Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Stage II-IV T-Cell Lymphoblastic Lymphoma

Phase 3

Active, not recruiting

Conditions: Adult T Acute Lymphoblastic Leukemia
Ann Arbor Stage II Adult Lymphoblastic Lymphoma
Ann Arbor Stage II Childhood Lymphoblastic Lymphoma
Ann Arbor Stage III Adult Lymphoblastic Lymphoma
Ann Arbor Stage III Childhood Lymphoblastic Lymphoma
Ann Arbor Stage IV Adult Lymphoblastic Lymphoma
Ann Arbor Stage IV Childhood Lymphoblastic Lymphoma
Childhood T Acute Lymphoblastic Leukemia

Interventions: Drug: Cyclophosphamide
Drug: Bortezomib
Drug: Cytarabine
Drug: Daunorubicin
Drug: Daunorubicin Hydrochloride
Drug: Dexamethasone
Drug: Doxorubicin
Drug: Doxorubicin Hydrochloride
Drug: Etoposide
Drug: Hydrocortisone Sodium Succinate
Drug: Ifosfamide
Drug: Leucovorin Calcium
Drug: Mercaptopurine
Drug: Methotrexate
Drug: Pegaspargase
Radiation: Radiation Therapy
Drug: Thioguanine
Drug: Vincristine
Drug: Vincristine Sulfate

Registration Number: NCT02112916

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase III trial compares how well combination chemotherapy works when given with or without bortezomib in treating patients with newly diagnosed T-cell acute lymphoblastic leukemia or stage II-IV T-cell lymphoblastic lymphoma. Bortezomib may help reduce the number of leukemia or lymphoma cells by blocking some of the enzymes needed for cell growth. It may also help chemotherapy work better by making cancer cells more sensitive to the drugs. It is not yet known if giving standard chemotherapy with or without bortezomib is more effective in treating newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.

Detailed Description: PRIMARY OBJECTIVES:

I. To compare event-free survival (EFS) in patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LLy) who are randomized to a modified augmented Berlin-Frankfurt-Munster (ABFM) backbone versus bortezomib plus the modified ABFM backbone.

SECONDARY OBJECTIVES:

I. To determine the safety and feasibility of modifying standard therapy for T-ALL and T-LLy based on the results of UKALL 2003, which includes a dexamethasone-based induction, additional doses of pegaspargase (PEG-ASP) during induction and delayed intensification (DI), and dexamethasone pulses during maintenance therapy.

II. To determine if prophylactic (presymptomatic) cranial radiation therapy (CRT) can be safely and effectively eliminated in the 85-90% of T-ALL patients classified as standard or intermediate risk.

III. To determine the proportion of end of consolidation (EOC) minimal residual disease (MRD) \>= 0.1% T-ALL patients who become MRD negative (undetectable by flow cytometry) after intensification of chemotherapy, using three high risk (HR) BFM blocks, and to compare EFS between the patients who become MRD negative after the three HR BFM blocks and continue on chemotherapy with those who continue to have detectable MRD and are eligible for other treatment strategies, including hematopoietic stem cell transplant (HSCT).

IV. To compare the EFS between very high risk (induction failure) T-LLy patients treated with HR BFM intensification blocks who have partial or complete response (PR or CR) with those who do not respond (NR).

CORRELATIVE OBJECTIVES:

I. To investigate the prognostic significance of day 29 bone marrow (BM) MRD in T-LLy patients.

II. To determine if protein expression patterns can predict bortezomib response and drug resistance in T-ALL.

III. To analyze and target relevant signaling pathways in T-ALL blasts, focusing on early T cell precursor (ETP) acute lymphoblastic leukemia (ALL).

OUTLINE: Patients are randomized to 1 of 2 treatment arms. Patients are risk assigned based on data from end of induction and/or consolidation therapy; this then modifies the subsequent therapy received.

