This is a phase II interventional trial to evaluate if the use of ponatinib, with or without chemotherapy, can induce a molecular remission in MRD-positive patients, in patients in hematologic and extra-hematologic relapse and in the few patients who never achieved an hematologic remission after whatever prior treatment.

This is a phase II interventional multicenter study for adult patients with Ph+ALL who:

• Are MRD+ (i.e. BCR-ABL1/ABL1 >0.01) (or loose their molecular response) after whichever kind of previous treatment. MRD positivity is indeed regarded as a relapse/resistance, since it represents the early recognition of cases who will eventually experience an hematologic recurrence of disease.
• Are in hematologic relapse after whichever kind of previous treatment.
• Have never achieved an hematologic remission at least after one month of treatment.

Patients will be treated with Ponatinib at a dose of 45 mg/die per os for 28 days for 3 cycles and - if in hematologic and extra-hematologic relapse/refractoriness, clinically fit and according to medical decision - with concurrent systemic chemotherapy. In case of CMR achievement, dosing will be reduced to 30 mg. In case of toxicity, Ponatinib will be reduced to 30 (or 15) mg daily.

Inclusion Criteria:

1. Ph+ ALL patients with evidence of MRD disease or in hematologic and extra-hematologic relapse/refractoriness after any previous treatment, will be considered eligible to enter the study.

2. Age ≥18 years old with no upper age limit.

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 enrollment.

6. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from enrollment 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. Uncontrolled active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubine ≥ 1.5 x ULN not due to the disease.

3. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.

4. History of alcohol abuse.

5. Ongoing or active uncontrolled 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
   • 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.

8. Taking medications that are known to be associated with Torsades de Pointes.

9. 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.

10. Creatinine level >2.5mg/dl or glomerular filtration rate (GFR) <20 ml/min or proteinuria >3.5 g/day.

11. 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.