Testing the Addition of the Anti-cancer Drug Venetoclax and/or the Anti-cancer Immunotherapy Blinatumomab to the Usual Chemotherapy Treatment for Infants With Newly Diagnosed KMT2A-rearranged or KMT2A-non-rearranged Leukemia

Phase 2

Recruiting

• Conditions: B Acute Lymphoblastic Leukemia; Acute Leukemia of Ambiguous Lineage
• Interventions: Drug: Asparaginase Erwinia chrysanthemi; Procedure: Biospecimen Collection; Biological: Blinatumomab; Procedure: Bone Marrow Aspiration; Drug: Calaspargase Pegol; Procedure: Computed Tomography; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin; Drug: Dexamethasone; Drug: Doxorubicin; Procedure: Echocardiography Test; Procedure: FDG-Positron Emission Tomography; Drug: Leucovorin; Drug: Levoleucovorin; Procedure: Lumbar Puncture; Procedure: Magnetic Resonance Imaging; Drug: Mercaptopurine; Drug: Methotrexate; Procedure: Multigated Acquisition Scan; Drug: Methylprednisolone; Drug: Therapeutic Hydrocortisone; Drug: Thioguanine; Drug: Prednisolone; Drug: Vincristine; Drug: Venetoclax; Drug: Prednisone

• Registration Number: NCT06317662
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase II trial tests the addition of venetoclax and/or blinatumomab to usual chemotherapy for treating infants with newly diagnosed acute lymphoblastic leukemia (ALL) with a KMT2A gene rearrangement (KMT2A-rearranged \[R\]) or without a KMT2A gene rearrangement (KMT2A-germline \[G\]). Venetoclax is in a class of medications called B-cell lymphoma-2 (Bcl-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Blinatumomab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding venetoclax and/or blinatumomab to standard chemotherapy may be more effective at treating patients with ALL than standard chemotherapy alone, but it may also cause more side effects. This clinical trial evaluates the safety and effectiveness of adding venetoclax and/or blinatumomab to chemotherapy for the treatment of infants with KMT2A-R or KMT2A-G ALL.

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 estimate the MRD-negative remission rate for all eligible infants with KMT2A-R ALL treated with venetoclax at the recommended phase 2 dose (RP2D).

II. To compare event free survival (EFS) rates of infants with KMT2A-R ALL treated on arm B to those treated on arm A.

III. To compare 3-year EFS rates of infants with KMT2A-R ALL treated on arm A to historical controls.

IV. 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 estimate the 3-year EFS rate of infants with KMT2A-G ALL treated on arm C.

V. To characterize the pharmacokinetics (PK) of venetoclax in infants.

EXPLORATORY OBJECTIVES:

I. To describe 3-year EFS rate of infants with KMT2A-R ALL treated on arm B. II. To evaluate the use of high-throughput sequencing (HTS) for MRD detection in infant ALL compared to centralized flow cytometry.

III. To characterize the PK of calaspargase pegol-mknl in infants with ALL. IV. To report the incidence of CD19 negative relapse and myeloid switch relapse with protocol therapy.

V. To evaluate the impact of venetoclax in combination with chemotherapy on T-cell subsets and function.

VI. 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.

VII. To determine predictors of response and resistance to venetoclax and overall protocol therapy.

VIII. 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) or methylprednisolone intravenously (IV) 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 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, 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 or levoleucovorin 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 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.

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, 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 or levoleucovorin 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 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 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, 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 or levoleucovorin 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 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, 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 or levoleucovorin 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 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, 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 or levoleucovorin 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 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, 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 or levoleucovorin 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 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, 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 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 or levoleucovorin 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, 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 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 or NG BID or methylprednisolone 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, collection of blood samples and echocardiography (ECHO) or multigated acquisition scan (MUGA) throughout the trial. Patients may undergo computed tomography (CT), magnetic resonance imaging (MRI), fludeoxyglucose-positron emission tomography (FDG-PET), and/or lumbar puncture if clinically indicated.

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

Study Timeline

• Study First Submitted: 2024-03-16
• Study First Submitted QC: 2024-03-16
• Study First Posted: 2024-03-19
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-22
• Last Update Posted: 2025-05-23
• Study Start: 2026-01-20
• Primary Completion: 2028-12-31
• Study Completion: 2028-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 153

Inclusion Criteria

• All patients must be enrolled on APEC14B1 and consented to eligibility screening (part A) prior to treatment and enrollment on AALL2321

• Infants (aged 365 days or less) on the date of diagnosis are eligible; infants must be > 36 weeks gestational age at the time of enrollment

• Patients must have newly diagnosed B-acute lymphoblastic leukemia (B-ALL, 2017 World Health Organization [WHO] classification), also termed B-precursor ALL, or acute leukemia of ambiguous lineage (ALAL), which includes mixed phenotype acute leukemia. For patients with ALAL, the immunophenotype of the leukemia must comprise at least 50% B lineage

