Ponatinib - Frontline for Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP)

1. Diagnosis of Ph-positive (by cytogenetics or FISH) or Bcr-ABL-positive (by PCR) CML with accelerated phase features at the time of diagnosis.
2. Patients must have received no or minimal prior therapy, defined as \</=1 month of prior IFN-α (with or without ara-C) and/or an FDA-approved tyrosine kinase inhibitor (e.g, dasatinib, nilotinib). Prior use of hydroxyurea or anagrelide is allowed with no limitations.
3. Age >/=18 years
4. Eastern Cooperative Oncology Group (ECOG) performance of 0-2.
5. Adequate end organ function, defined as the following: total bilirubin \<1.5x upper limit of normal (ULN), serum glutamate pyruvate transaminase (SGPT) \<2.5x ULN,creatinine clearance (CrCl) >/= 30 mL/min at screening (calculation according to Cockcroft \& Gault formula).
6. Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital.
7. Women of pregnancy potential must practice an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control. Adequate forms of contraception are barrier methods (e.g., condoms, diaphragm), oral, depo provera, or injectable contraceptives, intrauterine devices, spermicidal jelly or foam, abstinence, and tubal ligation. Women and men must continue birth control for the duration of the trial \& at least 3 months after the last dose of study drug.
8. **continued from above: All WOCBP MUST have a negative serum or urine pregnancy test within 7 days prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study.

Exclusion Criteria:

1. NYHA cardiac class 3-4 heart disease
2. Cardiac Symptoms: Patients meeting the following criteria are not eligible: History of unstable angina, myocardial infarction, transient ischemic attack (TIA), stroke, peripheral arterial occlusive disease, venous thromboembolism or pulmonary embolism; Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); Prolonged corrected QT interval (QTc) interval on pre-entry electrocardiogram (> 470 msec) on both the Fridericia and Bazett's correction; Symptomatic congestive heart failure within 3 months prior to first dose of ponatinib (NYHA class III or IV).
3. Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders.
4. Pregnant or breast-feeding women are excluded.
5. Patients with uncontrolled hypertension (defined as sustained stage 2 hypertension, i.e., systolic BP >/=160 mmHg or diastolic BP >/=100 mmHg).
6. Patients with history of pancreatitis.
7. Patients in late chronic phase (i.e., time from diagnosis to treatment >6 months), or blast phase are excluded. The definitions of CML phases are as follows: A. Early chronic phase: time from diagnosis to therapy \</= 6 months; B. Late chronic phase: time from diagnosis to therapy > 6 months; C. Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow; D. Accelerated phase CML: presence of any of the following features: Peripheral or marrow blasts 15% or more; Peripheral or marrow basophils 20% or more; Thrombocytopenia \< 100 x 10(9)/L unrelated to therapy; Documented extramedullary blastic disease outside liver or spleen.
8. **continued from above: E. Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has been historically been included as a criterion for accelerated phase. However, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis, and when present at diagnosis may not impact the prognosis at all. Thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study.