Clinical Trials

PRIMARY OBJECTIVES: I. To test whether the relapse-free survival after allogeneic stem cell transplantation among Philadelphia chromosome positive and/or BCR/ABL positive acute lymphoblastic leukemia (ALL) patients given an intensive short-term chemotherapy regimen of hyper-CVAD in combination with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant further investigation. SECONDARY OBJECTIVES: I. To test whether the continuous complete remission rate for previously untreated Philadelphia chromosome positive and/or BCR/ABL positive acute lymphoblastic leukemia (ALL) patients given an intensive short-term chemotherapy regimen of hyper-CVAD in combination with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant phase III investigation. II. To investigate in a preliminary manner the relative effectiveness of minimal residual disease (MRD) detection using real-time quantitative polymerase chain reaction (PCR) for BCR/ABL versus flow cytometry to predict the outcome of patients treated by the hyper-CVAD + dasatinib regimen and/or allogeneic stem cell transplant. TERTIARY OBJECTIVES: I. To estimate the frequency and severity of toxicities of the intensive short-term chemotherapy regimen in these patients. II. To estimate the overall survival of all patients on this study. OUTLINE: This is a multicenter study. Patients are stratified according to prior treatment and response (untreated vs achieved complete remission [CR] with or without [CRi] hematopoietic recovery vs treated, refractory, and no CR or CRi). INDUCTION/CONSOLIDATION THERAPY: All patients receive both of the following regimens in alternating courses: COURSES 1, 3, 5, 7 or 3, 5, 7, 9: Patients receive cyclophosphamide intravenously (IV) over 3 hours twice daily (BID) on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4; vincristine sulfate IV over 30 minutes on days 4 and 11; dexamethasone IV or orally (PO) once daily (QD) on days 1-4 and 11-14; dasatinib PO QD on days 1-14; cytarabine intrathecally (IT) on day 7; methotrexate IT on day 2; and filgrastim (G-CSF) subcutaneously (SC) QD or BID. COURSES 2, 4, 6, 8: Patients receive high-dose methotrexate IV over 24 hours on day 1; methylprednisolone IV over 30 minutes BID on days 1-3; dasatinib PO QD on days 1-14; high-dose cytarabine IV over 2 hours BID on days 2-3; leucovorin calcium IV on days 2 or 3; methotrexate IT on day 2; cytarabine IT on day 7; and G-CSF SC QD or BID. Treatment repeats every 14-21 days for 8 courses in the absence of disease progression, unacceptable toxicity, or if patient achieves CR or CRi. MAINTENANCE THERAPY*: Patients receive vincristine sulfate IV over 30 minutes on day 1, prednisone PO QD on days 1-5, and dasatinib PO QD on days 1-28. Treatment repeats every month for 24 courses in the absence of disease progression or unacceptable toxicity or until the transplant is ready. INTENSIFICATION: For courses 6 and 13, patients receive cyclophosphamide IV over 3 hours BID on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4; vincristine sulfate IV over 30 minutes on days 4 and 11; dexamethasone IV or PO QD on days 1-4 and 11-14; dasatinib PO QD on days 1-14; and G-CSF SC QD or BID. NOTE: *Only if transplantation is not ready after induction/consolidation therapy or patients are not undergoing a transplant. ALLOGENEIC STEM CELL TRANSPLANTATION (FOR PATIENTS ACHIEVING CR OR CRi): CONDITIONING REGIMEN: Patients receive 1 of the following regimens: REGIMEN A: Patients receive total-body irradiation (TBI) QD on days -7 to -4 and cyclophosphamide IV on days -3 and -2. REGIMEN B: Patients receive TBI BID on days -6 to -4 and cyclophosphamide IV on days -3 and -2. REGIMEN C: Patients receive cyclophosphamide IV on days -7 and -6 and TBI QD on days -4 to -1. REGIMEN D: Patients receive cyclophosphamide IV on days -6 and -5 and TBI BID on days -3 to -1. REGIMEN E: Patients receive TBI QD on days -7 to -4 and etoposide IV on day -3. REGIMEN F: Patients receive TBI BID on days -6 to -4 and etoposide IV on day -3. ALLOGENEIC STEM CALL TRANSPLANTATION: Patients undergo allogeneic stem cell transplantation on day 0. GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive 1 of the following regimens: REGIMEN A: Patients receive sirolimus PO and tacrolimus IV continuously (changing to PO BID) beginning on day -3 and continuing for 6 months. REGIMEN B: Patients receive tacrolimus IV continuously (changing to PO BID) and continuing for 6 months, and methotrexate IV on days 1, 3, 6, and 11. SINGLE-AGENT THERAPY: After completion of maintenance therapy or beginning on day 100 post-transplantation, patients receive dasatinib PO QD for up to 5 years. Bone marrow and blood samples are collected periodically for cytogenetic analysis by PCR and flow cytometry. After completion of study therapy, patients are followed every 6 months for up to 5 years.