  • Diagnostic immunophenotype: Leukemia cells must express CD19

Exclusion Criteria

• Patients with Down Syndrome

• Patients with secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy

• Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of infant ALL or for any cancer diagnosis prior to the initiation of protocol therapy, with the exception of:

  • Steroid pretreatment:

    • PredniSONE, prednisoLONE, or methylPREDNISolone for ≤ 72 hours (3 days) in the 7 days prior to enrollment. The dose of predniSONE, prednisoLONE or methylPREDNISolone does not affect eligibility
    • Inhaled and topical steroids are not considered pretreatment
    • Note: Pretreatment with dexamethasone in the 28 days prior to initiation of protocol therapy is not allowed with the exception of a single dose of dexamethasone used during or within 6 hours prior to or after sedation to prevent or treat airway edema. However, prior exposure to ANY steroids that occurred > 28 days before enrollment does not affect eligibility

  • Intrathecal cytarabine or methotrexate:

    • An intrathecal dose of cytarabine or methotrexate in the 7 days prior to enrollment does not affect eligibility
    • Note: The preference is to defer the diagnostic lumbar puncture with intrathecal chemotherapy to day 1 of induction to allow for cytoreduction of circulating blasts and decrease the potential for central nervous system (CNS) contamination due to a traumatic tap. If done prior to day 1 of induction, these results will be used to determine CNS status

  • Hydroxyurea:

    • Pretreatment with ≤ 72 hours (3 days) of hydroxyurea in the 7 days prior to enrollment does not affect eligibility

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug Administration (FDA) and National Cancer Institute (NCI) requirements for human studies must be met

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Arm A	Bone Marrow Aspiration	See Detailed Description for Arm A.
Arm A	Asparaginase Erwinia chrysanthemi	See Detailed Description for Arm A.
Arm A	Biospecimen Collection	See Detailed Description for Arm A.
Arm A	Blinatumomab	See Detailed Description for Arm A.
Arm A	Calaspargase Pegol	See Detailed Description for Arm A.
Arm A	Computed Tomography	See Detailed Description for Arm A.
Arm A	Cyclophosphamide	See Detailed Description for Arm A.
Arm A	Cytarabine	See Detailed Description for Arm A.
Arm A	Daunorubicin	See Detailed Description for Arm A.
Arm A	Levoleucovorin	See Detailed Description for Arm A.
Arm A	Dexamethasone	See Detailed Description for Arm A.
Arm A	Echocardiography Test	See Detailed Description for Arm A.
Arm A	FDG-Positron Emission Tomography	See Detailed Description for Arm A.
Arm A	Leucovorin	See Detailed Description for Arm A.
Arm A	Lumbar Puncture	See Detailed Description for Arm A.
Arm A	Magnetic Resonance Imaging	See Detailed Description for Arm A.
Arm A	Mercaptopurine	See Detailed Description for Arm A.
Arm A	Methotrexate	See Detailed Description for Arm A.
Arm A	Multigated Acquisition Scan	See Detailed Description for Arm A.
Arm A	Therapeutic Hydrocortisone	See Detailed Description for Arm A.
Arm A	Thioguanine	See Detailed Description for Arm A.
Arm A	Vincristine	See Detailed Description for Arm A.
Arm B, Cohort 1	Bone Marrow Aspiration	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Asparaginase Erwinia chrysanthemi	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Biospecimen Collection	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Blinatumomab	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Calaspargase Pegol	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Computed Tomography	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Cyclophosphamide	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Cytarabine	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Daunorubicin	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Dexamethasone	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Echocardiography Test	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	FDG-Positron Emission Tomography	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Leucovorin	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Levoleucovorin	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Lumbar Puncture	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Magnetic Resonance Imaging	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Mercaptopurine	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Methotrexate	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Multigated Acquisition Scan	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Therapeutic Hydrocortisone	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Thioguanine	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Venetoclax	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 1	Vincristine	See Detailed Description for Arm B, Cohort 1.
Arm B, Cohort 2	Asparaginase Erwinia chrysanthemi	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Biospecimen Collection	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Blinatumomab	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Bone Marrow Aspiration	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Calaspargase Pegol	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Computed Tomography	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Cyclophosphamide	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Cytarabine	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Daunorubicin	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Dexamethasone	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Echocardiography Test	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	FDG-Positron Emission Tomography	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Leucovorin	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Levoleucovorin	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Lumbar Puncture	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Magnetic Resonance Imaging	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Mercaptopurine	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Methotrexate	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Multigated Acquisition Scan	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Therapeutic Hydrocortisone	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Thioguanine	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Venetoclax	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 2	Vincristine	See Detailed Description for Arm B, Cohort 2.
Arm B, Cohort 3	Asparaginase Erwinia chrysanthemi	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Biospecimen Collection	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Blinatumomab	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Bone Marrow Aspiration	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Calaspargase Pegol	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Computed Tomography	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Cyclophosphamide	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Cytarabine	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Daunorubicin	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Dexamethasone	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Echocardiography Test	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	FDG-Positron Emission Tomography	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Leucovorin	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Levoleucovorin	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Lumbar Puncture	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Magnetic Resonance Imaging	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Mercaptopurine	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Methotrexate	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Multigated Acquisition Scan	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Therapeutic Hydrocortisone	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Thioguanine	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Venetoclax	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 3	Vincristine	See Detailed Description for Arm B, Cohort 3.
Arm B, Cohort 4	Asparaginase Erwinia chrysanthemi	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Biospecimen Collection	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Blinatumomab	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Bone Marrow Aspiration	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Calaspargase Pegol	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Computed Tomography	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Cyclophosphamide	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Cytarabine	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Daunorubicin	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Dexamethasone	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Echocardiography Test	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	FDG-Positron Emission Tomography	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Leucovorin	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Levoleucovorin	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Lumbar Puncture	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Magnetic Resonance Imaging	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Mercaptopurine	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Methotrexate	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Multigated Acquisition Scan	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Therapeutic Hydrocortisone	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Thioguanine	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Venetoclax	See Detailed Description for Arm B, Cohort 4.
Arm B, Cohort 4	Vincristine	See Detailed Description for Arm B, Cohort 4.
Arm C	Biospecimen Collection	See Detailed Description for Arm C.
Arm C	Blinatumomab	See Detailed Description for Arm C.
Arm C	Bone Marrow Aspiration	See Detailed Description for Arm C.
Arm C	Calaspargase Pegol	See Detailed Description for Arm C.
Arm C	Computed Tomography	See Detailed Description for Arm C.
Arm C	Cyclophosphamide	See Detailed Description for Arm C.
Arm C	Cytarabine	See Detailed Description for Arm C.
Arm C	Daunorubicin	See Detailed Description for Arm C.
Arm C	Dexamethasone	See Detailed Description for Arm C.
Arm C	Doxorubicin	See Detailed Description for Arm C.
Arm C	Echocardiography Test	See Detailed Description for Arm C.
Arm C	FDG-Positron Emission Tomography	See Detailed Description for Arm C.
Arm C	Leucovorin	See Detailed Description for Arm C.
Arm C	Levoleucovorin	See Detailed Description for Arm C.
Arm C	Lumbar Puncture	See Detailed Description for Arm C.
Arm C	Magnetic Resonance Imaging	See Detailed Description for Arm C.
Arm C	Mercaptopurine	See Detailed Description for Arm C.
Arm C	Methotrexate	See Detailed Description for Arm C.
Arm C	Methylprednisolone	See Detailed Description for Arm C.
Arm C	Multigated Acquisition Scan	See Detailed Description for Arm C.
Arm C	Prednisolone	See Detailed Description for Arm C.
Arm C	Prednisone	See Detailed Description for Arm C.
Arm C	Therapeutic Hydrocortisone	See Detailed Description for Arm C.
Arm C	Thioguanine	See Detailed Description for Arm C.
Arm C	Vincristine	See Detailed Description for Arm C.
Safety Phase Cohort	Asparaginase Erwinia chrysanthemi	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Biospecimen Collection	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Blinatumomab	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Bone Marrow Aspiration	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Calaspargase Pegol	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Computed Tomography	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Cyclophosphamide	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Daunorubicin	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Cytarabine	See Detailed Description for Safety Phase Cohort.
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Computed Tomography	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Echocardiography Test	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	FDG-Positron Emission Tomography	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Lumbar Puncture	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Magnetic Resonance Imaging	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Methylprednisolone	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Multigated Acquisition Scan	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Biospecimen Collection	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Bone Marrow Aspiration	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Safety Phase Cohort	Thioguanine	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Dexamethasone	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Echocardiography Test	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	FDG-Positron Emission Tomography	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Levoleucovorin	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Leucovorin	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Methotrexate	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Multigated Acquisition Scan	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Lumbar Puncture	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Magnetic Resonance Imaging	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Mercaptopurine	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Therapeutic Hydrocortisone	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Venetoclax	See Detailed Description for Safety Phase Cohort.
Safety Phase Cohort	Vincristine	See Detailed Description for Safety Phase Cohort.
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Prednisolone	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).
Steroid Prephase(prednisone, prednisolone, methylprednisolone)	Prednisone	All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).

