OBJECTIVES:

Primary

- 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

- 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.

- 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).

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 IV on days 1, 8, 15, and 22; oral
prednisone 3 times daily 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: *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 orally 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, 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(closed to accrual as of 09/2010)**: 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.

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 (closed to accrual as of 09/2010)**: Patients receive high-dose vincristine
IV on days 1, 8, and 15 and doxorubicin hydrochloride, dexamethasone,
pegaspargase, and methotrexate IT* as in arm I.

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 orally on days 8, 15,
22, 29, and 36; oral mercaptopurine once daily on days 1-42; oral dexamethasone
twice daily 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 once daily, 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.

PROJECTED ACCRUAL: A total of 418 patients will be accrued for this study.