OBJECTIVES: Primary - Determine the impact of the intervention program (IP) on adherence to mercaptopurine (6MP) using the following adherence assessments: Frequency of 6MP dosing using MEMS (primary measure of adherence); 6MP dosage- and thiopurine methyltransferase (TPMT)-normalized serial red blood cell (RBC) thioguanine nucleotide (6TGN) levels; and self-report of adherence. Secondary - Examine the modifying effect of socio-demographic and clinical characteristics as well as health beliefs/knowledge on changes in adherence with the IP. OUTLINE: This is a multicenter study. Patients are stratified according to ethnic background (Hispanic vs non-Hispanic white vs African-American). Patients are randomized to 1 of 2 intervention arms. - Arm I: Patients receive the Patients Supply Kit containing an electronic pill monitoring system, a Medication Event Monitoring Systems (MEMS®) medication bottle with TrackCap™ with standard resistant cap, and written instructions for the patient and pharmacist. Parents and/or caregivers are also trained to supervise patients' intake of the medication. Beginning on day 1, patients start using the MEMS® medication bottle with TrackCap™ . Clinical research assistants contact patients and parents by telephone the next day to confirm that TrackCap™ is being used, to identify any obstacles, and to determine solutions. Beginning on day 29, patients and caregivers view an interactive multimedia educational program on-line or via DVD. Patients also receive a customized electronic mercaptopurine schedule and automated customized text message reminders delivered via cellular phone or web-based interface. Patients and caregivers are instructed to return the MEMS® medication bottle with TrackCap™ to the clinic by day 141. - Arm II: Patients receive the usual standard of care and the mercaptopurine from the MEMS® medication bottle with TrackCap™ as patients in arm I. Patients and parents and/or caregivers in both arms complete the Demographic and the Acculturation Questionnaires on day 1. Patients and/or caregivers in arm I also complete the Adherence Questionnaires on days 29, 57, and 141 and the Intervention Rating Questionnaire on day 141. Blood samples are collected on days 1, 29, 57, and 141 for thiopurine methyltransferase phenotyping and thioguanine nucleotide levels by high-performance chromatography.

Open-Label, Dose-Escalating, Clinical and Pharmacokinetic Phase I Study of PM01183 in Patients with Advanced Acute Leukemia to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 administered as 1-hour intravenous (i.v.) infusion on three consecutive days (Days 1-3) to patients with advanced acute leukemia and to assess the safety profile and tolerability, to obtain preliminary information on the efficacy and to characterize the pharmacokinetics (PK) and pharmacogenomic (PGx) profile of PM01183.

OBJECTIVES: - To provide a risk-based classification system based on clinical, pathological, molecular, and early response data that will be used to assign all patients with newly diagnosed acute lymphoblastic leukemia (ALL) to the Children's Oncology Group (COG) frontline specific-treatment studies. - To capture classification data for correlative studies accompanying current COG ALL treatment protocols. - To provide a central reference guide for all required and research studies that will be conducted in local and reference laboratories for all newly diagnosed ALL patients. - To provide a mechanism for optional banking of leukemia and germline specimens for current and future research. OUTLINE: This is a multicenter study. Patients are stratified according to diagnosis (B-cell precursor vs infant vs T-cell acute lymphoblastic leukemia [ALL]). Patients undergo blood sample collection and bone marrow biopsies at baseline and during and after induction therapy for immunophenotyping for ALL confirmation and classification, DNA ploidy, genomic variation, and cytogenetic (BCR-ABL, trisomies 4+10, and molecular testing for translocations) analysis by flow cytometry and FISH. Immunophenotype results obtained on this study are used to determine patient's assignment to specific clinical-trial treatments. Some samples (leukemic and germline) may be banked for current and/or future analyses.

