• All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement for B-LLy patients. B-LLy patients may directly enroll on AALL1731.

• Age at diagnosis:

‣ Patients must be \>= 365 days and \< 10 years of age (B-ALL patients without DS).

⁃ Patients must be \>= 365 days and =\< 31 years of age (B-ALL patients with DS).

⁃ Patients must be \>= 365 days and =\< 31 years of age (B-LLy patients with or without DS).

• B-ALL patients without DS must have an initial white blood cell count \< 50,000/uL (performed within 7 days prior to enrollment).

• B-ALL patients with DS are eligible regardless of the presenting white blood cell count (WBC) (performed within 7 days prior to enrollment).

• Patient has newly diagnosed B-cell ALL, with or without Down syndrome: \> 25% blasts on a bone marrow (BM) aspirate;

‣ OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis can be established by a pathologic diagnosis of B-ALL on a BM biopsy;

⁃ OR a complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells;

⁃ OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without Down syndrome.

⁃ Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted (diagnostic biopsy for B-LLy must be performed within 14 days prior to enrollment).

• 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.