Primary Outcome Measures

Name	Time	Method
Minimal residual disease (MRD)-negative remission rate	At the end of induction	The end of induction MRD-negative remission rate will be compared between Arm A and Arm B. MRD negativity is defined as achievement of complete remission and MRD \< 0.01% by flow cytometry. The MRD-negative remission rate at the end of induction between Arm A and Arm B will be compared using a one-sided Z test of proportions with Type I error of 0.15.
Incidence of dose-limiting toxicities (DLTs) (safety phase)	For the duration of the induction + venetoclax cycle
Incidence of DLTs (expansion phase)	During the induction, consolidation, and MARMA cycles	For the expansion phase, DLTs of Arm B will be assessed and monitored for the cycles that contain venetoclax (induction, consolidation, and MARMA cycles of Arm B).

Secondary Outcome Measures

Name	Time	Method
MRD-negative remission rate	At the end of induction	The end of induction in infants with KMT2A-rearranged (R) acute lymphoblastic leukemia (ALL) who are treated with venetoclax at the recommended phase 2 dose (RP2D) MRD-negative remission rate at the end of induction and the standard error or 95% confidence interval will be estimated among patients treated with venetoclax at the RP2D. This analysis will include eligible KMT2A-R patients treated with venetoclax at the RP2D in the safety phase, as well as patients randomized to Arm B and treated with venetoclax in the expansion phase. MRD negativity is defined as achievement of complete remission as defined and MRD \< 0.01% by flow cytometry.
Event free survival (EFS) rates of infants with KMT2A-R ALL	From date of randomization to treatment failure, first documented relapse following achievement of remission-1, occurrence of a second or secondary malignant neoplasm, or death, assessed up to 3 years	The EFS rates from date of randomization of Arm B will be compared to Arm A. Comparison of EFS rates between Arm A and Arm B will be based on a one-sided logrank test with Type I error of 0.15.
3-year EFS of infants with KMT2A-R ALL	From date of randomization to treatment failure, first documented relapse following achievement of remission-1, occurrence of a second or secondary malignant neoplasm, or death, assessed up to 3 years	For Arm A, the 3-year EFS rate (representing a plateau rate based on the shape of EFS curves of historical data in this patient population) from the date of randomization will be compared to the stable historical 3-year EFS rate of 35% observed in AALL0631 and other international trials.
Proportion of KMT2A-germline (G) patients in Arm C who are able to receive all treatment cycles before maintenance	Up to interim maintenance 2	The feasibility of treating KMT2A-G patients with a high-risk ALL backbone and two cycles of blinatumomab (Arm C) will be assessed. Arm C treatment will be considered feasible for KMT2A-G patients if the proportion of KMT2A-G patients in Arm C who are able to receive all treatment cycles before maintenance (i.e., up to interim maintenance 2) is more than 76.8%. The proportion of patients receiving all cycles before Maintenance will be compared to 76.8% with a one-sample exact test of proportion with Type I error of 0.15.
3-year EFS of infants with KMT2A-G ALL treated on Arm C	From date of randomization to treatment failure, first documented relapse following achievement of remission-1, occurrence of a second or secondary malignant neoplasm, or death, assessed up to 3 years	Summary statistics will be calculated. When appropriate, comparisons of the endpoints will be conducted between patients who achieved MRD-negative remission vs those who did not, between arms, or between patients with different baseline characteristics. Analyses will be descriptive and exploratory. The 3-year EFS rate from date of enrollment of KMT2A-G patients in Arm C will be estimated with the Kaplan-Meier method.
Pharmacokinetics (PK) of venetoclax in infants	On days 7, 10, and 14 of induction	PK samples will be collected from patients enrolled in the safety phase of the study as well as from patients randomized to Arm B in the expansion phase who consent to participate, to determine the major secondary objective of characterizing the PK of venetoclax in infants. PK samples will be evaluated in batches and standard nonlinear mixed effect modeling will be used for model building and refinement of time-concentration data. After model refinement, a non-parametric bootstrap analysis will be performed reporting the 95% confidence intervals for each PK parameter.

Trial Locations

Locations (10)

Lurie Children's Hospital-Chicago; 🇺🇸 Chicago, Illinois, United States

ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital; 🇺🇸 Toledo, Ohio, United States

Kaiser Permanente-Oakland; 🇺🇸 Oakland, California, United States

Children's Hospital and Medical Center of Omaha; 🇺🇸 Omaha, Nebraska, United States

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital; 🇺🇸 New Brunswick, New Jersey, United States

Albany Medical Center; 🇺🇸 Albany, New York, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

BI-LO Charities Children's Cancer Center; 🇺🇸 Greenville, South Carolina, United States

Dell Children's Medical Center of Central Texas; 🇺🇸 Austin, Texas, United States

University of Virginia Cancer Center; 🇺🇸 Charlottesville, Virginia, United States