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.