Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma

PRIMARY OBJECTIVES:

I. To determine, through randomization, the relative safety and efficacy of the addition of
nelarabine (Compound 506U78) to augmented Berlin-Frankfurt-Münster (BFM) therapy (Regimen C,
Children's Cancer Group [CCG]-1961).

II. To determine the relative safety and efficacy of high dose methotrexate (5 g/m^2) with
leucovorin (leucovorin calcium) rescue compared to escalating methotrexate without leucovorin
rescue plus pegaspargase (Capizzi I) delivered during interim maintenance.

III. To gain preliminary data on the use of nelarabine in patients with high risk T-cell
lymphoblastic lymphoma and its effect on long-term survival.

SECONDARY OBJECTIVES:

I. To determine the relative safety and efficacy of withholding radiation in patients with
low risk T-cell acute lymphoblastic leukemia (T-ALL), while treating Intermediate and high
risk patients with 1200 cGy of prophylactic cranial radiation.

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

GROUP 0 (INDUCTION THERAPY): All patients (T-ALL and T-LLy) receive cytarabine intrathecally
(IT) on day 1; vincristine sulfate intravenously (IV) on days 1, 8, 15, and 22; prednisone IV
or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV
over 1 to 2 hours) on day 4, 5, or 6; duanorubicin IV on days 1, 8, 15 and 22; and
methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease).

GROUP I ARM I COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive
methotrexate IT on days 1, 8, 15, and 22; cyclophosphamide IV over 30 minutes on days 1 and
29; cytarabine IV over 15-30 minutes or subcutaneously (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; and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with DS also
receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose. 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 CRT (1,200
cGy/dose) QD on days 15-21 and 22-28. Patients with low-risk disease do not undergo conformal
radiation therapy (CRT). Patients with standard risk T-LLy received Arm I, and those with
high risk T-LLy were randomized between Arm I and Arm II combination chemotherapy.

GROUP I ARM I COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients
receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID 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 on days 1, 8, and 15;
pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; methotrexate IT on days
1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30
minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS
also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS
patients excluded as of 09/29/10). Standard risk T-LLy patients were assigned to Arm I and
those with high risk were randomized between Arm I and Arm II.

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

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.

GROUP I ARM I COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive
vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and
57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
57, 64, 71, and 78; and methotrexate 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), all patients with T-LLy, and 3 years from
the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).

GROUP I ARM II COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive
nelarabine IV over 60 minutes on days 1-5 and 43-47; methotrexate IT on days 15, 22, 57, and
64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or
SC on days 8-11, 15-18, 50-53 and 57-60; mercaptopurine PO on days 8-21 and 50-63;
vincristine sulfate 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 QD on days 22-28 and 29-35. Patients with high risk T-LLy were either
randomized to Arm I or Arm II. Patients with T-LLy who failed induction therapy were assigned
to Arm II.

GROUP I ARM II COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients
receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID 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 on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours
on day 4, 5, OR 6 AND day 50; methotrexate 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 over
15-30 minutes or SC on days 36-39 and 43-46; and thioguanine PO on days 36-49.

GROUP I ARM II COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive
vincristine sulfate IV and escalating doses of methotrexate IV on days 1, 11, 21, 31, and 41;
pegaspargase* IM or IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31.

Note: *Patients with an allergy to pegaspargase receive Erwinia asparaginase on Monday,
Wednesday and Friday for two consecutive weeks starting the day of asparaginase substitution.

GROUP I ARM II COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive
vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, methotrexate IT, and
nelarabine in Cycles 1, 2 and 3. Patients then receive treatment (without nelarabine) as
follows: vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, and methotrexate
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 for those with T-LLY, and 3 years from
the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).

GROUP I ARM III COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive
methotrexate IT on days 1, 8, 15, and 22; cyclophosphamide IV over 30 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;
and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with DS also receive
leucovorin calcium PO at 48 and 60 hours after each methotrexate dose. 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 CRT (1,200
cGy/dose) QD on days 15-21 and 22-28. Patients with low-risk disease do not undergo CRT.

GROUP I ARM III COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients
receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID 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 on days 1, 8, and 15;
pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; methotrexate IT on days
1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30
minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS
also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS
patients excluded as of 09/29/10).

