Low-Dose or High-Dose Vincristine and Combination Chemotherapy in Treating Young Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. 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 OBJECTIVES:

I. To determine levels of minimal residual disease (MRD) present at the end of the first &
third blocks of Induction and determine if higher MRD levels at these times identify
patients at higher risk of relapse who might be candidates for alternative therapies in
future trials.

II. To determine whether common polymorphisms in candidate genes are associated with the
frequency of vincristine adverse effects (peripheral neuropathy, syndrome of inappropriate
antidiuretic hormone secretion [SIADH], or constipation) and with anti-leukemic response
(level of end-Induction MRD).

III. 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).

IV. To use deoxyribonucleic acid (DNA) arrays to characterize patterns of gene expression
that predict treatment failure, and to compare gene expression profiles at the time of
relapse with those at initial diagnosis to gain an understanding of the pathways that may be
involved in disease resistance.

OUTLINE: This is a multicenter, randomized study. Patients are randomized to 1 of 2
treatment regimens (randomization closed as of 09/2010).

INDUCTION THERAPY 1 (WEEKS 1-5):

Regimen A: Patients receive low-dose vincristine intravenously (IV) on days 1, 8, 15, and
22; prednisone orally (PO) 3 times daily (TID) 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.

Regimen B: (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 Regimen A.

NOTE: *Central nervous system (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 Regimen B are crossover to Regimen A.

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 PO
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 (QD), 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 regimen in induction therapy 1).

INTENSIFICATION THERAPY 1 (WEEKS 16-27 or 17-28):

Regimen A: 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).

Regimen B: Patients receive high-dose vincristine IV on day 1 and high-dose methotrexate,
leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide, and methotrexate
IT* as in Regimen A. (closed to accrual as of 09/2010)

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 Regimen B are crossover to Regimen A.

Patients in both regimens then proceed to reinduction therapy (as per their randomized
regimen in induction therapy 1).

REINDUCTION THERAPY (WEEKS 28-32 or 29-33):

Regimen A: 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.

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

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive
ITT on days 1 and 28.

NOTE: ** Patients already enrolled on Regimen B are crossover to Regimen A. Patients in both
regimens then proceed to intensification therapy 2 (as per their randomized regimen in
induction therapy 1).

INTENSIFICATION THERAPY 2 (WEEKS 33-56 or 34-57):

Regimen A: 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).

Regimen B: Patients receive high-dose cytarabine, high-dose methotrexate, leucovorin
calcium, pegaspargase, mercaptopurine, etoposide phosphate, cyclophosphamide, methotrexate
IT*, and G-CSF as in Regimen A. 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 regimens then proceed to maintenance therapy (as per their randomized
regimen in induction therapy 1).

MAINTENANCE THERAPY (week 57-106 or 58-107):

Regimen A: Patients receive methotrexate IT on day 1* and then PO on days 8, 15, 22, 29, and
36; mercaptopurine PO QD on days 1-42; dexamethasone PO twice daily (BID) 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.

Regimen B: Patients receive methotrexate*, mercaptopurine, dexamethasone, and
cyclophosphamide as in Regimen A. 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 QD, 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.

Inclusion Criteria:

- Diagnosis of acute lymphoblastic leukemia (ALL)

- Bone marrow with > 25% L1 or L2 lymphoblasts (M3 marrow)

- Patients with > 25% L3 marrow lymphoblasts and/or evidence of c-myc
translocation are not eligible (considered Burkitt's or mature B-cell
leukemia)

- Intermediate-risk relapsed disease, meeting 1 of the following criteria:

- Bone marrow relapse ≥ 36 months after initial diagnosis (defined as M3 marrow
after previous remission from ALL)

- Combined bone marrow and extramedullary (CNS* and/or testicular**) relapse ≥ 36
months after initial diagnosis

- Isolated extramedullary (CNS* and/or testicular**) relapse < 18 months after
initial diagnosis

- The following subtypes are not allowed:

- T-lineage ALL

- Mature B-cell (Burkitt's) leukemia (defined as L3 morphology and/or evidence of
c-myc translocation)

- Philadelphia-chromosome positive disease

- No Down syndrome (trisomy 21)

- Shortening fraction >= 27% by echocardiogram OR ejection fraction >= 50% by
radionuclide angiogram

- Bilirubin < 3.0 mg/dL

- Not pregnant

- Fertile patients must use effective contraception

- No history of peripheral neuropathy >= grade 3 within the past month

- No toxicity (i.e. peripheral neuropathy) >= grade 3 attributable to vincristine
within the past month

- At least 5 days since prior intrathecal chemotherapy

- No prior hematopoietic stem cell or marrow transplantation

- No prior cranial radiotherapy > 1200 cGy (for patients with CNS relapse)

- No concurrent stem cell transplant

- No concurrent alternative therapy

- No concurrent itraconazole in patients receiving vincristine

- No concurrent intensity-modulated radiotherapy