Each year approximately 2,900 children and adolescents less than 20 years old are diagnosed with acute lymphoblastic leukemia or acute lymphoblastic lymphoma in the United States. (For the purposes of this protocol, ALL will be used to refer to patients with either acute lymphoblastic leukemia or acute lymphoblastic lymphoma as patients are treated in the same manner.) High-dose methotrexate (HDMTX; 5 g/m2) remains an important component of standard treatment for most ALL patients. However, high plasma and intracellular MTX concentrations (defined as a MTX level of >1 µmol/L at 42 hours and > 0.40 µmol/L at 48 hours) can quickly lead to acute kidney, bone marrow, liver, skin, central nervous system, and gastrointestinal toxicities requiring extended hospitalization and delays in subsequent chemotherapy treatments.