A 3-cohort Randomized Study Evaluating the Role of New Immunotherapeutic Agents and of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Frontline Therapy of Adults With Acute Lymphoblastic Leukemia

Prior treatment

• Patient previously treated with systemic chemotherapy, antibody-based therapy or TKI
• Chronic pancreatitis or acute pancreatitis within 6 months before study start
• Concurrent severe diseases which exclude the administration of therapy
• Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study
• Current use of prohibited medication
• Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study
  • If patients with Phpos ALL:
• Previous myocardial infarction within the last 12 months

Other illness

• Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
• History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, coordination/movement disorder, autoimmune disease with CNS involvement, psychosis (with the exception of CNS leukemia that is well controlled with intrathecal therapy)
• Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C.
• Chronic or current active uncontrolled infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment
• Known hypersensitivity or severe reaction to ponatinib (GRAAPH), blinatumomab (GRAAPH and GRAALL-B) , isatuximab (GRAALL-T) or their excipients.
• History of or presence of clinically significant ventricular or atrial tachyarrhythmias
• Symptomatic peripheral vascular disease
• History of ischemic stroke or transient ischemic attacks (TIAs) within the last 12 months
• Significant bleeding disorder or thrombophilia unrelated to the underlying malignancy indication for study participation
• Gastrointestinal disorders, such as malabsorption syndrome or any other illness that could affect oral absorption

Lab values

• Patients with LVEF\<50% or other clinically significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
• Prior documented chronic liver disease. Inadequate hepatic functions defined as AST or ALT \> 5 x the institutional upper limit of normal (ULN), or \> 5 x ULN unless if considered due to leukemia. Total bilirubin \> 1.5 x ULN unless if considered due to leukemia or Gilbert/Meulengracht
• Estimated glomerular filtration rate (GFR) \< 50 mL/mn using the MDRD equation
• Congenital long QT syndrome or QTcF \> 470 msec on screening ECG. If QTc \> 470 msec and electrolytes are not within normal ranges before ponatinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion
• Currently taking drug(s) that are known to have a risk of causing prolonged QTc or TdP unless the drug(s) can be changed to acceptable alternatives (ie, an alternate class of agents that do not affect the cardiac conduction system), or the participant can safely discontinue the drug(s)

Other

• Common exclusion criteria :
• Pregnancy and breast feeding
• Patients unwilling or unable to comply with the protocol
• Patients under a legal protection regime (guardianship, trusteeship, judicial safeguard)
• Complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bi-fascicular block
• Clinically significant resting bradycardia (\< 50 beats per minute)

• Patients aged 18 to 65 years old
• Newly diagnosed ALL or T-LL according to the WHO criteria
• Immunophenotypic, cytogenetic and/or FISH and molecular evaluation performed and allowing classifying the patient in one of the Phpos ALL, Phneg BCP-ALL or T-ALL/LL cohorts
• Not previously treated except with corticosteroids and/or intrathecal therapy (prephase)
• Eligible for allo-HSCT if Phpos ALL or Phneg BCP-ALL
• ECOG performance status ≤2
• Patient willing and able to understand the protocol requirements and comply with the treatment schedule, scheduled visits, electronic patient outcome reporting, exams and other requirements of the study
• Patients has signed written inform consent
• Willingness of women of child-bearing potential (WOCBP) and male subjects whose sexual partners are WOCBP to use an effective form of contraception, i.e. methods with a failure rate of \<1% per year when used consistently and correctly, during the study and at least 6 months thereafter
• Eligible for National Health Insurance (for French patients)