T-ALL Risk Group Definitions:

Standard Risk (SR): CNS1\*, lumbar puncture prior to steroid therapy (not steroid pretreated), Day 29 (end of induction) bone marrow M1, Day 29 bone marrow minimal residual disease (MRD) \<=0.01%, no testicular leukemia at diagnosis.

Intermediate Risk (IR): Not SR or VHR.

Very High Risk (VHR): M3 marrow at Day 29 and/or end of consolidation (EOC) MRD \>=0.1%.

\*CNS2 and CNS3 cannot be SR and are assigned to IR or VHR based on marrow response.

T-LL Risk Group Definitions:

Standard Risk (SR): CNS1\*, MRD at diagnosis \<1% in bone marrow, lumbar puncture prior to steroid therapy (not steroid pretreated), Day 29 (end of induction) complete response (CR) or partial response (PR).

Intermediate Risk (IR): Not SR or VHR.

Very High Risk (VHR): Stable Disease (SD)/No response (NR) at Day 29 (End of Induction).

\*CNS2 and CNS3 cannot be SR and are assigned to IR or VHR based on radiographic response.

ARM A INDUCTION: Patients receive cytarabine intrathecally (IT) at time of diagnostic lumbar puncture (if within 72 hours from start of protocol therapy) OR day 1; vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, and 22; dexamethasone orally (PO) twice daily (BID) on days 1-28 (no taper); daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22; pegaspargase IV over 1-2 hours on days 4 and 18; and methotrexate IT on days 8 and 29 (and on days 15 and 22 for central nervous system 3 involvement \[CNS3\] T-ALL patients).

ARM A CONSOLIDATION: Beginning on day 36 from Induction, patients receive methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 T-ALL or CNS3 T-LLy patients); cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO once daily (QD) on days 1-14 and 29-42; pegaspargase IV over 1-2 hours on days 15 and 43; and vincristine sulfate IV on days 15, 22, 43, and 50. Patients with persistent testicular disease undergo radiation therapy.

Patients are then assigned to subsequent therapy according to risk assignment. Patients with standard risk (SR) disease receive Interim Maintenance with Capizzi methotrexate (CMTX); patients with intermediate risk (IR) disease receive Interim Maintenance with high-dose methotrexate (HDMTX), Delayed Intensification, and then Interim Maintenance with CMTX; and patients with very high risk (VHR) disease receive 3 HR Intensification Blocks, Delayed Intensification, and then Interim Maintenance with CMTX.

ARM A CMTX INTERIM MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 11, 21, 31, and 41; methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) 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. The next course (based on risk assignment) begins on day 57 or when blood counts recover (whichever occurs later).

ARM A DELAYED INTENSIFICATION: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO BID or IV on days 1-7 and 15-21; doxorubicin hydrochloride IV over 15 minutes on days, 1, 8, and 15; pegaspargase IV over 1-2 hours on days 4, 18, and 43; methotrexate IT on days 1, 29, and 36; cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. The next course (based on risk assignment) begins on day 64 or when blood counts recover (whichever occurs later).

ARM A HDMTX INTERIM MAINTENANCE: Patients receive high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium IV or PO on days 3-4, 17-18, 31-32, and 45-46; vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. The next course (based on randomization assignment) begins on day 57 or when blood counts recover (whichever occurs later).

ARM A INTENSIFICATION BLOCK I: Patients receive dexamethasone IV or PO BID on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium IV or PO on days 3-4; vincristine sulfate IV on days 1 and 6; cyclophosphamide IV over 1-6 hours on days 2-4; high-dose cytarabine IV over 3 hours every 12 hours on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. The next course (Intensification Block II) begins on day 22 or when blood counts recover (whichever occurs later).

ARM A INTENSIFICATION BLOCK II: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium PO or IV on days 3-4; vincristine sulfate IV on days 1 and 6; ifosfamide IV over 1 hour every 12 hours on days 2-4; daunorubicin hydrochloride IV over 30 minutes on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 1 as in Intensification Block I. The next course (Intensification Block III) begins on day 22 or when blood counts recover (whichever occurs later).