PRIMARY OBJECTIVES: I. Determine the efficacy of an intensive chemotherapy regimen (based on POG-9412) for pediatric patients with intermediate-risk relapsed B-precursor acute lymphoblastic leukemia. SECONDARY OBJECTIVES: I. Compare the 3-year event-free survival and frequency and severity of adverse effects in patients treated with high-dose (closed to accrual as of 9/2010) vs low-dose vincristine. II. To determine levels of minimal residual disease (MRD) present at the end of the first & third blocks of Induction and determine if higher MRD levels at these times identify patients at higher risk of relapse who might be candidates for alternative therapies in future trials. III. To determine whether common polymorphisms in candidate genes are associated with the frequency of vincristine adverse effects (peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion [SIADH], or constipation) and with anti-leukemic response (level of end-Induction MRD). IV. Compare, descriptively, the outcomes of patients treated with combination chemotherapy vs those treated with matched sibling-related donor hematopoietic stem cell transplantation (for those with eligible donors). V. To use deoxyribonucleic acid (DNA) arrays to characterize patterns of gene expression that predict treatment failure, and to compare gene expression profiles at the time of relapse with those at initial diagnosis to gain an understanding of the pathways that may be involved in disease resistance. OUTLINE: This is a multicenter, randomized study. Patients are randomized to 1 of 2 treatment arms (randomization closed as of 09/2010). INDUCTION THERAPY 1 (WEEKS 1-5): ARM I: Patients receive low-dose vincristine intravenously (IV) on days 1, 8, 15, and 22; prednisone orally (PO) 3 times daily (TID) on days 1-28; doxorubicin hydrochloride IV over 15 minutes on day 1; pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22; cytarabine intrathecally (IT) on day 1; and methotrexate IT* on days 15 and 29. ARM II (closed to accrual as of 09/2010)***: Patients receive high-dose vincristine IV on days 1, 8, 15, and 22 and prednisone, doxorubicin hydrochloride, pegaspargase, cytarabine, and methotrexate* as in arm I. NOTE: *Central nervous system (CNS)-positive patients do not receive methotrexate IT. In both arms, CNS-positive patients receive intrathecal triple therapy (ITT) comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, 22, and 29. CNS-positive patients not achieving remission after induction therapy 1 receive one additional dose of ITT on day 36. Patients in both arms then proceed to induction therapy 2**. NOTE: **Patients who are CNS-positive at relapse receive induction therapy 3 BEFORE induction therapy 2. NOTE: ***Patients already enrolled on arm II are crossover to arm I. INDUCTION THERAPY 2 (WEEKS 6-10 or 7-11): Once blood counts recover, all patients receive etoposide phosphate IV over = 1 hour and cyclophosphamide IV over 1 hour on days 1-5; high-dose methotrexate IV continuously over 24 hours on day 22; leucovorin calcium IV or PO beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; and methotrexate IT* on days 1 and 22. Patients also receive filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 22. Patients with testicular-relapse with persistent testicular disease at the end of induction therapy 1 undergo testicular radiotherapy once daily (QD), 5 days a week, for 12 days during induction therapy 2**. NOTE: **Radiotherapy should be completed before beginning high-dose methotrexate (week 9) chemotherapy. All patients then proceed to induction therapy 3. INDUCTION THERAPY 3 (WEEKS 11-15 or 12-16): All patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9, and asparaginase IM on days 2 and 9. Patients also receive G-CSF IV or SC beginning on day 10 and continuing until blood counts recover. Patients with a suitable HLA-matched related donor are removed from study and proceed to stem cell transplantation. Patients without a suitable HLA-matched related donor proceed to intensification therapy 1 (as per their randomized arm in induction therapy 1). INTENSIFICATION THERAPY 1 (WEEKS 16-27 or 17-28): ARM I: Patients receive low-dose vincristine IV and high-dose methotrexate IV continuously over 24 hours on day 1; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 2-6; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 8; and methotrexate IT* on day 15. Treatment repeats every 21 days for 4 courses (with the exception of IT methotrexate which repeats for only 3 courses). ARM II: Patients receive high-dose vincristine IV on day 1 and high-dose methotrexate, leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide, and methotrexate IT* as in arm I. (closed to accrual as of 09/2010) NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 15. ITT repeats every 3 weeks for 3 courses. NOTE: ** Patients already enrolled on arm II are crossover to arm I. Patients in both arms then proceed to reinduction therapy (as per their randomized arm in induction therapy 1). REINDUCTION THERAPY (WEEKS 28-32 or 29-33): ARM I: Patients receive low-dose vincristine IV and doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15, oral dexamethasone twice daily on days 1-7 and 15-21, pegaspargase IM on days 2 and 15, and methotrexate IT* on days 1 and 28. ARM II: Patients receive high-dose vincristine IV on days 1, 8, and 15 and doxorubicin hydrochloride, dexamethasone, pegaspargase, and methotrexate IT* as in arm I. (closed to accrual as of 09/2010) NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 28. NOTE: ** Patients already enrolled on arm II are crossover to arm I. Patients in both arms then proceed to intensification therapy 2 (as per their randomized arm in induction therapy 1). INTENSIFICATION THERAPY 2 (WEEKS 33-56 or 34-57): ARM I: Once blood counts recover, patients receive high-dose cytarabine IV over 3 hours on days 1 and 2; pegaspargase IM on day 2; low-dose vincristine IV on days 22 and 29; high-dose methotrexate IV on day 22; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 23-27; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 29; and methotrexate IT* on day 36. Patients also receive G-CSF IV or SC beginning on day 3 and continuing until blood counts recover. Treatment repeats every 42 days for 4 courses (with the exception of IT methotrexate which only repeats for 3 courses). ARM II: Patients receive high-dose cytarabine, high-dose methotrexate, leucovorin calcium, pegaspargase, mercaptopurine, etoposide phosphate, cyclophosphamide, methotrexate IT*, and G-CSF as in arm I. Patients also receive high-dose vincristine IV on days 22 and 29. NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 36. Treatment repeats every 6 weeks for 3 courses. Patients in both arms then proceed to maintenance therapy (as per their randomized arm in induction therapy 1). MAINTENANCE THERAPY (week 57-106 or 58-107): ARM I: Patients receive methotrexate IT on day 1* and then PO on days 8, 15, 22, 29, and 36; mercaptopurine PO QD on days 1-42; dexamethasone PO twice daily (BID) on days 1-5; and low-dose vincristine IV and cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64. Treatment repeats every 70 days for 5 courses. ARM II: Patients receive methotrexate*, mercaptopurine, dexamethasone, and cyclophosphamide as in arm I. Patients also receive high-dose vincristine IV on days 43, 50, 57, and 64. NOTE: *CNS-positive patients receive methotrexate IT on day 1, instead of oral methotrexate. Beginning in week 1 of the first maintenance therapy course, patients with CNS relapse undergo cranial radiotherapy QD, 5 days a week, for 10 days. Patients with CNS relapse do not receive any IT therapy during maintenance therapy. After completion of study therapy, patients are followed periodically for 5 years.

OBJECTIVES:

       -  Establish a mechanism to bank specimens of tumor cells and host germline DNA from patients with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma at first and subsequent relapse.

       -  Make these specimens available to qualified researchers to study the biology of ALL.

     OUTLINE: This is a multicenter study.

     Patients undergo collection of bone marrow and peripheral blood at diagnosis of relapse and/or at the end of the first month of treatment.

     Patients are followed periodically for up to 10 years.

     PROJECTED ACCRUAL: Not specified.

PRIMARY OBJECTIVES:

     I. Compare the relative safety and efficacy of augmented Berlin-Frankfurt-Münster-86 multiagent chemotherapy with or without nelarabine in younger patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-NHL).

     II. Compare the relative safety and efficacy of interim maintenance therapy comprising high-dose methotrexate (with leucovorin calcium rescue) and mercaptopurine vs escalating-dose methotrexate (without leucovorin calcium rescue) and pegaspargase in these patients.

