Study of Revumenib, Azacitidine, and Venetoclax in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia

Inclusion Criteria: Participants must have a diagnosis of AML or ALAL and meet the criteria below:

• Refractory leukemia, defined as persistent leukemia after at least two courses ofinduction chemotherapy (one course for secondary AML), or relapsed leukemia, definedas the re-appearance of leukemia after the achievement of remission. Patients musthave ≥5% blasts in the bone marrow as assessed by morphology or ≥1% blasts flowcytometry.

However, if an adequate bone marrow sample cannot be obtained (e.g., in a patient with acute megakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if there is unequivocal evidence of leukemia with ≥5% blasts by morphology or ≥1% blasts flow cytometry in the blood.

• Presence of KMT2A rearrangement (KMT2Ar), NUP98 rearrangement (NUP98r), NPM1mutation or fusion, PICALM::MLLT10, DEK::NUP214, UBTF-TD, KAT6A rearrangement (KAT6Ar), or SET::NUP214

• Adequate organ function, defined as total bilirubin < 1.5 × institutional upperlimit of normal for age or normal conjugated bilirubin (for patients with knownGilbert's syndrome, total bilirubin <3 × the ULN) unless attributed to leukemia,calculated creatinine clearance ≥60 mL/min/1.73 m^2, and left ventricular ejectionfraction ≥ 40%

• QTcF < 480 msec (average of triplicate)

• Age ≥ 1 year and ≤ 30 years. The upper age limit may be defined by each institution,but may not exceed 30 years.

• Lansky ≥ 60 for patients who are < 16 years old and Karnofsky ≥ 60% for patients whoare > 16 years old.

• At least 14 days or 5 half-lives (whichever is longer) must have elapsed since thecompletion of myelosuppressive therapy, with the exception of low-dose therapy usedfor cytoreduction according to institutional standards, such as hydroxyurea orlow-dose cytarabine (up to 200 mg/m^2/day). In addition, all toxicities must haveresolved to grade 1 or less.

• Patients must have a leukocyte count <25,000 cells/uL. Low-dose therapy, such ashydroxyurea or cytarabine as described above, to achieve this limit is acceptable.

• For patients who have received prior HCT, there can be no evidence of GVHD andgreater than 60 days must have elapsed since the HCT, and patients should be offcalcineurin inhibitors for at least 28 days prior to the start of protocol therapy.Physiologic prednisone for the treatment of adrenal insufficiency is acceptable..

• Patients must be taking posaconazole or voriconazole, which must be started at least 24 hours prior to the start of therapy.

• Patients of reproductive potential must agree to use effective contraception for theduration of study participation.

Patients who meet the criteria listed above are eligible for enrollment and treatment on the trial. However, patients in first relapse who are suitable for and willing to receive intensive remission induction therapy should be offered such therapy if deemed appropriate by the treating physician.

Exclusion Criteria:

• Patients who are pregnant or breastfeeding are not eligible.

• Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocyticleukemia, or bone marrow failure syndromes are not eligible.

• Patients with uncontrolled infection are not eligible. Patients with infections thatare controlled on concurrent anti-microbial agents are eligible.