ARM A INTENSIFICATION BLOCK III: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose cytarabine IV over 3 hours every 12 hours on days 1-2; etoposide IV over 1-2 hours every 12 hours on days 3-5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 5 as in Intensification Block I. The next course (based on randomization) begins on day 22 or when blood counts recover (whichever occurs later).

ARM A MAINTENANCE THERAPY: All patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 29 for SR patients during the first 4 cycles); methotrexate IT on day 1 (and day 29 during the first 4 cycles for SR patients and during the first 2 cycles for IR patients). Patients with CNS1-3VHR and CNS2 VHR, and CNS3 IR disease also undergo cranial radiation therapy during the first 4 weeks (cycle 1). Treatment in female patients with T-ALL and patients with T-LLY repeats every 12 weeks for up to 2 years from the start of Interim Maintenance (week 119). Treatment in male patients with T-ALL repeats every 12 weeks for up to 3 years from the start of Interim Maintenance (week 171).

ARM B INDUCTION: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11(1.3 mg/m\^2 per dose); and cytarabine, vincristine sulfate, dexamethasone, daunorubicin hydrochloride, pegaspargase, and methotrexate as in Induction Arm A.

ARM B CONSOLIDATION: Beginning on day 36 from Induction, patients receive methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 T-ALL or CNS3 T-LLy patients); cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO once daily (QD) on days 1-14 and 29-42; pegaspargase IV over 1-2 hours on days 15 and 43; and vincristine sulfate IV on days 15, 22, 43, and 50. Patients with persistent testicular disease undergo radiation therapy.

Patients are then assigned to subsequent therapy according to risk assignment. Patients with standard risk (SR) disease receive Interim Maintenance with Capizzi methotrexate (CMTX); patients with intermediate risk (IR) disease receive Interim Maintenance with high-dose methotrexate (HDMTX), Delayed Intensification, and then Interim Maintenance with CMTX; and patients with very high risk (VHR) disease receive 3 HR Intensification Blocks, Delayed Intensification, and then Interim Maintenance with CMTX.

ARM B CMTX INTERIM MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 11, 21, 31, and 41; methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) 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. The next course (based on risk assignment) begins on day 57 or when blood counts recover (whichever occurs later).

ARM B DELAYED INTENSIFICATION: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 15, and 18 (1.3 mg/m\^2 per dose); and vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, methotrexate, cyclophosphamide, cytarabine, and thioguanine as in Delayed Intensification Arm A. The next course (based on risk assignment) begins on day 64 or when blood counts recover (whichever occurs later).

ARM B HDMTX INTERIM MAINTENANCE: Patients receive high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium IV or PO on days 3-4, 17-18, 31-32, and 45-46; vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. The next course (based on randomization assignment) begins on day 57 or when blood counts recover (whichever occurs later).

ARM B INTENSIFICATION BLOCK I: Patients receive dexamethasone IV or PO BID on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium IV or PO on days 3-4; vincristine sulfate IV on days 1 and 6; cyclophosphamide IV over 1-6 hours on days 2-4; high-dose cytarabine IV over 3 hours every 12 hours on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. The next course (Intensification Block II) begins on day 22 or when blood counts recover (whichever occurs later).

ARM B INTENSIFICATION BLOCK II: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium PO or IV on days 3-4; vincristine sulfate IV on days 1 and 6; ifosfamide IV over 1 hour every 12 hours on days 2-4; daunorubicin hydrochloride IV over 30 minutes on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 1 as in Intensification Block I. The next course (Intensification Block III) begins on day 22 or when blood counts recover (whichever occurs later).

ARM B INTENSIFICATION BLOCK III: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose cytarabine IV over 3 hours every 12 hours on days 1-2; etoposide IV over 1-2 hours every 12 hours on days 3-5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 5 as in Intensification Block I. The next course (based on randomization) begins on day 22 or when blood counts recover (whichever occurs later).