     III. Gain preliminary data on the use of nelarabine in patients with high-risk T-NHL and its effect on long-term survival.

     SECONDARY OBJECTIVES:

     I. Determine the relative safety and efficacy of withholding radiotherapy in patients with low -risk T-ALL and administering prophylactic cranial radiotherapy in patients with intermediate- or high-risk T-ALL.

     II. Characterize T-NHL biologic samples using conventional immunophenotyping, cytogenetic analysis, detection of activating Notch 1 mutations, comparative genomic hybridization (CGH), and gene expression profiling, and correlate these with long-term survival and identify potential targets for future therapy.

     OUTLINE: This is a randomized, controlled, factorial-group, multicenter study.

     INDUCTION THERAPY: (weeks 1-5) Patients receive cytarabine intrathecally (IT) on day 1; vincristine IV and daunorubicin hydrochloride IV on days 1, 8, 15, and 22; prednisone IV or orally twice daily on days 1-28; pegaspargase intramuscularly (IM) or IV over 1-2 hours on day 4, 5, OR 6; and methotrexate (MTX) IT on days 8 and 29*. Patients with Down syndrome (DS) also receive oral leucovorin calcium at 48 and 60 hours after each MTX dose (DS patients excluded as of 09/29/10).

     After completion of induction therapy, patients undergo risk assessment. Patients with M1 marrow and minimal residual disease (MRD) < 1% (defined as low- and intermediate-risk) proceed to consolidation therapy at day 36 or when blood counts recover (whichever occurs later). Patients with M2 marrow (5-25% blasts) and/or MRD ≥ 1% (defined as high-risk) proceed to consolidation therapy as soon as possible (i.e., they should not wait until day 36 or for blood counts to recover). Patients with M3 marrow (≥ 25% blasts) (defined as induction failure) proceed to consolidation therapy as soon as possible.

     NOTE: *Patients with CNS3 disease also receive MTX IT on days 15 and 22.

     CONSOLIDATION THERAPY: (weeks 6-13) During the safety phase portion of the study, patients with low-risk or intermediate-risk disease are randomized to arms I or III. Patients with high-risk disease are randomized to arms I, II, III, or IV. (safety phase closed for accrual as of 09/29/10) During the efficacy phase portion of the study, patients with low-risk* disease are randomized to arms I and III. Patients with intermediate-risk or high-risk** disease are randomized to arms I, II, III, or IV. The safety phase ends when the first 20 high-risk patients to receive nelarabine have been evaluated. Patients with DS are nonrandomly assigned to arm I (DS patients excluded as of  09/29/10). Patients with induction failure*** are nonrandomly assigned to arm IV.

     NOTE: *Patients with T-cell lymphoblastic lymphoma (T-NHL) are nonrandomly assigned to arm I.

     NOTE: ** Patients with T-NHL are randomly assigned to arms I or II without cranial radiotherapy.

     NOTE: *** Patients with T-NHL are nonrandomly assigned to arm II.

     ARM I: Patients receive MTX IT on days 1, 8, 15, and 22*; cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; oral mercaptopurine on days 1-14 and 29-42; vincristine IV on days 15, 22, 43 and 50; and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 11-12, 15-19, and 22-26 (DS patients excluded as of 09/29/10). Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic cranial radiotherapy (CRT) (1,200 cGy/dose) once daily on days 15-21 and 22-28. Patients with low-risk disease do not undergo CRT.

     NOTE: *Patients with CNS3 disease omit MTX IT on days 15 and 22; patients with high-risk disease omit MTX IT on day 1 and add an extra dose at day 29.

     ARM II: Patients receive nelarabine IV over 60 minutes on days 1-5 and 43-47; MTX IT on days 15, 22*, 57, and 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV or SC on days 8-11, 15-18, 50-53 and 57-60; oral mercaptopurine on days 8-21 and 50-63; vincristine IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours on days 22 and 64. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 15, 22-26, and 29-33(DS patients excluded as of 09/29/10). Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT once daily on days 22-28 and 29-35.

     NOTE: *Patients with CNS3 disease omit MTX IT on day 22.

     ARM III: Patients receive MTX, cyclophosphamide, cytarabine, mercaptopurine, vincristine, and pegaspargase as in arm I. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy as in arm I (DS patients excluded as of 09/29/10).

     ARM IV: Patients receive nelarabine, MTX, cyclophosphamide, cytarabine, mercaptopurine, vincristine, and pegaspargase as in arm II. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy as in arm II (DS patients excluded as of 09/29/10). Once blood counts recover, patients proceed to interim maintenance therapy according to their randomized/assigned arm. Patients not achieving M1 marrow by the end of consolidation therapy are removed from the study.

     INTERIM MAINTENANCE THERAPY (weeks 14-21 for arms I and III; weeks 17-24 for arms II and IV):

     ARM I: Patients* receive vincristine IV and escalating doses of MTX IV on days 1, 11, 21, 31, and 41; pegaspargase** IM or IV over 1-2 hours on days 2 and 22; and MTX IT on days 1 and 31. Patients with DS also receive oral leucovorin calcium 48 and 60 hours after each MTX IT dose (DS patients excluded as of 09/29/10).

     NOTE: * Patients with T-NHL are randomized or assigned to arms I or II only.

     NOTE: **Patients with an allergy to pegaspargase receive Erwinia asparaginase on days 2, 4, 6, 8, 10, 12, 22, 24, 26, 28, 30, and 32.

     ARM II: Patients* receive vincristine, escalating doses of MTX, pegaspargase, and MTX IT as in arm I.

