NCT06317662 | NOT YET RECRUITING | Acute Leukemia of Ambiguous Lineage

Detailed Description:

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of venetoclax in addition to a standard chemotherapy backbone and two cycles of blinatumomab in infants (aged 365 days or less at diagnosis) with newly diagnosed KMT2A-R ALL. II. To determine in a randomized manner if the addition of venetoclax to induction chemotherapy improves end of induction minimal residual disease (MRD)-negative remission rates in infants with KMT2A-R ALL. SECONDARY OBJECTIVES: I. To compare event free survival (EFS) rates of infants with KMT2A-R ALL treated on arm B to those treated on arm A. II. To compare 3-year EFS of infants with KMT2A-R ALL treated on arm A to historical controls. III. To determine the feasibility of treating infants with KMT2A-G ALL with a Children's Oncology Group (COG) high-risk ALL chemotherapy backbone and two cycles of blinatumomab and describe their outcomes. IV. To characterize the pharmacokinetics (PK) of venetoclax in infants. EXPLORATORY OBJECTIVES: I. To describe 3-year EFS of infants with KMT2A-R ALL treated on arm B. II. To describe 3-year EFS of infants with KMT2A-G ALL treated on arm C. III. To evaluate the use of high-throughput sequencing (HTS) for MRD detection in infant ALL compared to centralized flow cytometry. IV. To characterize the PK of calaspargase pegol-mknl in infants with ALL. V. To report the incidence of CD19 negative relapse and myeloid switch relapse with protocol therapy. VI. To evaluate the impact of venetoclax in combination with chemotherapy on T-cell subsets and function. VII. To describe the feasibility of T-cell collection and success of T-cell manufacturing for infants with KMT2A-R ALL who receive chimeric antigen receptor (CAR) T- cell therapy after coming off protocol therapy. VIII. To determine predictors of response and resistance to venetoclax and overall protocol therapy. IX. To evaluate the impact of subsequent anti-cancer therapy on overall survival after coming off protocol therapy. OUTLINE: STEROID PREPHASE: All patients receive prednisone or prednisolone orally (PO) or nasogastrically (NG) three times daily (TID) for 7 days prior to the start of induction therapy (on days 1-7). Patients who are KMT2A gene rearrangement positive are assigned to the safety phase cohort. Patients who are KMT2A gene rearrangement negative are assigned to Arm C. SAFETY PHASE COHORT: INDUCTION: Patients receive venetoclax PO or NG once daily (QD) on days 1-7, 1-10, or 1-14, daunorubicin intravenously (IV) over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase intramuscularly (IM) or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy (methotrexate, hydrocortisone, cytarabine) intrathecally (IT) on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when absolute neutrophil counts (ANC) \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values. BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \> 1% or who have residual non-central nervous system (CNS) extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine subcutaneously (SC) QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity. EXPANSION PHASE: After completion of Safety phase, patients who are KMT2A gene rearrangement positive are randomized to Arm A or Arm B. ARM A: INDUCTION: Patients receive daunorubicin IV over 1-15 minutes on days 1 and 2, cytarabine SC or IV over 15-30 minutes on days 1-14, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29, or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values. BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \> 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity. ARM B: Patients are assigned to 1 of 4 cohorts. COHORT 1: INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values. BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \> 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. MARMA + VENETOCLAX: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, venetoclax PO or NG QD, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity. COHORT 2: INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values. BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \> 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. CONSOLIDATION + VENETOCLAX: Patients receive venetoclax PO or NG QD, cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity. COHORT 3: INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values. BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \> 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. CONSOLIDATION + VENETOCLAX: Patients receive venetoclax PO or NG QD, cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. MARMA + VENETOCLAX: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, venetoclax PO or NG QD, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity. COHORT 4: INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values. BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \> 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity. ARM C: INDUCTION: Patients receive daunorubicin IV over 1-15 minutes on days 1 and 2, cytarabine SC or IV over 15-30 minutes on days 1-14, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29, or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values. BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and methotrexate IT on days 15 and 29. Patients who are MRD \> 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, methotrexate IT on days 8, 15, and 22, vincristine IV on days 15, 22, 43, and 50, and pegaspargase IM or IV over 2 hours of calaspargase pegol IV over 1-2 hours on days 15 and 43. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to interim maintenance 1 the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. INTERIM MAINTENANCE 1: Patients receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, mercaptopurine PO or NG on days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on days 1 and 29, and leucovorin PO or NG or IV on days 3-4, 17-18, 31-32, and 45-46. At the end of interim maintenance 1 (day 63), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL. BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28, and methotrexate IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. DELAYED INTENSIFICATION: Patients receive methotrexate IT on days 1, 29, and 36, dexamethasone PO, NG, or IV TID on days 1-7 and 15-21, vincristine IV on days 1, 8, 15, 43, and 50, doxorubicin IV over 3-15 minutes on days 1, 8, and 15, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO or NG on days 29-42, and cytarabine SC or IV over 15-30 minutes on days 29-32 and 36-39. At the end of delayed intensification (day 63), all patients proceed directly to interim maintenance 2 the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. INTERIM MAINTENANCE 2: Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV push over 2-5 minutes of IV over 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IM or IV over 2 hours on days 2 and 22 or calaspargase pegol IV over 1-2 hours on days 2 and 23. At the end of interim maintenance 2 (day 56), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL. MAINTENANCE: Patients receive methotrexate IT on day 1 of each cycle, vincristine IV on day 1 of each cycle, prednisone or prednisolone PO, NG, or IV BID on days 1-5 of each cycle, mercaptopurine PO or NG on days 1-84 of each cycle, and methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of interim maintenance 1 in the absence of disease progression or unacceptable toxicity. All patients undergo bone marrow aspiration and collection of blood samples throughout the trial and undergo ECHO or MUGA at screening and end of therapy. Patients may undergo CT, MRI, FDG-PET, and/or lumbar puncture if clinically indicated. After completion of study treatment, patients are followed up for up to 3 years.