Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm

Inclusion Criteria:

• Diagnosis:

• Phase I cohort: Adults ≥ 18 years with relapsed/refractory FLT3-mutated AML orCMML or other MDS/MPN that is intermediate-2 or high-risk by the InternationalPrognostic Scoring System

• Phase II cohort A: Adults ≥ 18 years with newly diagnosed FLT3-mutated AML

• Phase II cohort B: Adults ≥ 18 years with relapsed/refractory FLT3-mutated AMLor CMML or other MDS/MPN that is intermediate-2 or high-risk by theInternational Prognostic Scoring System

• For all cohorts, patients with either FLT3-internal tandem duplication (FLT3-ITD) or FLT3 D835 mutations will be eligible

• Performance status ≤ 3 (Eastern Cooperative Oncology Group [ECOG] scale)

• Total serum bilirubin ≤ 2.5 x upper limit of normal (ULN), unless due to Gilbert'ssyndrome, hemolysis or the underlying leukemia approved by the principalinvestigator (PI)

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3 x ULN, unlessdue to the underlying leukemia approved by the PI

• Creatinine clearance ≥ 30 mL/min

• Ability to swallow

• Signed informed consent

Exclusion Criteria:

• Prior therapies:

• Phase I cohort: No restriction based on prior therapies

• Phase II cohort A: Patients with prior therapy for AML are not eligible. Priortherapy for antecedent hematologic disorder is allowed. Prior hydroxyurea orcytarabine given for purposes of cytoreduction is also allowed. Prior alltrans-retinoic acid given for presumed acute promyelocytic leukemia is alsoallowed

• Phase II cohort B: No restriction on number of prior therapies

• Patients suitable for and willing to receive intensive induction chemotherapy (forPhase II cohort A only)

• Congenital long QT syndrome or corrected QT interval by Fridericia (QTcF) > 450msec. Repeat electrocardiograms (EKGs) after correction of electrolytes ordiscontinuation of QT prolonging medications are allowed to meet entry criteria. Incases where QTcF > 450 msec is considered to be falsely increased due to inaccurateautomated reading and not clinically significant (e.g. due to bundle branch block),patients are still eligible if cardiologist reviews and documents that QTcF is ≤ 450msec when manually measured

• Active serious infection not controlled by oral or intravenous antibiotics (e.g.persistent fever or lack of improvement despite antimicrobial treatment)

• Active grade III-V cardiac failure as defined by the New York Heart Associationcriteria

• Active central nervous system leukemia

• Known human immunodeficiency virus (HIV) seropositive

• Known hepatitis B surface antigen seropositive or known or suspected activehepatitis C infection

• Note: Patients who have isolated positive hepatitis B core antibody (i.e., inthe setting of negative hepatitis B surface antigen and negative hepatitis Bsurface antibody) must have an undetectable hepatitis B viral load. Patientswho have positive hepatitis C antibody may be included if they have anundetectable hepatitis C viral load

• Patients with a prior or concurrent malignancy whose natural history or treatment isnot anticipated to interfere with the safety or efficacy assessment of theinvestigational regimen may be included only after discussion with the PI

• Consumed strong inducer of cytochrome P450, family 3, subfamily A (CYP3A) orp-glycoprotein within 3 days of study enrollment. Agents include but are not limitedto: carbamazepine, phenytoin, rifampin, and St. John's wort

• Treatment with any investigational antileukemic agents or chemotherapy agents in thelast 7 days before study entry, unless full recovery from side effects has occurredor patient has rapidly progressive disease judged to be life-threatening by theinvestigator. Prior recent treatment with corticosteroids, hydroxyurea and/orcytarabine (given for cytoreduction) permitted

• Pregnant women will not be eligible; women of childbearing potential should have anegative pregnancy test prior to entering on the study and be willing to practicemethods of contraception throughout the study period and for at least 6 months afterthe last dose of study drugs. Women do not have childbearing potential if they havehad a hysterectomy or are postmenopausal without menses for 12 months. In addition,men enrolled on this study should understand the risks to any sexual partner ofchildbearing potential and should practice an effective method of birth controlthroughout the study period and for at least 4 months after the last dose of studydrugs. Lactating women (or those planning to breastfeed) should not breastfeedduring treatment of gilteritinib and for at least 2 months after the last dose ofgilteritinib