     ARM III: Patients receive high-dose methotrexate (HDMTX) IV over 24 hours and vincristine IV on days 1, 15, 29, and 43; oral mercaptopurine on days 1-56; and MTX IT on days 1 and 29. Beginning 42 hours after the start of HDMTX, patients also receive leucovorin calcium IV or orally once every 6 hours for 3 doses.

     ARM IV: Patients receive HDMTX, vincristine, mercaptopurine, MTX IT, and leucovorin calcium as in arm III.

     Once blood counts recover, patients proceed to delayed intensification therapy according to their randomized/assigned arm.

     DELAYED INTENSIFICATION THERAPY (weeks 22-30 for arms I and III; weeks 25-33 for arms II and IV):

     ARM I: Patients* receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone IV or orally twice daily on days 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients ≥ 10 years of age and for patients with DS); doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; MTX IT on days 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or SC on days 29-32 and 36-39; and oral thioguanine on days 29-42. Patients with DS also receive oral leucovorin calcium at 48 and 60 hours after each MTX dose (DS patients excluded as of 09/29/10).

     NOTE: *T-NHL patients with standard-risk are nonrandomly assigned to arm I.

     ARM II: Patients** receive vincristine IV on days 1, 8, 15, and 50; dexamethasone IV or orally twice daily on days 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients ≥ 10 years of age); doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6 AND day 50; MTX IT on days 1, 36, and 43; nelarabine IV over 60 minutes on days 29-33; cyclophosphamide IV over 30 minutes on day 36; cytarabine IV or SC on days 36-39 and 43-46; and oral thioguanine on days 36-49.

     NOTE: ** T-NHL patients with induction failure are nonrandomly assigned to arm II.

     ARM III: Patients receive vincristine, dexamethasone, doxorubicin hydrochloride, pegaspargase, MTX IT, cyclophosphamide, cytarabine, and thioguanine as in arm I. Patients with intermediate- or high-risk disease (CNS1 or CNS2 disease) undergo prophylactic CRT (1,200 cGy/dose) once daily on days 50-54 and 57-59.

     ARM IV: Patients receive vincristine, dexamethasone, doxorubicin hydrochloride, pegaspargase, MTX IT, nelarabine, cyclophosphamide, cytarabine, and thioguanine as in arm II. Patients with intermediate- or high-risk disease (CNS 1 or CNS2 disease) undergo prophylactic CRT on days 50-54 and 57-59.

     All patients with CNS3 disease at diagnosis undergo CRT (1,800cGy/dose) once daily on days 50-54 and 57-61. Once blood counts recover, patients proceed to maintenance therapy according to their randomized/assigned arm.

     MAINTENANCE THERAPY (week 31 until the end of therapy for arms I and III; weeks 34-69 for arms II and IV):

     ARM I: Patients* receive vincristine IV on days 1, 29, and 57; oral dexamethasone twice daily on days 1-5, 29-33, and 57-61; oral mercaptopurine once daily on days 1-84; oral MTX** on days 8, 15, 22, 29*, 36, 43, 50, 57, 64, 71, and 78; and MTX IT on day 1. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).

     NOTE: * Patients with T-NHL and standard-risk are nonrandomly assigned to arm I.

     NOTE: **Patients with low-risk disease receive MTX IT, instead of oral MTX, on day 29 during the first 4 courses of therapy.

     ARM II: Patients*** receive vincristine IV on days 1 and 57; oral dexamethasone on days 1-5 and 57-61; oral mercaptopurine once daily on days 1-84; oral MTX on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; MTX IT on day 1; and nelarabine IV over 60 minutes on days 29-33. Treatment (that includes nelarabine) repeats every 84 days for 3 courses. Patients then receive treatment (without nelarabine) as follows: vincristine IV on days 1 and 57; oral dexamethasone on days 1-5, 29-33, and 57-61; oral mercaptopurine on days 1-84; oral MTX on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and MTX IT on day 1. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).

     NOTE: *** T-NHL patients with induction failure are nonrandomly assigned to arm II.

     ARM III: Patients receive vincristine, dexamethasone, mercaptopurine, oral MTX*, and MTX IT as in arm I. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).

     NOTE: *Patients with low-risk disease receive MTX IT, instead of oral MTX, on day 29 during the first 4 courses of therapy.

     ARM IV: Patients receive vincristine, dexamethasone, mercaptopurine, oral MTX, MTX IT, and nelarabine as in arm II. Patients then receive treatment (without nelarabine) as follows: vincristine, dexamethasone, mercaptopurine, oral MTX, and MTX IT as in arm II. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).

     After completion of study therapy, patients are followed periodically for at least 10 years.

