The study's aim is to treat adult patients affected by Ph-like ALL, a Philadelphianegative ALL subtype, with a combination of the tyrosine kinase inhibitor ponatinib and chemotherapy. The main objective of the trial is to improve the percentace of patients that achieve a disease remission also at the molecular level.

Prior treatment

• Taking medications that are known to be associated with torsades de pointes
• Patients who have received any investigational drug = 4 weeks.
• Patients who have undergone major surgery = 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• 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

• 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.
• Gastrointestinal (GI) function impairment, or a GI disease that may significantly alter the absorption of study drugs.
• Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
• History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
• History of alcohol abuse
• Ongoing or active infections

Lab values

• Patients who are currently receiving treatment with any of the medications with potential to prolong QT interval (listed in Appendix F) if the medications cannot be either discontinued or switched to a different medication prior to starting study drug
• 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). Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ two effective reliable methods of birth control throughout the study and for up to 12 months following discontinuation of study drugs
• Creatinine levels > 2.5mg/dl or glomerular filtration rate (GFR) < 20 ml/min or proteinuria >3.5 g/day.
• Active HBV or HCV hepatitis, or AST/ALT > 2.5 x ULN and bilirubin > 1.5 x ULN.
• 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, - 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.

Other

• WHO performance status >2.
• Patients unwilling or unable to comply with the protocol

• Age18-65 years.
• De novo Ph+-like ALL, as defined by the BCR/ABL1-like predictor (13).
• WHO score =2
• Adequate liver 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 or aspartate aminotransferase (AST) =2.5 x ULN or leukemia related.
• Adequate pancreatic function as defined by serum lipase and amylase =1.5 × ULN or leukemia related
• No history of dyslipidemia, thrombotic events or cardiac disease.
• For females of childbearing potential, a negative pregnancy test must be documented. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from enrollment through 12 months after the end of treatment.
• Signed informed consent, according to ICH/EU/GCP and national regulation.