ARM B MAINTENANCE THERAPY: All patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 29 for SR patients during the first 4 cycles); methotrexate IT on day 1 (and day 29 during the first 4 cycles for SR patients and during the first 2 cycles for IR patients). Patients with CNS1-3VHR and CNS2 VHR, and CNS3 IR disease also undergo cranial radiation therapy during the first 4 weeks (cycle 1). Treatment in female patients with T-ALL and patients with T-LLY repeats every 12 weeks for up to 2 years from the start of Interim Maintenance (week 119). Treatment in male patients with T-ALL repeats every 12 weeks for up to 3 years from the start of Interim Maintenance (week 171).

All treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 10 years.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 847

Inclusion Criteria

T-ALL: T-ALL patients must be enrolled on AALL08B1 or Project:EveryChild (APEC14B1, if open for the classification of ALL patients) prior to treatment and enrollment on AALL1231
All patients must be > 1 and < 31 years of age
Patients must have newly diagnosed T-lymphoblastic leukemia (T-ALL) or T-lymphoblastic lymphoma (T-LLy) stages II-IV
- Note: a diagnosis of T-ALL is established when leukemic blasts lack myeloperoxidase or evidence of B-lineage derivation (cluster of differentiation [CD]19/CD22/CD20), and express either surface or cytoplasmic CD3 or two or more of the antigens CD8, CD7, CD5, CD4, CD2 or CD1a, and are present either in peripheral blood or > 25% in the bone marrow; if surface CD3 is expressed on all leukemic cells, additional markers of immaturity, including terminal deoxynucleotidyl transferase (TdT), CD34 or CD99 will be assessed for expression; cases with uncertain expression will receive additional review within the appropriate Children's Oncology Group (COG) reference laboratory
- For T-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to T-ALL; for tissue processed by other means (i.e. paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of T-LLy defined by the submitting institution will be accepted
All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria

Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of T-ALL, T-L-Ly or for any cancer diagnosis prior to the initiation of protocol therapy on AALL1231, with the exception of:
- Steroid pretreatment: prednisone or methylprednisolone for =< 120 hours (5 days) in the 7 days prior to initiating induction chemotherapy or for =< 336 hours (14 days) in the 28 days prior to initiating induction chemotherapy; prior exposure to ANY steroids that occurred > 28 days before the initiation of protocol therapy does not affect eligibility; the dose of prednisone or methylprednisolone does not affect eligibility
- Intrathecal cytarabine (the CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment) system chemotherapy must begin with 72 hours of this IT therapy; or
- Pretreatment with hydroxyurea; or
- 600 cGy of chest irradiation, if medically necessary
  - Pre-treatment with dexamethasone in the 28 days prior to initiation of protocol therapy is not allowed with the exception of a single dose of dexamethasone use during sedation to prevent or treat airway edema; inhalation steroids and topical steroids are not considered pretreatment
Pre-existing >= grade 2 sensory or motor peripheral neurotoxicity
Uncontrolled seizure disorder
Diagnosis of Down syndrome (Trisomy 21)
Patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential
Lactating females who plan to breastfeed
Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
Patient has hypersensitivity to bortezomib, boron, or mannitol
Serious medical or psychiatric illness likely to interfere with participation in this clinical study
Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and within 30 days of any dose of bortezomib

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (combination chemotherapy)	Cyclophosphamide	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Cytarabine	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Daunorubicin	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Daunorubicin Hydrochloride	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Dexamethasone	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Doxorubicin	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Doxorubicin Hydrochloride	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Etoposide	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Hydrocortisone Sodium Succinate	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Ifosfamide	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Leucovorin Calcium	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Mercaptopurine	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Methotrexate	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Pegaspargase	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Radiation Therapy	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Thioguanine	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Vincristine	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm A (combination chemotherapy)	Vincristine Sulfate	Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Bortezomib	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Cyclophosphamide	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Cytarabine	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Daunorubicin	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Daunorubicin Hydrochloride	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Dexamethasone	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Doxorubicin	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Doxorubicin Hydrochloride	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Etoposide	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Hydrocortisone Sodium Succinate	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Ifosfamide	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Leucovorin Calcium	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Mercaptopurine	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Methotrexate	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Pegaspargase	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Radiation Therapy	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Thioguanine	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Vincristine	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.
Arm B (combination chemotherapy, bortezomib)	Vincristine Sulfate	Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.

