PRE-PHASE: Patients may receive corticosteroids and/or hydroxyurea at the discretion of the treating physician prior to beginning induction therapy. A seven-day corticosteroid pre-phase, which can include days of corticosteroid receipt prior to protocol registration, will precede initiation of TKI therapy on day 1. Corticosteroid dose and schedule are at the discretion of the investigator during the pre-phase, with dosing caps of prednisone 120 mg/day, dexamethasone 24 mg/day, or biologic equivalents thereof. In the event the treating investigator feels delaying induction therapy (TKI + dexamethasone) would be unsafe (e.g. ALL progressing despite corticosteroids), the patient may proceed to day 1 (begin TKI + dexamethasone) before completion of 7-day pre-phase if investigator feels delay would be unsafe.

INDUCTION THERAPY: Induction therapy consists of dexamethasone in combination with TKI. TKI therapy will generally begin with dasatinib 140 mg daily (dose changes or transition to alternative TKI permitted subject to the provisions in the protocol). Patients will receive dexamethasone 10 mg/m2/day (up to 24 mg /day) in single or divided doses, days 1-24. Dexamethasone will be tapered days 25-32 (±3 days for start and end of taper); the TKI will be continued during and following the dexamethasone taper. Recommended CNS prophylaxis consists of intrathecal (IT) or intra-Ommaya (IO) methotrexate 12 mg day 22 and day 43 (±7 days); of note, methotrexate 12 mg is recommended though agent/dosing left to discretion of investigator. Hydrocortisone IT may be given along with methotrexate at the discretion of the investigator. Bone marrow evaluations will be performed on days 22 (±3 days) and day 43 (±3 days) and will include minimal residual disease (MRD) assessment by BCR-ABL1 transcript studies and flow cytometry. Under certain circumstances, the induction period may be extended for up to 21 days with bone marrow studies repeated at that time.

CONSOLIDATION THERAPY: Patients in complete response (CR) or CR with incomplete hematologic recovery (CRi) following remission induction, with or without MRD, proceed to consolidation therapy, defined as day 1 of cycle 1 of blinatumomab, within 21 days of day 43 or the date of BMA establishing CR/CRi, whichever is later. TKI will be administered continuously. Patients will begin Blinatumomab 28 mcg/daily IVCI for patients ≥45 kg; patients \<45 kg will be treated at a dose of 15 mcg/m2/day, capped at a dose of 28 mcg/day, given for a 28-day cycle, with dose adjustments further subject to the provisions outlined in the protocol. Inpatient admission is recommended for at least days 1-3 of cycle 1 of blinatumomab (≥72 hours from start of infusion). Following each 28-day infusion of blinatumomab, a mandatory period of 14 days off blinatumomab will follow during which bone marrow evaluation will be performed with MRD assessment and CNS prophylaxis will be administered. The consolidation period will consist of 3 cycles of blinatumomab given as such. Patients may come off therapy at any point to undergo allogeneic hematopoietic cell transplantation (alloHCT).

MAINTENANCE THERAPY: Patients in complete molecular response (as defined within the protocol) following blinatumomab cycle 3 and not proceeding immediately to alloHCT may proceed to maintenance therapy, defined as day 1 of cycle 4 of blinatumomab, within 28 days of completion of blinatumomab infusion in cycle 3. TKI will be administered continuously. Blinatumomab will be given for up to 4 additional 28-day cycles (cycles 4-7) with a mandatory period of 28 days (±7 days) off blinatumomab between cycles, during which CNS prophylaxis will be administered. Bone marrow evaluation with MRD assessment will be performed after cycles 5 and 7 of blinatumomab.

FOLLOW-UP: TKI maintenance is recommended but not required. Further post-remission therapy, if any, at the discretion of the treating physician. Following completion of all required study treatments and assessments, patients enrolled will be followed for long-term survival and relapse outcomes as outlined in the protocol.