Ponatinib Plus Chemotherapy in Acute Lymphoblastic Leukemia Patients

This is an interventional, phase II study, foreseeing a run-in phase for adult BCR/ABL1-like ALL patients. Thirty-two newly-diagnosed B-lineage ALL cases with a BCR/ABL1-like profile will be treated (≥18 years old, up to the age of 65 years). This implies that about 100-120 B-lineage ALL patients negative at the conventional molecular screening (BCR/ABL1, ALL1/AF4, E2A/PBX1) will undergo the recently reported "BCR/ABL1 predictor" (13). The estimated timing for both the conventional and the BCR/ABL1-like screening is within the steroid pre-phase (7 days). After a steroid pre-treatment phase (prednisone: 60 mg/m2/day, day -6 up to day 0), that can occurr before enrollment during the screening period, patients who prove BCR/ABL1-like will be treated with Ponatinib in combination with a pediatric-inspired and minimal residual disease (MRD)-driven treatment scheme - as in the previous GIMEMA LAL1913 protocol (EudraCT number 2009-016075-30) -, for the first 2 cycles (C1 and C2). In order to avoid toxicity, namely thrombotic, pancreatic and hepatic events, Asparaginase will be omitted from this scheme. As for the run-in phase, patients will receive ponatinib at the dosage of 15 mg. If no relevant toxicities are observed (i.e. 2 distinct patients developing a Grade IV non hematologic toxicity related to ponatinib within the first cycle of induction, 28 days), Ponatinib will be administered at the dose of 30 mg in the remaining patients. MRD will be evaluated at week 4, 10, 16, and 22. If a donor is available (MUD and haploidentical donors allowed, HLA typing carried out as soon as possible), MRD-positive patients will proceed to an allogeneic transplant after cycle 3; otherwise, if no donor is available, they will continue treatment with 5 additional consolidation/reinduction blocks, followed by 24 28-day cycles of maintenance, as detaield in the treatment scheme. If beneficial for the patients, ponatinib will be provided until disease progression. CNS prophylaxis will be carried out throughout the course of treatment with 12 medicated rachicenteses (Methotrexate 12.5 mg, Aracytin 50 mg, Urbason 20 mg).