Primary Outcome Measures

Name	Time	Method
Event-free Survival (EFS) for Modified Augmented Berlin-Frankfurt-Munster Backbone With or Without Bortezomib in All Randomized Patients	3 years	EFS is calculated as time from randomization at study entry to first event (induction failure, induction death, relapse, second malignancy, remission death) or date of last contact. Three-year EFS rates will be calculated for both groups.

Secondary Outcome Measures

Name	Time	Method
Toxicity Rates Associated With Modified Standard Therapy, Including Dexamethasone and Additional Pegaspargase	3 years from start of therapy by patient	Percentage of patients who experienced Grade 3 or higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
EFS for Standard (SR) and Intermediate Risk (IR) T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no Cranial Radiation Therapy [CRT]) and Similar Patients on AALL0434 (Received CRT)	3 years	EFS is calculated as time from randomization at study entry to first event (induction failure, induction death, relapse, second malignancy, remission death) or date of last contact.
Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT)	3 years	Cumulative incidence of isolated CNS relapse adjusting for competing risks using the method of: Gray R, A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1141:1154, 1988
EFS for Very High Risk (VHR) T-ALL Patients Treated With High Risk (HR) Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Become Minimal Residual Disease (MRD) Negative and Those Who Remain MRD Positive at the End of HR Block 3	3 years	EFS will be calculated as time from the end of the three high-risk blocks of therapy to first event (relapse, second malignancy, remission death) or date of last contact.
EFS for Very High Risk (VHR) T-LLy Patients Treated With HR Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Have Complete or Partial Remission and Those Who do Not Respond	3 years	EFS for very high risk (VHR) T-LLy patients treated with HR Berlin-Frankfurt-Munster (BFM) intensification blocks who have complete or partial remission and those who do not respond

