Revumenib and Venetoclax for the Treatment of Patients with Acute Myeloid Leukemia with Measurable Residual Disease

Inclusion Criteria

• Age ≥ 12 years with weight ≥ 45Kg
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 (if aged ≥ 18 years); Karnofsky performance scale of ≥ 50 (if aged ≥ 16 years and < 18 years); Lansky Performance Score of ≥ 50 (if aged < 16 years)
• Leukemia status: * Known history of NPM1mt, or KMT2Ar, or NUP98r AML * Bone marrow assessment showing no leukemia by morphology (blasts < 5%) in first remission following high intensity chemotherapy or at least 2 cycles of low intensity therapy (e.g. hypomethylating agent or low-dose cytarabine-based), or in second remission following any therapy, with MRD ≥ 0.1% identified by multiparameter flow cytometry using central lab testing * No clinically active extramedullary disease
• Baseline ejection fraction must be > 40%
• Adequate hepatic function (direct bilirubin < 1.5 x upper limit of normal (ULN) unless increase is due leukemic involvement, and aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT < 5 x ULN will be considered eligible)
• Adequate renal function with an estimated glomerular filtration rate ≥ 60 mL/min based on local institutional practice for age-appropriate determination
• Able to swallow pills
• Patient or parent/guardian is willing and able to provide informed consent. 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, whichever is shorter. Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted
• 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

• Prior treatment with a menin inhibitor
• Patients who are expected to receive standard therapy (either intensive or hypomethylating agent and venetoclax) with continued tolerability and benefit
• Patients who are expected to be able to proceed with stem cell transplantation within the next 30 days
• Patients with any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the patient at unacceptable risk of study treatment
• The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions * Intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia * Use of hydroxyurea for patients with rapidly proliferative disease or for control of counts during differentiation syndrome * Use of steroids for treatment of differentiation syndrome
• Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
• Patients with a concurrent active malignancy under treatment
• Known active hepatitis B (HBV) or hepatitis C (HCV) or human immunodeficiency virus (HIV) infection
• Female subjects who are pregnant or breast-feeding
• Patient has an active uncontrolled infection
• 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
• QTc > 450 msec for males and QTc > 470 msec for females using the Fridericia Formula
• 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
• Clinically active central nervous system (CNS) leukemia
• Patients on immunosuppressive therapy post-hematopoietic stem cell transplantation (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 daily are permitted
• Patients with grade > 2 active acute graft versus host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity