The aim of the study is to evaluate the efficacy of Ponatinib, either alone or in combination with chemotherapy, in inducing remission in patients: MRD positive (persistent or relapsed), patients after haematological and extra-haematological relapse and patients who do not have never achieved remission after any previous treatment.

Prior treatment

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

Other illness

• History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
• History of alcohol abuse.
• Ongoing or active uncontrolled infections.

Lab values

• Creatinine level >2.5mg/dl or glomerular filtration rate (GFR) <20 ml/min or proteinuria >3.5 g/day.
• 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.
• Uncontrolled active HBV or HCV hepatitis, or AST/ALT = 2.5 x ULN and bilirubine = 1.5 x ULN not due to the disease.
• Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
• 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.

Other

• WHO performance status = 50% (Karnofsky) or = 3 (ECOG).

• 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.
• Age =18 years old with no upper age limit.
• 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.
• Adequate pancreatic function as defined by the following criterion: - serum lipase and amylase =1.5 × ULN.
• For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
• 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.
• Signed written informed consent according to ICH/EU/GCP and national local laws.