Phase II Front-line Ponatinib in Adult Philadelphia+/BCR-ABL+ Acute Lymphoblastic Leukemia.

Inclusion Criteria:

1. To be classified as having Ph+ ALL, patients must have \>20% blasts in bone marrow at the time of diagnosis and no prior history of CML.
2. Patients with previously untreated Ph+ and/or BCR/ABL + ALL:

   * age ≥ 60 years old or
   * age ≥ 18 years old, but unfit for program of intensive therapy and allogeneic SCT
3. Adequate hepatic function as defined by the following criteria:

   * total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome
   * alanine aminotransferase (ALT) ≤2.5 × ULN
   * aspartate aminotransferase (AST) ≤2.5 × ULN.
4. Adequate pancreatic function as defined by the following criterion:

   \- serum lipase and amylase ≤1.5 × ULN.
5. For females of childbearing potential, a negative pregnancy test must be documented prior to randomization.
6. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from randomization through 4 months after the end of treatment.
7. Signed written informed consent according to ICH/EU/GCP and national local laws.

Exclusion Criteria:

1. WHO performance status ≤ 50% (Karnofsky) or ≥ 3 (ECOG).
2. Active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubin ≥ 1.5 x ULN.
3. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
4. History of alcohol abuse.
5. Ongoing or active infections.
6. Uncontrolled hypertriglyceridemia (triglycerides \>450 mg/dL).
7. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

   * any history of myocardial infarction, stroke, or revascularization
   * unstable angina or transient ischemic attack within 6 months prior to enrollment
   * congestive heart failure within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards within 6 months prior to enrollment
   * history of clinically significant (as determined by the treating physician) atrial arrhythmia
   * any history of ventricular arrhythmia
   * any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism .
8. 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.
9. Taking medications that are known to be associated with Torsades de Pointes.
10. Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib.
11. Creatinine level \> 2.5mg/dl or Glomerular Filtration Rate (GFR) \< 20 ml/min or proteinuria \> 3.5 g/day.
12. Impairment of gastrointestinal (GI) function, or a GI disease that may significantly alter the absorption of study drugs (e.g. rare hereditary problems of galactose intolerance , the Lapp lactase deficiency or glucose-galactose malabsorption, severe malabsorption syndrome, or extended small bowel resection).
13. Patients who are currently receiving treatment with any of the medications listed in Appendix E if the medications cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Appendix E have the potential to prolong QT.
14. Patients who have received any investigational drug ≤ 4 weeks.
15. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
16. Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of Ponatinib). Post menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 4 months following discontinuation of study drugs.
17. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
18. Patients unwilling or unable to comply with the protocol.