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

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-Münster (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). Similarly, 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).

TERTIARY 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.

INDUCTION ARM A: 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).

INDUCTION ARM B: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11; and
cytarabine, vincristine sulfate, dexamethasone, daunorubicin hydrochloride, pegaspargase, and
methotrexate as in Induction 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.

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).

DELAYED INTENSIFICATION ARM A: 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).

DELAYED INTENSIFICATION ARM B: Patients receive bortezomib IV over 3-5 seconds on days 1, 4,
15, and 18; 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).

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).

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).

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).

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).

MAINTENANCE THERAPY: All patients receive vincristine sulfate IV 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 courses); methotrexate IT on day 1 (and day 29 during the first 4
courses for SR patients and during the first 2 courses for IR patients). Patients with CNS3
IR disease also undergo cranial radiation therapy during the first 4 weeks (course 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.

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

- 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

- 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; 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