Inclusion Criteria:

1. Diagnosis of Ph-positive (by cytogenetics or FISH) or BCR-ABL-positive (by PCR) CML
in chronic phase.

2. Patients should have demonstrated to have failure to therapy to one FDA-approved TKI
(currently imatinib, dasatinib, and nilotinib are approved as frontline therapy),
defined as per European leukemiaNet (ELN) recommendations: 1. Less than complete
hematologic response (CHR) at or beyond 3 months; 2. No cytogenetic response at or
beyond 6 months; 3. Less than PCyR (Ph+ >35%) at or beyond 12 months; 4. Less than
CCyR at or beyond 18 months; 5. Loss of response or development of mutations or other
clonal chromosomal abnormalities at any time during imatinib treatment; 6.
Intolerance to imatinib defined as grade 3 or 4 toxicity, or persistent grade 2
toxicity despite optimal management including dose adjustment, or in a patient where
dose reductions are considered to be not in the patients best interest to obtain or
maintain an adequate response. Intolerant patients should not have achieved or have
lost major cytogenetic response at the time of enrollment.

3. Age >/= 18 years.

4. ECOG performance of 0-2.

5. Adequate end organ function, defined as the following: total bilirubin (unless due to Gilbert syndrome, in which case it should be 2.5x ULN, creatinine
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. Reliable telephone access to receive calls from an interactive voice response system
(IVR) (only applicable to patients who will participate in optional symptom burden
assessment).

8. 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:
1. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised
of the importance of avoiding pregnancy during trial participation & the potential
risk factors for an unintentional pregnancy; 2. Postmenopausal women must be
amenorrheic for at least 12 months to be considered of non-childbearing potential; 3.
In addition, men enrolled on this study should understand the risks to any sexual
partner of childbearing potential & should practice an effective method of birth
control; 4. Women & men must continue birth control for the duration of the trial &
at least 3 months after the last dose of study drug;

9. **continued from above: 5. All WOCBP MUST have a negative pregnancy test prior to
first receiving investigational product. If the pregnancy test is positive, the
patient must not receive investigational product & must not be enrolled in the study.

10. Patients should have discontinued therapy with imatinib or other anti-leukemia
therapy (except hydroxyurea), at least 48 hours prior to start of study therapy and
recovered from any toxicity due to these therapies to at least grade 1. The use of
hydroxyurea is allowed immediately prior to study entry.

Exclusion Criteria:

1. Prior therapy with other BCR-ABL-targeted TKIs except imatinib (e.g., dasatinib,
nilotinib, bosutinib).

2. NYHA cardiac class 3-4 heart disease.

3. Cardiac Symptoms: Patients meeting the following criteria are not eligible: Unstable
angina or myocardial infarction within 3 months; Any history of clinically
significant ventricular arrhythmias (such as ventricular tachycardia, ventricular
fibrillation, or Torsades de pointes); Prolonged QTc interval on pre-entry
electrocardiogram (> 470 msec) on both the Fridericia and Bazett's correction;
Congestive heart failure within 3 months prior to first dose of ponatinib.

4. Patients with active, uncontrolled psychiatric disorders including: psychosis, major
depression, and bipolar disorders.

5. Pregnant or breast-feeding women are excluded.

6. Patients with history of pancreatitis.

7. Patients in accelerated or blast phase, as patients who have ever been documented to
be in blast phase CML, are excluded. The definitions of CML phases are as follows: a.
Early chronic phase: time from diagnosis to therapy phase: time from diagnosis to therapy > 12 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; 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.

8. **continued from above: However, patients with clonal evolution as the only criterion
of accelerated phase have a significantly better prognosis. Thus, patients with
clonal evolution and no other criteria for accelerated phase will be eligible for
this study, but analyzed separately.

9. Patients who have received more than one FDA-approved TKI for CML, or any
investigational, non-FDA approved TKI.