PRIMARY OBJECTIVES: I. To determine if the administration of post-Induction age-adjusted intrathecal triple therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance (IM) high-dose methotrexate (IMHDM) backbone will improve 5-year disease-free survival (DFS) of children with high-risk (HR) acute lymphoblastic leukemia (ALL) compared to age-adjusted intrathecal (IT) methotrexate (MTX). II. To determine, in a randomized fashion, if the cyclophosphamide + etoposide-containing regimen (Experimental Arm 1) or the clofarabine + cyclophosphamide + etoposide-combination regimen (Experimental Arm 2) will improve the 4-year DFS of children, adolescents, and young adults with very high-risk (VHR) ALL compared to a modified MBFM-IMHDM regimen that contains a second IM (Control Arm). III. To determine, in a randomized fashion, if the cyclophosphamide + etoposide + clofarabine-containing combination regimen (Experimental Arm 2) will improve the 4-year DFS of children, adolescents, and young adults with VHR-ALL compared to the cyclophosphamide + etoposide combination regimen (Experimental Arm 1). SECONDARY OBJECTIVES: I. To determine the toxicity and tolerability of post-Induction age-adjusted ITT compared to age-adjusted IT MTX in children with HR-ALL. To determine the toxicity and tolerability of Experimental Arms 1 and 2 compared to the Control Arm in children, adolescents, and young adults with VHR-ALL. II. To determine whether a single-arm, modified Induction with limited anthracycline exposure and post-Induction therapy regimen with MBFM-IMIDM and reduced vincristine/steroid pulse frequency and enhanced supportive care in children with Down syndrome (DS) and HR-ALL will result in a ≥ 65% 5-year DFS and < 10% Induction mortality, and to gather clinical and biologic data that will facilitate further study to improve outcomes for this biologically and clinically unique patient subgroup. III. To determine the toxicity and tolerability of MBFM-IMIDM in children with DS and HR-ALL. IV. To determine if the reduction of minimal-residual disease (MRD) from end-Induction to end-Consolidation is greater for children, adolescents, and young adults with VHR-ALL receiving Experimental Arms 1 and/or 2 compared to the Control Arm. V. To estimate overall survival (OS) rates both overall and by regimen for HR-ALL and VHR-ALL patients. VI. To determine if peripheral blood absolute lymphocyte count (ALC) at day 29 of Induction is predictive of DFS in children, adolescents, and young adults with HR-ALL. VII. To determine the incidence and prognostic significance of recently discovered recurrent genomic lesions, including high cytokine receptor-like factor 2 (CRLF2) expression, CRLF2-activating genomic lesions, janus kinase (JAK) mutations, and IKAROS family zinc finger 1 (Ikaros) (IKZF1) mutations/deletions, in patients treated on this trial. VIII. To determine the prognostic significance of molecular risk classifiers using Low Density Array (LDA) Taqman cards. IX. To define the frequency of occurrence of key adverse events across all patient subgroups of HR-ALL in order to provide data for linked correlative biology studies that seek to develop biomarkers predictive of patients at risk for such events, including the following specific events: Grade 2 or higher (CNS hemorrhage, pancreatitis, osteonecrosis [ON], and seizure), Grade 3 or higher (GI bleed, encephalopathy, neuropathy, allergic reaction, ileus, mucositis/stomatitis, hyperbilirubinemia, and thrombosis), and all grades (transient ischemic attacks, strokes). X. To define the differences in the burden of therapy between HR-ALL and VHR-ALL when treated on the various arms of this study by collecting and comparing the total number of days admitted to the hospital. XI. To determine the incidence of ON, defined by magnetic resonance (MR) imaging, and to characterize the natural history of clinically silent ON in children, adolescents, and young adults 10 years of age and greater and to assess the role of drugs (i.e., asparaginase and methotrexate) in addition to corticosteroids, in the risk for development of ON. XII. To determine if the prevalence of cognitive deficits measured by CogState, in children (ages 6 to 11 years) with HR- and VHR-ALL at 1 year off therapy, is significantly higher than the normative population (> 14%) in the following domains: working memory, executive function, visual motor, processing speed, and visual attention. XIII. To compare the drug delivery of vincristine, pegaspargase, and methotrexate during Induction, Consolidation, Delayed Intensification, and Interim Maintenance II in 16-30 year olds treated on the control arm of the VHR study to that of adolescents and young adults (AYAs) with ALL treated with the same therapy on the C10403 adult cooperative group trial. OUTLINE: This is a multicenter study. Patients are stratified according to Down syndrome (no vs yes). Induction therapy for ALL patients without Down syndrome (35 days): Patients receive induction chemotherapy comprising cytarabine intrathecally (IT) on day 1; vincristine sulfate intravenously (IV) on days 1, 8, 15, and 22; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22; dexamethasone orally (PO) or IV twice daily (BID) on days 1-14 (patients under 10 years old) or prednisone PO or IV BID on days 1-28 (patients at least 10 years old); pegaspargase IV over 1-2 hours on day 4; and methotrexate IT on days 8 and 29 (plus days 15 and 22 for CNS3). Patients are stratified according to National Cancer Institute (NCI) ALL risk criteria (high-risk or standard-risk vs very high-risk). High-risk or standard-risk ALL: Patients are randomized to 1 of 2 treatment arms. Consolidation therapy (56 days): Arm I HR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-4 and 29-42, methotrexate IT on days 1, 8, 15, and 22; vincristine sulfate IV on days 15, 22, 43, and 50; and pegaspargase IV over 1-2 hours on days 15 and 43. Patients with continuing clinical evidence of testicular leukemia undergo radiotherapy (RT) once daily, 5 days a week, for approximately 2½ weeks (12 fractions total). Arm II HR-ALL C: Patients receive intrathecal triple therapy (ITT) comprising methotrexate, hydrocortisone sodium succinate, and cytarabine on days 1, 8, 15, and 22. Patients also receive consolidation therapy as patients in arm I HR-ALL C. Patients with testicular leukemia also undergo RT as in arm I HR-ALL C. Interim maintenance therapy (63 days): Arm I HR-ALL IM: Patients receive interim maintenance (IM) therapy comprising vincristine sulfate IV on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; methotrexate IT on days 