Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) (EPIC)

Inclusion Criteria: 1. CP CML within 6 months of diagnosis * CP-CML will be defined by (i) \<15% blasts in bone marrow; (ii) \<30% blasts plus promyelocytes in bone marrow; (iii) \<20% basophils in peripheral blood; (iv) ≥100 × 10\^9/L platelets (≥100,000/mm\^3); (v) No evidence of extramedullary disease except hepatosplenomegaly; AND (vi) No prior diagnosis of AP-CML or BP-CML 2. Cytogenetic assessment must demonstrate the BCR-ABL fusion by presence of the t(9;22) Philadelphia chromosome * (a)Variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques; (b) Conventional chromosome banding must be performed; AND (c) A minimum of 20 metaphases must be assessable at entry 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 4. Adequate hepatic function as defined by the following criteria: (a) Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome; (b) Alanine aminotransferase (ALT) ≤2.5 × ULN; AND (c) Aspartate aminotransferase (AST) ≤2.5 × ULN 5. Adequate renal function as defined as defined by serum creatinine \<1.5 x ULN 6. Adequate pancreatic function as defined by serum lipase and amylase ≤1.5 × ULN Exclusion Criteria: 1. Received prior imatinib therapy 2. Received prior dasatinib therapy 3. Received prior nilotinib therapy 4. Received, for CML, any other systemic anticancer therapy, experimental therapy, or radiation therapy with the exception of anagrelide or hydroxyurea 5. Major surgery within 28 days prior to initiating therapy 6. History of bleeding disorder unrelated to CML 7. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis 8. History of alcohol abuse 9. Have uncontrolled hypertriglyceridemia (triglycerides \>450 mg/dL) 10. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: 1. Myocardial infarction, within 6 months prior to randomization 2. Unstable angina within 6 months prior to randomization 3. Congestive heart failure within 6 months prior to randomization 4. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any ventricular arrhythmia 5. Any history of ventricular arrhythmia 6. Cerebrovascular accident or transient ischemic attack within 6 months prior to randomization 7. Any history of peripheral arterial occlusive disease requiring revascularization 8. Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism 11. Uncontrolled hypertension (diastolic blood pressure \>90 mm Hg; systolic \>140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control 12. Taking medications that are known to be associated with Torsades de Pointes 13. Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection 14. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history 15. Pregnant or breastfeeding 16. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs 17. Diagnosed with or received anticancer therapy for another primary malignancy within 3 years prior to entry (except for non-melanoma skin cancer or cervical cancer in situ) 18. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug