PRIMARY OBJECTIVE:

      I. To compare disease-free survival (DFS) of standard risk pediatric Philadelphia chromosome
      (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib)
      combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or
      the more intensive European (Es)PhALL chemotherapy backbone.

      SECONDARY OBJECTIVES:

      I. To determine the feasibility of administration of imatinib after allogeneic hematopoietic
      stem cell transplantation (HSCT) in high risk Ph+ ALL patients.

      II. To determine event-free survival (EFS) of high risk pediatric Ph+ ALL patients treated
      with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.

      III. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients
      between the two randomized arms.

      IV. To evaluate event free survival (EFS) and overall survival (OS) of all enrolled
      participants.

      V. To evaluate OS in SR patients. VI. To evaluate OS in high risk (HR) patients.

      EXPLORATORY OBJECTIVES:

      I. To describe the toxicities associated with post-HSCT administration of imatinib.

      II. To evaluate the long-term toxicities in SR patients treated with chemotherapy plus
      imatinib (no transplant), overall and between both randomized arms.

      III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at
      various time points during therapy.

      IV. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals post-HSCT
      and explore the association of these measurements with long-term outcome.

      V. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase
      chain reaction (PCR) assay and next generation sequencing (NGS) assays.

      VI. To determine prognostic significance of IKZF1 gene aberrations and deletions.

      VII. To determine frequency and prognostic significance of p190 and p210 BCR-ABL1 fusion
      variants in pediatric Ph+ ALL.

      VIII. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine, and
      methotrexate) during the maintenance phase in SR Ph+ ALL patients.

      IX. To identify factors associated with poor adherence. X. To determine association between
      relapse risk and adherence to each oral chemotherapeutic agent (separately and combined).

      XI. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and
      identify factors associated with poor adherence.

      OUTLINE:

      INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days
      1-14.

      INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or twice
      daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone
      intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22,
      daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate
      intrathecally (IT) on day 29.

      INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35, cyclophosphamide
      IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or
      subcutaneously (SC) on days 1-4, 8-11, 15-18, and 22-25, and methotrexate IT on days 8 and
      22.

      POST-INDUCTION THERAPY: Patients with standard risk are randomized to 1 of 2 arms. Patients
      with high risk are assigned to Arm C.

      ARM A:

      CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21,
      methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose
      methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6,
      dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4,
      leucovorin calcium PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and
      pegaspargase IV over 1-2 hours or intramuscularly (IM) on day 5, and filgrastim SC on days
      7-11 in the absence of disease progression or unexpected toxicity.

      CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21,
      methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose
      methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine
      sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days 2-4, leucovorin
      calcium PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 5-15 minutes and
      daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase IV over 1-2 hours or
      IM on day 6, and filgrastim SC on days 7-11 in the absence of disease progression or
      unexpected toxicity.

      CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high
      dose cytarabine IV over 3 hours on days 1-2, dexamethasone PO BID or IV on days 1-5,
      etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic
      hydrocortisone IT on day 5, pegaspargase IV over 1-2 hours or IM on day 6, and filgrastim SC
      on days 7-11 in the absence of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days
      1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine
      sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV
      over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours or IM on day
      8 in the absence of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63,
      cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV
      over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the
      absence of disease progression or unexpected toxicity.

      INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28,
      methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence
      of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days
      1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine
      sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV
      over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours or IM on day
      8 in the absence of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49,
      cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV
      over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the
      absence of disease progression or unexpected toxicity.

      MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate PO
      once weekly (QW) and IT on days 1 and 43 of cycles 1, 2, and 3, and mercaptopurine PO on days
      1-84. Cycles with imatinib mesylate and mercaptopurine repeat every 84 days for up to 104
      weeks from the start of Induction IA in the absence of disease progression or unexpected
      toxicity.

      ARM B:

      INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63,
      vincristine sulfate IV over 1 minute and high dose methotrexate IV over 24 hours on days 1,
      15, 29, and 43, leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46,
      mercaptopurine PO on days 1-56, and methotrexate IT on days 1 and 29 in the absence of
      disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-28,
      methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine
      sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV
      over 1-15 minutes on days 1, 8, and 15, and pegaspargase IV over 1-2 hours or IM on day 4 in
      the absence of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56,
      cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV
      over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36,
      vincristine sulfate IV over 1 minute on days 43 and 50, and pegaspargase IV over 1-2 hours or
      IM on day 43 in the absence of disease progression or unexpected toxicity.

      INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD or
      BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes
      on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2
      hours or IM on days 2 and 22 in the absence of disease progression or unexpected toxicity.

      MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine
      sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV
      for cycle 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84,
      methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for cycle 1 and 2). Cycles
      repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of
      disease progression or unexpected toxicity.

      ARM C:

      CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine,
      therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone,
      leucovorin calcium, high dose cytarabine, and pegaspargase as in Arm A Consolidation Block 1,
      and filgrastim SC on day 7 in the absence of disease progression or unexpected toxicity.

      CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine,
      therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate,
      ifosfamide, leucovorin calcium, dexrazoxane hydrochloride, daunorubicin hydrochloride,
      pegaspargase, and filgrastim as Arm A Consolidation Block 2 in the absence of disease
      progression or unexpected toxicity.

      CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide,
      methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase, and filgrastim as in Arm
      A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence
      of disease progression or unexpected toxicity.

      HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed
      Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm
      A.

      POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the in
      the absence of disease progression or unexpected toxicity.

      After completion of study treatment, patients are followed up every year for 3 years.