1 and 29; and mercaptopurine PO on days 1-56. Arm II HR-ALL IM: Patients receive ITT on days 1 and 29 and IM therapy as in arm I HR-ALL IM. Delayed intensification therapy (56 days): Arm I HR-ALL DI: Patients receive delayed intensification (DI) therapy comprising vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID on days 1-7, and 15-21; doxorubicin hydrochloride IV on days 1, 8, and 15; methotrexate IT on days 1, 29, and 36; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV on days 29-32 and 36-39; and thioguanine PO on days 29-42. Arm II HR-ALL DI: Patients receive ITT on days 1, 29, and 36 and DI therapy as in arm I HR-ALL DI. Maintenance therapy: Arm I HR-ALL M: Patients receive maintenance therapy comprising vincristine sulfate IV on days 1, 29, and 57; methotrexate IT on days 1 (also day 29 of courses 1-4) ; prednisone PO BID on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. Arm II HR-ALL M: Patients receive ITT on day 1 (also day 29 of courses 1-4) and maintenance therapy as in arm I HR-ALL M. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. Very high-risk ALL: Patients are randomized to 1 of 3 treatment arms. Consolidation therapy part 1 (days 1-28): In all arms, patients receive cyclophosphamide IV over 30-60 minutes on day 1; cytarabine IV or SC on days 1-4 and 8-11; mercaptopurine PO on days 1-14; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS patients): vincristine sulfate IV on days 15 and 22; and pegaspargase IV over 1-2 hours on day 15. Patients with continuing clinical evidence of testicular leukemia undergo RT once daily, 5 days a week, for approximately 2½ weeks (12 fractions total). Consolidation therapy part 2 (days 29-57): Arm A VHR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; mercaptopurine PO on days 29-42; vincristine IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm B VHR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 1-2 hours on days 29-33; vincristine sulfate IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm C VHR-ALL C: Patients receive clofarabine IV over 2 hours on days 29-33 and consolidation therapy as in arm B VHR-ALL C. Interim Maintenance I (63 days): In all arms, patients receive vincristine IV on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Delayed Intensification part 1 (days 1-28): In all arms, patients receive vincristine sulfate IV on days 1, 8, and 15; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on day 1; and pegaspargase IV over 1-2 hours on day 4. Delayed Intensification part 2 (days 29-57): Arm A VHR-ALL DI: Patients receive DI therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; thioguanine PO on days 29-42; methotrexate IT on days 29 and 36; vincristine sulfate IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm B VHR-ALL DI: Patients receive DI therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 1-2 hours on days 29-33; methotrexate IT on days 29 and 36; vincristine sulfate IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm C VHR-ALL DI: Patients receive clofarabine IV over 2 hours on days 29-33 and DI therapy as in arm II B VHR-ALL DI. Interim Maintenance II (56 days): In all arms, patients receive vincristine sulfate IV and methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Maintenance therapy: Patients with CNS3 disease at diagnosis undergo RT once daily over 4 weeks (10 fractions total). In all arms, patients receive vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (except on methotrexate IT days); mercaptopurine PO on days 1-84; methotrexate IT on day 1 (also day 29 of courses 1 and 2 for CNS patients who did not receive RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities. High-risk ALL patients with Down syndrome: Patients are stratified according to response to induction therapy (days 1-14) (rapid early responders [RER; M1 day 15 bone marrow] vs slow early responders [SER; M2/M3 day 15 bone marrow]). Induction therapy (days 1-14): All patients receive cytarabine IT on day 1; vincristine sulfate IV on days 1 and 8, dexamethasone PO or IV BID (patients under 10 years old) or prednisone PO BID (patients at least 10 years old) on days 1-14, pegaspargase IV over 1-2 hours on day 4; methotrexate IT on day 8; and leucovorin calcium PO on days 10-11. Induction therapy (day 15-29): RER patients receive induction therapy comprising vincristine sulfate IV on days 15 and 22; dexamethasone PO BID or prednisone PO BID on days 15-28; methotrexate IT on day 29 (also days 15 and 22 for CNS3 patients); and leucovorin calcium PO on days 31-32 (also days 17-18 and 24-25 for CNS3 patients). SER patients receive daunorubicin hydrochloride IV over 1-15 minutes on day 15 and induction therapy as RER patients. Consolidation therapy (56 days): All patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 15-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43, and 50; pegaspargase IV over 1-2 hours on days 15 and 43; methotrexate IT on days 1, 8, 15, and 22; and leucovorin calcium PO on days 3-4, 10-11, 17-18, and 24-25. Patients with continuing clinical evidence of testicular leukemia undergo RT once daily, 5 days a week, for approximately 2½ weeks (12 fractions total). Interim maintenance therapy (63 days): Patients receive vincristine sulfate IV on days 1, 15, 29, and 43; methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Delayed intensification therapy: Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone PO BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO on days 29-42; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; methotrexate IT on days 1, 29, and 36; and leucovorin calcium PO on days 3-4, 31-32 and 38-39. Maintenance therapy: Patients with CNS3 disease undergo RT once daily, 5 days a week, for 2 weeks (10 fractions total). Patients receive vincristine IV on day 1; prednisone PO BID on days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and methotrexate IT on day 1 (also day 29 of courses 1-4 for CNS3 patients who did not receive RT). Treatment repeats every 12 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo peripheral blood and bone marrow collection for correlative studies. Patients who are at least 10 years old have MRIs during Consolidation, Maintenance, and End of therapy and blood draws during Consolidation, Delayed Intensification, and Interim Maintenance II (VHR-ALL only). Patients may also undergo neurocognitive assessment during consolidation therapy, periodically during maintenance therapy, and at 1 year after completion of study therapy. After completion of study therapy, patients are followed up periodically for 10 years.

