This is a randomised, open-label, multicenter, phase III study for adult de novo Ph+ ALL patients based on the combination of Ponatinib with Blinatumomab. The control arm will be represented by a chemotherapeutic scheme combined with Imatinib for patients aged 18-65 and by Imatinib plus age-adjusted chemotherapy for elderly patients (>65 years old).

Patients will be randomized 2:1 to receive the experimental or control arm. If patients in the control arm do not achieve a CHR and/or MRD negativity, after the sixth consolidation cycle (week 20), a crossover to receive Blinatumomab is planned. Likewise, if patients in the control arm develop an ABL1 mutation at any time of treatment, they will switch to experimental arm. HLA typing will be performed immediately after diagnosis in both arms for patients aged up to 65 years.

After the 2 cycles of Blinatumomab in the experimental arm and after consolidation in the control arm, patients aged 18-65 will be stratified for transplant allocation.

This is a randomised, open-label, multicenter, phase III study for adult de novo Ph+ ALL patients (≥18 years, no upper age-limit) based on the combination of the pan-TKI Ponatinib, with the bispecific monoclonal antibody Blinatumomab. The control arm will be represented by a chemotherapeutic scheme combined with Imatinib for patients aged 18-65 and by Imatinib plus age-adjusted chemotherapy for elderly patients (>65 years old).

Patients (≥18 years, no upper age limit) will be randomized 2:1 to receive the experimental or control arm. If patients in the control arm do not achieve a CHR and/or MRD negativity, after the sixth consolidation cycle (week 20), a crossover to receive Blinatumomab is planned. Likewise, if patients in the control arm develop an ABL1 mutation at any time of treatment, they will switch to experimental arm. HLA typing will be performed immediately after diagnosis in both arms for patients aged up to 65 years.

After the 2 cycles of Blinatumomab in the experimental arm and after consolidation in the control arm, patients aged 18-65 will be stratified for transplant allocation.

Inclusion Criteria:

1. Signed written informed consent according to ICH/EU/GCP and national local laws.

2. Newly diagnosed adult B-precursor Ph+ ALL patients.

3. WHO performance status less or equal to 2.

4. Age greater or equal to18 years, with no upper age limit.

5. Renal and hepatic function as defined below:

   • AST (GOT), ALT (GPT), and AP <2 x upper limit of normal (ULN).
   • Total bilirubin <1.5 x ULN.
   • Creatinine clearance equal or greater than 50 mL/min.

6. Pancreatic function as defined below:

   • Serum amylase less or equal to 1.5 x ULN and serum lipase less or equal to1.5 x ULN.

7. Normal cardiac function.

8. No evidence of CNS leukemia at blinatumomab start.

9. Negative HIV test, negative hepatitis B (HBsAg) and hepatitis C virus (anti-HCV) test.

10. Negative pregnancy test in women of childbearing potential.

11. Bone marrow specimen from primary diagnosis available.

Exclusion Criteria:

1. History of or current relevant CNS pathology (ongoing grade ≥2 epilepsy, seizure, paresis, aphasia, clinically relevant apoplexia, severe brain injuries, dementia, Parkinson's disease, organic brain syndrome, psychosis).

2. Impaired cardiac function, including any one of the following:

   • LVEF <45% as determined by MUGA scan or echocardiogram.
   • Complete left bundle branch block.
   • Use of a cardiac pacemaker.
   • ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads.
   • Congenital long QT syndrome.
   • History of or presence of significant ventricular or atrial arrhythmia.
   • Clinically significant resting bradycardia (<50 beats per minute).
   • QTc >450 msec on screening ECG (using the QTcF formula).
   • Right bundle branch block plus left anterior hemiblock, bifascicular block.
   • Myocardial infarction within 3 months prior to starting Ponatinib.
   • Angina pectoris.

3. Other clinically significant vascular and heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).

4. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Ponatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

5. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).

6. Taking medications that are known to be associated with Torsades de Pointes and medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib.

7. History of or current autoimmune disease.

8. Systemic cancer chemotherapy within 2 weeks prior to study.

9. Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation.

10. Active malignancy other than ALL with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix.

11. Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator.

12. Nursing women or women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least 3 months thereafter or male patients not willing to ensure effective contraception during participation in the study and at least three months thereafter.