AALL1131, A Phase 3 Randomized Trial for Newly Diagnosed High Risk B- Lymphoblastic Leukemia (B-ALL) Including a Stratum Evaluating Dasatinib (IND#73789, NSC#732517) in Patients with Ph-like Tyrosine Kinase Inhibitor (TKI) Sensitive Mutations

eligible participants will be assigned to a risk classification of HR or VHR based on factors that include the result of research tests, as well as age and the presence or absence of leukemia cells in the spinal fluid or brain. HR aLL participants will receive standard induction therapy, and then will be randomly assigned to 1 of 2 treatment arms for all phases of post-induction therapy. The 2 treatment arms are the same except for differences in the type of intrathecal therapy subjects receive. arm a: Patients receive therapy that is standard including age adjusted intrathecal methotrexate. This is the standard arm. arm B: Patients receive therapy that is standard with triple intrathecal therapy (methotrexate, hydrocortisone and cytosine arabinoside) instead of intrathecal methotrexate. This is the experimental arm. VHR aLL participants will receive standard induction therapy, and then will be randomly assigned to one of three treatment arms for all phases of post-induction therapy. The same treatment is given on all 3 arms of the study during most phases of therapy: during the first half of Consolidation, during interim Maintenance i and ii, during the first half of Delayed intensification, as well as during Maintenance. Differences in the therapy subjects receive will be during the second halves of Consolidation and Delayed intensification therapies. DS HR-aLL participants will receive modified therapy that is less intense than standard chemotherapy. all participants will receive the same treatment in the first half of induction, except for the type of steroid used, which will be determined by age. a bone marrow test will be done during induction treatment to assess disease response, and the result will used to determine if the drug daunorubicin will be used. Prior to amendment #2 To assess the feasibility and tolerability of CLoF in combination with CPM+eToP, the VHR B-aLL randomization will commence with a safety phase as outlined in Section 10.4 of the protocol. The initial CLoF dosing utilized on this study will be 30 mg/m2/day for 5 days. if this is not tolerated, the CLoF dosage will be decreased to 20 mg/m2/day for 5 days. Post-amendment #2 With this amendment, the VHR B-aLL randomization will re-start with a new safety phase (as outlined in Section 10.4 protocol) to continue to assess the feasibility and tolerability of CLoF in combination with CPM+eToP. The dose of clofarabine will be reduced to 20 mg/ m2/day for 5 days during Consolidation Part 2 and Delayed intensification Part 2. enrollment on the VHR strata will be suspended temporarily after 100 patients are enrolled (20 to Control and 40 to each of experimental arms 1 and 2). after all patients have completed Consolidation and entered interim Maintenance, the data will be reviewed. if the protocol defined safety criteria are met, then the VHR strata will reopen to accrual. if these criteria are not met, then experimental arm 2 will be closed permanently. Myeloid growth factor support (for example filgrastim) is required for patients in experimental arm 2 starting on Day 34, at least 24 hours after the completion of the last dose of Day 33 chemotherapy. This should continue until the anC is [GreaterThanorequalTo] 750/[MiCRo-SYMBoL]L on 2 consecutive days post nadir. Myeloid growth factor support need not be limited to filgrastim; pegfilgrastim is also permitted according to the institution's standard guidelines. additional data required by the FDa will be collected for VHR B-aLL patients on experimental arms 1 and 2. This will comprise additional physical examinations and laboratory evaluations, collected on approximately 200 patients (100 patients randomized to each experimental arm post amendment #2) during Consolidation, interim Maintenance i and ii and Delayed intensification.