PRIMARY OBJECTIVES:

     I. To determine the clinical efficacy (2-year disease-free survival rate) of nilotinib and combination chemotherapy in adult patients newly diagnosed with Philadelphia chromosome positive B-cell acute lymphoblastic leukemia or blast crisis of chronic myeloid leukemia.

     SECONDARY OBJECTIVES:

     I. Determine the 2-year overall survival rate. II. Determine the complete response (CR) rates (hematological, cytogenetic, and molecular) in patients treated with this regimen.

     III. Determine the CR duration in patients treated with this regimen. IV. Assess the safety and toxicity of this regimen by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

     TERTIARY OBJECTIVES:

     I. Assess the prognostic and predictive factors for patients treated with this regimen.

     II. Assess the cerebrospinal fluid (CSF) penetration for Nilotinib (CSF Nilotinib levels) in humans.

     III. Assess the Abelson (ABL) kinase domain mutations frequency at diagnosis, during therapy, and at relapse.

     OUTLINE:

     INDUCTION AND CONSOLIDATION SCHEDULE A (COURSES 1, 3, 5, 7): Patients receive cyclophosphamide intravenously (IV) twice daily (BID) over 2 hours on days 1-3, mesna IV continuously on days 1-3, doxorubicin hydrochloride IV push on day 4, vincristine sulfate IV on days 4 and 11, dexamethasone IV or orally (PO) on days 1-4 and 11-14, methotrexate intrathecally (IT) on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV on days 1 and 11.

     INDUCTION AND CONSOLIDATION SCHEDULE B (COURSES 2, 4, 6, 8): Patients receive methotrexate IV continuously over 24 hours on day 1, cytarabine IV over 2 hours on days 2-3, leucovorin calcium IV every 6 hours on days 2-3, methotrexate IT on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV on days 1 and 11.

     MAINTENANCE (COURSES 9-32): Patients receive nilotinib PO BID on days 1-28 (days 1-14 for minimal residual disease [MRD]-positive patients), vincristine sulfate IV on day 1, and prednisone PO on days 1 to 5. Patients also receive rituximab IV on day 1 of each course if CD20-positive, every sixth course if MRD-negative, or every third course if MRD-positive.

     INTENSIFICATION: Patients receive treatment as in Schedule A in courses 14 and 21 of maintenance therapy and treatment as in Schedule B in courses 15 and 22 of maintenance therapy.

     DELAYED MAINTENANCE (COURSES 33-36): Patients receive nilotinib PO BID on days 1 to 84. Treatment repeats every 84 days for up to 4 courses.

     Treatment continues in the absence of disease progression or unacceptable toxicity.

     After completion of study treatment, patients are followed up every 6-12 months for 4 years.

PRIMARY OBJECTIVES: I. To estimate the toxicity, second complete response (CR2) rate at the end of Block 1 therapy, and 4-month event-free survival (EFS) for pediatric and young adult patients with relapsed acute lymphoblastic leukemia (ALL) treated with bortezomib in combination with intensive re-Induction chemotherapy. II. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination regimen. SECONDARY OBJECTIVES: I. To assess minimal residual disease (MRD) in bone marrow following completion of each therapy block. II. To assess the feasibility of measuring leukemia initiating cells (LIC) in patient samples before and after chemotherapy. III. To discover biologic pathways associated with response and drug resistance using gene and protein expression profiles at baseline and following initial exposure to chemotherapy. IV. To determine if bortezomib inhibits lymphoblast NF-kappa-B activity in leukemia patients. OUTLINE: REINDUCTION BLOCK 1: Patients receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV on days 1, 8, 15, and 22; doxorubicin hydrochloride IV over 15 minutes on day 1; oral prednisone twice daily on days 1-29; bortezomib IV on days 1, 4, 8, and 11; and pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22. Patients with central nervous system (CNS)-negative disease (CNS1 or CNS2) also receive methotrexate IT on days 15 and 29; patients with CNS-positive disease (CNS3) receive triple intrathecal therapy (TIT) comprising methotrexate, hydrocortisone, and cytarabine IT on days 8, 15, 22, and 29. After completion of reinduction block 1, patients with ALL and M2 or M3 bone marrow proceed directly to reinduction block 2. Patients with ALL and M1 bone marrow or lymphoblastic lymphoma proceed to reinduction block 2 after blood counts recover. Patients with persistent cerebral spinal fluid (CSF) blasts after 6 doses of TIT or patients with progressive lymphoblastic lymphoma are removed from the study. REINDUCTION BLOCK 2: Patients receive etoposide phosphate IV over 1-2 hours on days 1-5; cyclophosphamide IV over 1 hour on days 1-5; bortezomib IV on days 1, 4, and 8; filgrastim (G-CSF) subcutaneously (SC) or IV daily beginning on day 6 and continuing until blood counts recover*; high-dose methotrexate IV on day 22; and leucovorin calcium orally or IV every 6 hours on days 23 and 24. Patients with CNS-negative disease also receive methotrexate IT on days 1 and 22; patients with CNS-positive disease receive TIT on days 1 and 22. After completion of reinduction block 2, patients proceed to reinduction block 3 immediately or when blood counts recover. Patients with disease progression are removed from the study. NOTE: *Patients do not receive G-CSF on day 8. REINDUCTION BLOCK 3: Patients receive cytarabine IV over 3 hours twice daily on days 1, 2, 8, and 9; L-asparaginase IM on days 2 and 9; and G-CSF SC or IV daily beginning on day 10 and continuing until blood counts recover. After completion of study treatment, patients are followed every 6 months for 3 years and then annually for 2 years.