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

GROUP I ARM III COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive
vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and
57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
57, 64, 71, and 78; and methotrexate 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 all patients with T-LLy, and 3 years from
the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).

GROUP I ARM IV COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive
nelarabine IV over 60 minutes on days 1-5 and 43-47; methotrexate IT on days 15, 22, 57, and
64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or
SC on days 8-11, 15-18, 50-53 and 57-60; mercaptopurine PO on days 8-21 and 50-63;
vincristine sulfate IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours
on days 22 and 64. (DS patients excluded as of 09/29/10). (Patients with intermediate-risk or
high-risk disease (CNS1 or CNS2) undergo prophylactic CRT QD on days 22-28 and 29-35.

GROUP I ARM IV COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients
receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID 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 on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours
on day 4, 5, OR 6 AND day 50; methotrexate 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 over
15-30 minutes or SC on days 36-39 and 43-46; and thioguanine PO on days 36-49.

GROUP I ARM IV COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive
HDMTX IV over 24 hours and vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine
PO on days 1-56; and methotrexate IT on days 1 and 29. Beginning 42 hours after the start of
HDMTX, patients also receive leucovorin calcium IV or PO once every 6 hours for 3 doses.

GROUP I ARM IV COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive
vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, methotrexate IT, and
nelarabine in Cycles 1, 2 and 3. Patients then receive treatment (without nelarabine) as
follows: vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, and methotrexate
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 for those with T-LLY, 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.

Inclusion Criteria:

- T-ALL patients must be enrolled on AALL08B1 prior to treatment and enrollment on
AALL0434

- Patients must have newly diagnosed T-ALL or T-lineage lymphoblastic lymphoma (T-NHL)
stage II-IV; B-lineage lymphoblastic lymphoma will not be eligible for this study; 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; if surface CD3 is expressed on all leukemic cells, additional
markers of immaturity, including transmission disequilibrium test (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

- T-NHL PATIENTS:

- For T-NHL 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-NHL defined by the submitting institution will be
accepted

- Prior therapy restrictions

- Patients shall have had no prior cytotoxic chemotherapy with the exception of
steroids and/or IT cytarabine

- IT chemotherapy with cytarabine is allowed prior to registration for patient
convenience; this is usually done at the time of the diagnostic bone marrow or
venous line placement to avoid a second lumbar puncture; (Note: the CNS status
must be determined based on a sample obtained prior to administration of any
systemic or intrathecal chemotherapy, except for steroid pretreatment); systemic
chemotherapy must begin within 72 hours of this IT therapy

- Patients diagnosed as having T-NHL or T-ALL with respiratory distress or
hyperleukocytosis may require steroids prior to the initiation of additional
systemic therapy; they are eligible for AALL0434 and will be stratified, based on
the initial complete blood count (CBC); steroid pretreatment may alter the risk
group assessment; if the T-ALL patient's clinical status precludes a lumbar
puncture within 48 hours of the initiation of steroid therapy, T-ALL patients
CANNOT be classified as low risk and will be Intermediate or high risk based on
the results of the day 29 marrow as above; patients with T-NHL who receive
steroid pre-treatment will be classified as high risk; the dose and duration of
previous steroid therapy should be carefully documented

- For the management of airway compromise, patients who have received emergent
chest irradiation up to 600 cGy will be eligible for this study

- Patients with a prior seizure disorder requiring anti-convulsant therapy are not
eligible to receive nelarabine; in addition, patients with pre-existing grade 2 (or
greater) peripheral neurotoxicity, as determined prior to Induction treatment by the
treating physician or a neurologist, are not eligible to receive nelarabine; these
restrictions in eligibility are designed to prevent excessive nelarabine-induced
central and peripheral neurotoxicity in at-risk patients; for the purposes of this
study, this includes any patient that has received anticonvulsant therapy to
prevent/treat seizures in the prior two years

Exclusion Criteria:

- Pregnant or lactating females are ineligible

- Patients with Down syndrome are ineligible to enroll onto this study

- For T-NHL patients the following additional exclusion criteria apply:

- B-precursor lymphoblastic lymphoma

- Morphologically unclassifiable lymphoma

- Absence of both B-cell and T-cell phenotype markers in a case submitted as
lymphoblastic lymphoma

- CNS3-positive or testicular involvement