Adding Dasatinib Or Venetoclax To Improve Responses In Children With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia (ALL) Or Lymphoma (T-LLY) Or Mixed Phenotype Acute Leukemia (MPAL)

Patients will be identified in the first 3 days of therapy during their treatment on INITIALL.

Treatment will consist of 3 main phases: Induction, Early Post Induction [including Consolidation, High-Dose Methotrexate, Intensification, Interim 1, Reinduction 1, Interim 2, and Reinduction 2], and Maintenance.

Induction:

• Remission Induction includes 3 days of therapy on the INITIALL classification protocol as well as the remainder of a total of 4 weeks of induction treatment on this trial. Treatment includes a total of 28 days of dexamethasone, 4 weekly doses of vincristine, 3 doses of daunorubicin, 1 dose of Calaspargase pegol, 6 doses of Intrathecal triple therapy (IT MHA), and one of 3 additional drugs. Patients with T-ALL without near-ETP or ETP phenotype (hereafter referred to simply as T-ALL) will receive 25 days of dasatinib. Patients with ETP or near-ETP ALL as well as those with MPAL will receive 14 days of venetoclax. Patients with T-LLy will receive bortezomib. Patients will have a week without chemotherapy at the end of Induction, although patients with Induction failure (MRD ≥5% disease) will proceed directly to consolidation.

Early Post Induction:

• Consolidation will be given following completion of Remission Induction Therapy. Patients will receive 2 cycles of BFM-1b therapy (a single dose of cyclophosphamide at the start of week 1, 4 daily doses of cytarabine in two consecutive weeks, and 2 weeks of mercaptopurine) separated by a week of nelarabine. Patients will have a week without chemotherapy at the end of Consolidation.
• High-dose Methotrexate will be given for 4 cycles to all patients. Patients will also receive an intrathecal chemotherapy treatment with each of the 2-week cycles and will take oral mercaptopurine continuously if tolerated.
• Intensification will be given to patients with T-ALL or ETP/ near-ETP. This therapy includes a week of nelarabine, one week of combination cyclophosphamide and cytarabine, and 1 week of rest without chemotherapy.
• Interim Therapy 1 includes 6 weeks of oral mercaptopurine, 2 weeks (5 days of each week) of dexamethasone, and two doses (weeks 1 and 4) of daunorubicin, vincristine, and calaspargase pegol.
• Reinduction Therapy 1 will consist of 3 weekly doses of vincristine, 1 dose of daunorubicin and calaspargase pegol at the start of the first week, and dexamethasone for 7 days in the first and third weeks. Patients will also receive the same additional agent received during induction based on immunophenotype.
• Interim Therapy 2 includes 6 weeks of oral mercaptopurine, two doses (weeks 1 and 4) of daunorubicin, vincristine, and calaspargase pegol.
• Reinduction Therapy 2 will consist of 3 weekly doses of vincristine, 1 dose of daunorubicin and calaspargase pegol at the start of the first week, and dexamethasone for 7 days in the first and third weeks. Patients will also receive the same additional agent received during induction based on immunophenotype.

Maintenance therapy:

• Early Maintenance Therapy follows Reinduction 2 and lasts 31 weeks. Patients will receive mercaptopurine and methotrexate interrupted by 1 week of nelarabine (week 3), 5 cyclophosphamide/ cytarabine pulses, and every 4-week dexamethasone/ vincristine pulses. For the first 32 weeks, patients will also receive every 4-week pulses including 5 days of dexamethasone and 1 dose of vincristine. Patients will receive low-dose methotrexate in all weeks when they do not receive dexamethasone or vincristine. All patients will receive every 4-week intrathecal chemotherapy beginning 4 weeks after the week of nelarabine.
• Late Maintenance Therapy follows early maintenance and includes daily mercaptopurine, weekly methotrexate, and every 8-week intrathecal chemotherapy. It lasts a total of 44 weeks.

Duration of therapy is approximately 2¼ years. It is recommended that patients be followed every 4 months for 1 year, every 6 months for 1 year and then yearly until the patient is in remission for 10 years and is at least 18 years old.

Inclusion criteria

• Enrollment on INITIALL.
• Age 1-18.99 years at the time of enrollment on INITIALL.
• T-Acute lymphoblastic leukemia or lymphoblastic lymphoma or mixed phenotype acute leukemia/ lymphoma
• No prior chemotherapy excluding therapy given on or allowed by INITIALL.
• Patient has completed no more than 3 days of chemotherapy on INITIALL.
• Direct bilirubin ≤ 1.5x the upper limit of normal for age
• Alanine aminotransferase (ALT) ≤ 5x the upper limit of normal for age
• Calculated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m^2 using the Bedside Schwartz equation OR creatinine below or equal to the maximum defined below:

• Age: 1 to < 2 years - Maximum serum creatinine (mg/dL): 0.6 (Male), 0.6 (Female)
• Age: 2 to < 6 years - Maximum serum creatinine (mg/dL): 0.8 (Male), 0.8 (Female)
• Age: 6 to < 10 years - Maximum serum creatinine (mg/dL): 1 (Male), 1 (Female)
• Age: 10 to < 13 years - Maximum serum creatinine (mg/dL): 1.2 (Male), 1.2 (Female)
• Age: 13 to < 16 years - - Maximum serum creatinine (mg/dL): 1.5 (Male), 1.4 (Female)
• Age: ≥ 16 years - Maximum serum creatinine (mg/dL): 1.7 (Male), 1.4 (Female)

Exclusion criteria

• Inability or unwillingness to give informed consent/ assent as applicable.
• Patients with > Grade 2 neuropathy at the time of enrollment (participant with T-LLy only).
• Documented malabsorption syndrome or any other condition that precludes receipt of oral medications.
• Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive).
• Pregnant or lactating.
• For patients of reproductive potential, unwillingness to use highly effective contraception for the duration of protocol therapy and for 90 days afterwards.
• Receipt of a strong or moderate CYP3A4 inducer such as rifampin, carbamazepine, phenytoin, and St. John's wort within 7 days of the start of protocol treatment.
• Consumption of grapefruit, grapefruit products, Seville oranges, or starfruit within 3 days of the start of protocol therapy.