Brief Summary: RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known which regimen of combination chemotherapy given together with or without monoclonal antibodies is more effective in treating patients with newly diagnosed acute lymphoblastic leukemia. PURPOSE: This randomized phase III trial is studying standard chemotherapy to see how well it works when given together with or without rituximab, and with or without nelarabine in treating patients with newly diagnosed acute lymphoblastic leukemia.

Detailed Description: OBJECTIVES: Primary * To determine if the addition of a monoclonal antibody (none vs. rituximab) improves event-free survival (EFS) in patients with newly diagnosed precursor B-cell acute lymphoblastic leukemia (ALL). * To determine if the addition of nelarabine improves outcome for patients with T-cell ALL. Secondary * To determine the tolerability of pegaspargase in induction therapy of all patients. * To compare anti-asparaginase antibody levels in patients with B-lineage ALL. * To determine whether risk-adapted introduction of unrelated donor hematopoietic stem cell transplantation (HSCT) (myeloablative conditioning in patients ≤ 40 years old and non-myeloablative conditioning in patients \> 40 years old) results in greater EFS for patients at highest risk of relapse. * To compare the efficacy of two schedules (standard vs collapsed) of palifermin in preventing severe mucosal toxicity in patients treated with etoposide, total-body irradiation, and HSCT-conditioning therapy. * To assess the late effects of this treatment in these patients. * To identify and describe some of the adverse physical and psychosocial consequences of this disease and its treatment. OUTLINE: This is a multicenter study. There are 3 randomizations at different timepoints in the trial, each patient undergoes at least 1 but no more than 2 randomizations. * Part 1 standard induction therapy (all patients\*, weeks 1-4): Patients receive daunorubicin hydrochloride IV over 20 minutes and vincristine sulfate IV over 5-10 minutes on days 1, 8, 15, and 22; oral dexamethasone once a day on days 1-5, 8-11, and 15-18; pegaspargase IV over 1-2 hours on days 4 and 18; and methotrexate intrathecally (IT) on day 14. NOTE: \*Patients with Philadelphia-positive (Ph+) disease should also receive oral imatinib mesylate once a day on days 1-28. * Randomized concurrent monoclonal antibody therapy (for patients with precursor B-cell acute lymphoblastic leukemia \[ALL\]): Patients with precursor B-cell ALL are randomized to 1 of 4 monoclonal antibody treatment arms (given concurrently with part 1 standard induction therapy): * Arm B1: Patients do not receive any monoclonal antibody therapy. * Arm B2 : Patients receive rituximab IV on days 3, 10, 17, and 24. * Part 2 standard induction therapy (all patients\*, weeks 5-8): Patients receive cyclophosphamide IV over 30 minutes on days 1 and 15; cytarabine IV on days 2-5, 9-12, 16-19, and 23-26; oral mercaptopurine once a day on days 1-28; and methotrexate IT on days 1, 8, 15, and 22. NOTE: \*Patients with Ph+ disease should also receive oral imatinib mesylate once a day on days 1-30. * Randomized subsequent nelarabine therapy (for Patients with T-cell ALL) Patients with T-cell ALL are randomized to 1 of 2 treatment arms, to be administered after completion of part 2 standard induction therapy. * Arm T1: Patients do not receive any other therapy during induction. * Arm T2: Patients receive nelarabine IV over 2 hours on days 1, 3, and 5. Patients who do not achieve complete remission (CR) after part 2 standard induction therapy are taken off study. * Intensification/central nervous system prophylaxis (patients not eligible for transplant OR patients \> 40 years at study entry and eligible for transplant)\*: Beginning after recovery from part 2 standard induction therapy, patients receive high-dose methotrexate IV on days 1 and 15 and pegaspargase IV over 1-2 hours on days 2 and 16. NOTE: \*Patients with Philadelphia-positive (Ph+) disease should also receive oral imatinib mesylate once a day on days 1-28. Patients eligible for allogeneic hematopoietic stem cell transplantation (HSCT) (i.e., any patient with an HLA-compatible sibling donor or high risk patients with a molecularly matched donor) undergo transplantation; patients not eligible for HSCT undergo consolidation followed by maintenance therapy. * Consolidation therapy\* (patients not eligible for transplantation): * Course 1: Beginning after completion of intensification therapy, patients receive cytarabine IV and high-dose etoposide IV over 30 minutes on days 1-5, pegaspargase IV over 1-2 hours on day 5, and methotrexate IT on day 1. Patients proceed to course 2 beginning 3 weeks after the start of course 1 or when neutrophils recover. * Course 2: Patients receive cytarabine IV and high-dose etoposide IV over 30 minutes on days 1-5 and methotrexate IT on day 1. Patients proceed to course 3 beginning 3 weeks after the start of course 2 or when neutrophils recover. * Course 3 (delayed intensification): Patients receive daunorubicin hydrochloride IV over 20 minutes and vincristine sulfate IV over 5-10 minutes on days 1, 8, 15, and 22; pegaspargase IV over 1-2 hours on day 4; oral dexamethasone once a day on days 1-4, 8-11, 15-18, and 22-25; methotrexate IT on days 2 and 17; cyclophosphamide IV on day 29; cytarabine IV on days 30-33 and 37-40; and oral mercaptopurine once a day on days 29-42. Patients proceed to course 4 after neutrophils recover. * Course 4: Patients receive cytarabine IV, high-dose etoposide IV, and methotrexate IT as in course 2. NOTE: \*Patients with Ph+ disease should also receive oral imatinib mesylate once a day on days 1-7 in courses 1 and 2, on days 2-42 in course 3, and on days 1-8 in course 4. * Maintenance therapy (patients not eligible for transplantation): Patients receive vincristine sulfate IV every 3 months, oral prednisolone once a day on days 1-5 every 3 months, oral mercaptopurine once daily, methotrexate IV or orally once a week, and methotrexate IT every 3 months for 2 years. * Transplant conditioning and allogeneic HSCT: * Myeloablative-conditioning and allogeneic HSCT (patients ≤ 40 years old at study entry): Patients undergo total-body irradiation on days -7 to -4 and receive high-dose etoposide IV over 4 hours on day -3 or high-dose cyclophosphamide IV over 2 hours on days -3 and -2. Patients then undergo allogeneic HSCT on day 0. Patients are stratified according to gender, donor (sibling donor vs. matched unrelated donor), and cellular type of ALL (precursor B-lineage vs. T-lineage). Patients are randomized to receive 1 of 2 palifermin treatment arms. * Arm P1 (standard dose): Patients receive palifermin IV on days -3 to 2. * Arm P2 (collapsed dose): Patients receive palifermin IV on days -1 to 2. * Non-myeloablative-conditioning and allogeneic HSCT (patients \> 40 years old at study entry): Patients receive fludarabine phosphate IV over 30-60 minutes on days -7 to -3 and melphalan IV over 90 days on day -1. Recipients of unrelated donor HSCT also receive alemtuzumab IV over 2 hours on day -2 and -1; recipients of sibling HSCT receive alemtuzumab IV over 2 hours on day -1. Patients then undergo allogeneic HSCT on day 0. Patients also receive post transplant methotrexate IT every 3 months for 2 years. Patients undergo blood and bone marrow sample collection periodically for correlative studies. After completion of study treatment, patients are followed annually. Peer Reviewed and Funded or Endorsed by Cancer Research UK