Trial Locations

Locations (212): Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Mercy Children's Hospital
🇺🇸
Toledo, Ohio, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
USA Health Strada Patient Care Center
🇺🇸
Mobile, Alabama, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Banner Children's at Desert
🇺🇸
Mesa, Arizona, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Valley Children's Hospital
🇺🇸
Madera, California, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸
Oakland, California, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Sutter Medical Center Sacramento
🇺🇸
Sacramento, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
Naval Medical Center -San Diego
🇺🇸
San Diego, California, United States
UCSF Medical Center-Mission Bay
🇺🇸
San Francisco, California, United States
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
🇺🇸
Torrance, California, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸
Denver, Colorado, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Yale University
🇺🇸
New Haven, Connecticut, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Broward Health Medical Center
🇺🇸
Fort Lauderdale, Florida, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸
Fort Myers, Florida, United States
University of Florida Health Science Center - Gainesville
🇺🇸
Gainesville, Florida, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸
Hollywood, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸
Jacksonville, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸
Miami, Florida, United States
Nicklaus Children's Hospital
🇺🇸
Miami, Florida, United States
Miami Cancer Institute
🇺🇸
Miami, Florida, United States
AdventHealth Orlando
🇺🇸
Orlando, Florida, United States
Arnold Palmer Hospital for Children
🇺🇸
Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸
Orlando, Florida, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
Tampa General Hospital
🇺🇸
Tampa, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸
Tampa, Florida, United States
Saint Mary's Medical Center
🇺🇸
West Palm Beach, Florida, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
🇺🇸
Atlanta, Georgia, United States
Augusta University Medical Center
🇺🇸
Augusta, Georgia, United States
Memorial Health University Medical Center
🇺🇸
Savannah, Georgia, United States
Kapiolani Medical Center for Women and Children
🇺🇸
Honolulu, Hawaii, United States
Saint Luke's Cancer Institute - Boise
🇺🇸
Boise, Idaho, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Loyola University Medical Center
🇺🇸
Maywood, Illinois, United States
Advocate Children's Hospital-Oak Lawn
🇺🇸
Oak Lawn, Illinois, United States
Advocate Children's Hospital-Park Ridge
🇺🇸
Park Ridge, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸
Peoria, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸
Springfield, Illinois, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸
Indianapolis, Indiana, United States
Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
Norton Children's Hospital
🇺🇸
Louisville, Kentucky, United States
Children's Hospital New Orleans
🇺🇸
New Orleans, Louisiana, United States
Ochsner Medical Center Jefferson
🇺🇸
New Orleans, Louisiana, United States
Eastern Maine Medical Center
🇺🇸
Bangor, Maine, United States
Maine Children's Cancer Program
🇺🇸
Scarborough, Maine, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸
Baltimore, Maryland, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
Walter Reed National Military Medical Center
🇺🇸
Bethesda, Maryland, United States
Tufts Children's Hospital
🇺🇸
Boston, Massachusetts, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Baystate Medical Center
🇺🇸
Springfield, Massachusetts, United States
UMass Memorial Medical Center - University Campus
🇺🇸
Worcester, Massachusetts, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Henry Ford Health Saint John Hospital
🇺🇸
Detroit, Michigan, United States
Michigan State University Clinical Center
🇺🇸
East Lansing, Michigan, United States
Hurley Medical Center
🇺🇸
Flint, Michigan, United States
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
🇺🇸
Grand Rapids, Michigan, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
🇺🇸
Grand Rapids, Michigan, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
West Michigan Cancer Center
🇺🇸
Kalamazoo, Michigan, United States
Corewell Health Children's
🇺🇸
Royal Oak, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
🇺🇸
Minneapolis, Minnesota, United States
Mayo Clinic in Rochester
🇺🇸
Rochester, Minnesota, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
University of Missouri Children's Hospital
🇺🇸
Columbia, Missouri, United States
Children's Mercy Hospitals and Clinics
🇺🇸
Kansas City, Missouri, United States
Cardinal Glennon Children's Medical Center
🇺🇸
Saint Louis, Missouri, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Children's Hospital and Medical Center of Omaha
🇺🇸
Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
University Medical Center of Southern Nevada
🇺🇸
Las Vegas, Nevada, United States
Sunrise Hospital and Medical Center
🇺🇸
Las Vegas, Nevada, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸
Las Vegas, Nevada, United States
Summerlin Hospital Medical Center
🇺🇸
Las Vegas, Nevada, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸
Lebanon, New Hampshire, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Morristown Medical Center
🇺🇸
Morristown, New Jersey, United States
