Decitabine, Venetoclax, and Ponatinib for the Treatment of Philadelphia Chromosome-Positive Acute Myeloid Leukemia or Myeloid Blast Phase or Accelerated Phase Chronic Myelogenous Leukemia

Inclusion Criteria:

• Patients with Philadelphia (Ph)+ acute myeloid leukemia (AML) or myeloid acceleratedphase (AP)-chronic myelogenous leukemia (CML) or blast phase (BP)-CML (eithert[9;22] and/or BCR-ABL1 positive by fluorescent in situ hybridization or polymerasechain reaction). Both untreated and relapsed/refractory patients are eligible

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

• Total serum bilirubin =< 2 x upper limit of normal (ULN), unless due to Gilbert'ssyndrome, hemolysis or the underlying leukemia approved by the principalinvestigator (PI)

• Alanine aminotransferase (ALT) =< 1.5 x ULN, unless due to the underlying leukemiaapproved by the PI

• Aspartate aminotransferase (AST) =< 1.5 x ULN unless due to the underlying leukemiaapproved by the PI

• Creatinine clearance >= 30 mL/min

• Serum lipase =< 1.5 x ULN

• Amylase =< 1.5 x ULN

• Ability to swallow

• Signed informed consent

Exclusion Criteria:

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

• History of acute pancreatitis within 6 months of study or history of chronicpancreatitis

• Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

• Active secondary malignancy that in the investigator's opinion will shorten survivalto less than 1 year

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

• Clinically significant, uncontrolled, or active cardiovascular disease, specificallyincluding, but not restricted to:

• Myocardial infarction (MI), stroke, revascularization, unstable angina ortransient ischemic attack within 6 months

• Left ventricular ejection fraction (LVEF) less than lower limit of normal perlocal institutional standards prior to enrollment

• Diagnosed or suspected congenital long QT syndrome

• Clinically significant atrial or ventricular arrhythmias (such as uncontrolled,clinically significant atrial fibrillation, ventricular tachycardia,ventricular fibrillation, or torsades de pointes) as determined by the treatingphysician

• Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 480msec) unless corrected after electrolyte replacement

• History of venous thromboembolism including deep venous thrombosis or pulmonaryembolism within the past 3 months, excluding line-associated deep venousthrombosis (DVT) of the upper extremity

• Uncontrolled hypertension (diastolic blood pressure > 100 mmHg; systolic > 150mmHg)

• Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3days prior to starting venetoclax

• 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, or a Foodand Drug Administration (FDA)-approved BCR-ABL tyrosine kinase inhibitor (TKI) ispermitted

• Pregnant and lactating women will not be eligible; women of childbearing potentialshould have a negative pregnancy test prior to entering on the study and be willingto practice methods of contraception throughout the study period. Women do not havechildbearing potential if they have had a hysterectomy or are postmenopausal withoutmenses for 12 months. In addition, men enrolled on this study should understand therisks to any sexual partner of childbearing potential and should practice aneffective method of birth control