-MLF1 = t(3;5)(q25;q34); NUP98r = 11p15 rearrangements; SET-NUP214 = t(9;9)(q34;q34); RUNX1-EVI1 = t(3;21)(q26;q22); MYST3-CREBBP = t(8;16)(p11;p13); CDX2-ETV6 = t(12;13)(p13;q12); CALM-AF10 = t(10;11)(p13;q14-21); MN1-ETV6 = t(12;22)(p13;q12); UBTF-TD = Normal karyotype

4. WBC must be below 25,000/ uL at time of enrollment. Participants may receive cytoreduction prior to enrollment.

5. Baseline ejection fraction must be > 40%.

6. Adequate hepatic function (direct bilirubin < 1.5x upper limit of normal (ULN) unless increase is due leukemic involvement, and AST and/or ALT < 3x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT < 5x ULN will be considered eligible).

7. Adequate renal function with an estimated glomerular filtration rate ≥ 60 mL/min based on local institutional practice for age-appropriate determination.

8. Participants or parent/guardian is willing and able to provide informed consent.

9. In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 14 days for cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half-lives of the prior therapy. Oral hydroxyurea and/or cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI). Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.

10. Women of childbearing potential must agree to adequate methods of contraception during the study and at least 3 months after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study and at least 3 months after the last treatment.

Exclusion Criteria:

1. Participants with any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the participant at unacceptable risk of study treatment.
2. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea for participants with rapidly proliferative disease or for control of counts during differentiation syndrome. (3) use of steroids for treatment of differentiation syndrome.
3. Participants with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
4. Participants with concurrent active malignancy under treatment.
5. Known active hepatitis B (HBV) or hepatitis C (HCV) or human immunodeficiency virus (HIV) infections.
6. Female subjects who are pregnant or breast-feeding.
7. Participant has an active uncontrolled infection.
8. Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
9. QTc >450 msec for males and QTc >470 msec for females using the Fridericia Formula using an average of the 3 Screening EKGs.
10. History of or any concurrent condition, therapy, or laboratory abnormality that in the Investigator's opinion might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate.
11. Clinically active central nervous system (CNS) leukemia.
12. Participants on immunosuppressive therapy post-HSCT at the time of screening (must be off all systemic immunosuppression therapy for at least 2 weeks and calcineurin inhibitors for at least 4 weeks). The use of topical steroids for cutaneous graft-versus-host disease (GVHD) or stable systemic steroid doses less than or equal to 20 mg of prednisone (or equivalent) daily are permitted.
13. Participants with Grade > 2 active acute GVHD, moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.