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)

This is a clinical trial testing whether the addition of one of two chemotherapy agents, dasatinib or venetoclax, can improve outcomes for children and young adults with newly diagnosed T-cell acute lymphoblastic leukemia and lymphoma or mixed phenotype acute leukemia.

Primary Objective

* To evaluate if the end of induction MRD-negative rate is higher in patients with T-ALL treated with dasatinib compared to similar patients treated with 4-drug induction on AALL1231.
* To evaluate if the end of induction MRD-negative rate is higher in patients with ETP or near-ETP ALL treated with venetoclax compared to similar patients treated with 4-drug induction on AALL1231.

Secondary Objectives

* To assess the event free and overall survival of patients treated with this therapy.
* To compare grade 4 toxicities, event-free survival (EFS) and overall survival (OS) of patients treated with this therapy in induction and reinduction to toxicities of similar patients treated on TOT17.

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.

Eligibility Criteria:
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.