Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL)

• Patients \>= 1 year and \< 31 years of age at the time of relapse will be eligible

• First relapse of B-ALL, allowable sites of disease include isolated bone marrow, combined bone marrow and CNS and/or testicular, and isolated CNS and/or testicular; extramedullary sites are limited to the CNS and testicles

• No waiting period for patients who relapse while receiving standard maintenance therapy

• Patients who relapse on frontline therapy in phases other than maintenance must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

• Cytotoxic therapy: at least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy, or maintenance chemotherapy, or intrathecal chemotherapy (methotrexate strongly preferred) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status

• Biologic (anti-neoplastic) agent: at least 7 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur

• Stem cell transplant or rescue: patient has not had a prior stem cell transplant or rescue

• Patient has not had prior treatment with blinatumomab

• With the exception of intrathecal chemotherapy (methotrexate strongly preferred; cytarabine is permissible) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status, patient has not received prior relapse-directed therapy (i.e., this protocol is intended as the INITIAL treatment of first relapse)

• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows:

‣ 1 to \< 2 years: =\< 0.6 mg/dL

⁃ 13 to \< 16 years: =\< 1.5 mg/dL (males) and =\< 1.4 mg/dL (females)

⁃ \>= 16 years: =\< 1.7 mg/dL (males) and =\< 1.4 mg/dL (females)

• Direct bilirubin \< 3.0 mg/dL

• Shortening fraction of \>= 27% by echocardiogram, or

• Ejection fraction of \>= 50% by radionuclide angiogram

• All patients and/or their parent or legal guardian 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