Saint Peter's University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Newark Beth Israel Medical Center
🇺🇸
Newark, New Jersey, United States
Saint Joseph's Regional Medical Center
🇺🇸
Paterson, New Jersey, United States
University of New Mexico Cancer Center
🇺🇸
Albuquerque, New Mexico, United States
Albany Medical Center
🇺🇸
Albany, New York, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
NYU Langone Hospital - Long Island
🇺🇸
Mineola, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸
New Hyde Park, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸
New York, New York, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States
NYP/Weill Cornell Medical Center
🇺🇸
New York, New York, United States
University of Rochester
🇺🇸
Rochester, New York, United States
Stony Brook University Medical Center
🇺🇸
Stony Brook, New York, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
New York Medical College
🇺🇸
Valhalla, New York, United States
Mission Hospital
🇺🇸
Asheville, North Carolina, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Novant Health Presbyterian Medical Center
🇺🇸
Charlotte, North Carolina, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
East Carolina University
🇺🇸
Greenville, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Sanford Broadway Medical Center
🇺🇸
Fargo, North Dakota, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸
Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Legacy Emanuel Children's Hospital
🇺🇸
Portland, Oregon, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Lehigh Valley Hospital-Cedar Crest
🇺🇸
Allentown, Pennsylvania, United States
Lehigh Valley Hospital - Muhlenberg
🇺🇸
Bethlehem, Pennsylvania, United States
Geisinger Medical Center
🇺🇸
Danville, Pennsylvania, United States
Penn State Children's Hospital
🇺🇸
Hershey, Pennsylvania, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Saint Christopher's Hospital for Children
🇺🇸
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
Prisma Health Richland Hospital
🇺🇸
Columbia, South Carolina, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
T C Thompson Children's Hospital
🇺🇸
Chattanooga, Tennessee, United States
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
The Children's Hospital at TriStar Centennial
🇺🇸
Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Dell Children's Medical Center of Central Texas
🇺🇸
Austin, Texas, United States
Inova Fairfax Hospital
🇺🇸
Falls Church, Virginia, United States
Children's Hospital of The King's Daughters
🇺🇸
Norfolk, Virginia, United States
Naval Medical Center - Portsmouth
🇺🇸
Portsmouth, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
Carilion Children's
🇺🇸
Roanoke, Virginia, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸
Tacoma, Washington, United States
Madigan Army Medical Center
🇺🇸
Tacoma, Washington, United States
West Virginia University Charleston Division
🇺🇸
Charleston, West Virginia, United States
West Virginia University Healthcare
🇺🇸
Morgantown, West Virginia, United States
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸
Green Bay, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸
Madison, Wisconsin, United States
Marshfield Medical Center-Marshfield
🇺🇸
Marshfield, Wisconsin, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
John Hunter Children's Hospital
🇦🇺
Hunter Regional Mail Centre, New South Wales, Australia
The Children's Hospital at Westmead
🇦🇺
Westmead, New South Wales, Australia
Queensland Children's Hospital
🇦🇺
South Brisbane, Queensland, Australia
Women's and Children's Hospital-Adelaide
🇦🇺
North Adelaide, South Australia, Australia
Monash Medical Center-Clayton Campus
🇦🇺
Clayton, Victoria, Australia
Royal Children's Hospital
🇦🇺
Parkville, Victoria, Australia
Princess Margaret Hospital for Children
🇦🇺
Perth, Western Australia, Australia
Perth Children's Hospital
🇦🇺
Perth, Western Australia, Australia
Alberta Children's Hospital
🇨🇦
Calgary, Alberta, Canada
University of Alberta Hospital
🇨🇦
Edmonton, Alberta, Canada
British Columbia Children's Hospital
🇨🇦
Vancouver, British Columbia, Canada
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
Janeway Child Health Centre
🇨🇦
Saint John's, Newfoundland and Labrador, Canada
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦
Hamilton, Ontario, Canada
Kingston Health Sciences Centre
🇨🇦
Kingston, Ontario, Canada
Children's Hospital
🇨🇦
London, Ontario, Canada
Children's Hospital of Eastern Ontario
🇨🇦
Ottawa, Ontario, Canada
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Saskatoon Cancer Centre
🇨🇦
Saskatoon, Saskatchewan, Canada
Starship Children's Hospital
🇳🇿
Grafton, Auckland, New Zealand
Christchurch Hospital
🇳🇿
Christchurch, New Zealand
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
El Paso Children's Hospital
🇺🇸
El Paso, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Covenant Children's Hospital
🇺🇸
Lubbock, Texas, United States
UMC Cancer Center / UMC Health System
🇺🇸
Lubbock, Texas, United States
Children's Hospital of San Antonio
🇺🇸
San Antonio, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸
San Antonio, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸
San Antonio, Texas, United States
Primary Children's Hospital
🇺🇸
Salt Lake City, Utah, United States
University of Vermont and State Agricultural College
🇺🇸
Burlington, Vermont, United States
University of Virginia Cancer Center
🇺🇸
Charlottesville, Virginia, United States