Trial Information

Treatment of Acute Lymphoblastic Leukemia in Children

OBJECTIVES:

Primary

- Compare the relative toxicity of pegasparaginase vs E. coli asparaginase when
administered with combination chemotherapy in children with newly diagnosed acute
lymphoblastic leukemia (ALL).

Secondary

- Compare the relative efficacy of these regimens in these patients.

- Determine the prognostic significance of asparaginase antibody formation.

- Correlate trough enzyme levels with outcome (toxicity and relapse).

- Compare the quality of life in patients treated with pegasparaginase vs E. coli
asparaginase.

- Compare trough serum asparaginase enzyme levels, asparagine levels, and
anti-asparaginase antibody levels in patients treated with these regimens.

- Determine the rate of infections (episodes of bacteremia and disseminated fungal
infections) during the remission induction phase of combination chemotherapy in these
patients.

- Determine the prognostic significance of response to remission induction chemotherapy
as measured by morphology and minimal residual disease (MRD) measures.

- Determine the outcome of patients based on MRD status after 28 days of multiagent
chemotherapy that intensifies treatment for B-lineage patients with MRD levels greater
than 0.001 at the end of remission induction therapy.

- Determine the outcome of patients based on MRD status after 14 days of multiagent
chemotherapy and at various other time points while on treatment (every 18 weeks after
achieving complete remission and at the completion of all chemotherapy).

- Compare the outcome (based on bone marrow morphology after 14 days of multiagent
chemotherapy) of patients with M2/M3 status at that time point vs M1 status or
hypoplastic marrows.

- Determine the efficacy and CNS-related toxicity of CNS-directed treatments in these
patients.

- Determine the efficacy and CNS-related toxicity (acute and long-term) of the high-risk
(HR) regimen in which a subset of HR patients are treated with intensive intrathecal
(IT) chemotherapy and the remainder are treated with cranial radiation therapy
(concurrent with IT chemotherapy).

- Determine the efficacy and CNS-related toxicity (acute and long-term) of intensive IT
therapy in standard-risk patients.

- Correlate dietary antioxidant micronutrient intake (including ascorbic acid, vitamin E,
vitamin A, beta carotene, and total carotenoids) with the rate of infections (episodes
of bacteremia and disseminated fungal infections) during remission induction therapy
and the consolidation IA phase.

- Correlate dietary calcium intake with risk for development of fractures during the
continuation phase of therapy.

OUTLINE: This is a randomized, multicenter, open-label study. Patients are stratified
according to disease risk (standard-risk [SR] vs high-risk [HR] vs very high risk [VHR]).

- Steroid prophase*: Patients receive intrathecal (IT) cytarabine on day 1 and
methylprednisolone IV every 8 hours on days 1-3. Patients then proceed to remission
induction therapy.

Patients with CNS leukemia (CNS-2, CNS-3, or traumatic lumbar puncture [LP] with blasts) on
initial LP receive additional IT cytarabine twice weekly beginning on days 4-6 and
continuing until cerebrospinal fluid (CSF) is clear, followed by 2 additional doses.
Patients with cranial nerve palsy but no leukemia blasts in CSF or leukemic eye infiltrates
also receive additional IT cytarabine as above.

NOTE: *Patients who received steroids within the past 7 days do not receive steroid prophase
treatment; instead they proceed directly to remission induction therapy according to their
risk group.

- Remission induction therapy (SR patients): Patients receive oral prednisone or
prednisolone 2-3 times daily OR methylprednisolone IV every 8 hours on days 4-32;
vincristine IV on days 4, 11, 18, and 25; doxorubicin hydrochloride (DOX) IV over 15
minutes on days 4 and 5; methotrexate (MTX) IV on day 6; pegasparaginase IV over 1 hour
on day 7; triple intrathecal therapy (TIT) comprising methotrexate, cytarabine, and
hydrocortisone on day 18; and IT MTX on day 32.

NOTE: Patients who do not receive steroid prophase treatment also receive IT cytarabine on
day 4.

- Remission induction therapy (HR and VHR patients): Patients receive
prednisone/prednisolone OR methylprednisolone; vincristine; DOX; MTX IV;
pegasparaginase; TIT; and IT MTX as in the SR group. Patients also receive dexrazoxane
hydrochloride IV over 15 minutes preceding the DOX infusions on days 4 and 5.

NOTE: Patients who do not receive steroid prophase treatment also receive IT cytarabine on
day 4.

Patients who are in complete remission (CR) on day 32 proceed to consolidation I. Patients
who are not in CR on day 32 receive vincristine IV weekly until CR is achieved. Patients
with persistent marrow (greater than 5% leukemic blasts) or those who do not achieve CR by
day 53 are removed from the study.

Patients with CSF blasts on cytospin and at least 5 WBC/high-power field (hpf) in the CSF
(CNS-3) after remission induction therapy are removed from the study. Patients with CSF
blasts and less than 5 WBC/hpf in the CSF (CNS-2) receive 1 course of systemic chemotherapy
comprising vincristine IV once a week for 4 weeks; dexrazoxane hydrochloride IV over 15
minutes followed by DOX IV over 15 minutes once a day for 2 days; and oral mercaptopurine
once a day for 2 weeks. Patients with persistent CNS blasts at day 53 are removed from the
study. Patients with no CNS blasts at day 53 proceed to consolidation I.

- Consolidation I (SR patients): Patients receive vincristine IV and IT MTX on day 1 and
oral mercaptopurine once daily on days 1-14. Patients also receive high-dose MTX (HDM)
IV continuously over 24 hours on day 1 and leucovorin calcium IV every 6 hours
beginning 36 hours after the start of the HDM infusion and continuing until MTX levels
are undetectable. Patients proceed to CNS therapy after day 21.

- Consolidation I (HR patients): Patients receive vincristine, IT MTX, and mercaptopurine
as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes
followed by DOX IV over 15 minutes on day 1 and HDM with leucovorin calcium support as
in the SR group beginning 8-24 hours after the completion of the DOX infusion. Patients
proceed to CNS therapy after day 21.

- Consolidation I (VHR patients): Patients receive consolidation therapy in 3 stages.

- Stage IA: Patients receive vincristine, IT MTX, and mercaptopurine as in the SR
group. Patients also receive dexrazoxane hydrochloride, DOX, HDM, and leucovorin
calcium as in the HR group.

- Stage IB: Patients receive cyclophosphamide IV over 1 hour and IT MTX on day 22;
oral mercaptopurine once daily on days 22-35; and cytarabine IV on days 23-26 and
30-33.

- Stage IC: Patients receive high-dose cytarabine IV over 3 hours every 12 hours on
days 43 and 44; etoposide IV over 1 hour on days 45-47; and oral dexamethasone
twice daily on days 43-47. Patients also receive E. coli asparaginase*
intramuscularly (IM) weekly beginning on day 48 and continuing for up to 30 weeks
OR pegasparaginase* IV over 1 hour every 2 weeks beginning on day 48 and
continuing for up to 30 weeks. Patients proceed to CNS therapy after day 49.

NOTE: *Patients are either randomized to receive E. coli asparaginase or pegasparaginase OR
are assigned to receive E. coli asparaginase. Patients continue to receive E. coli
asparaginase or pegasparaginase during CNS therapy and consolidation II therapy.

- CNS therapy (SR patients): Patients receive vincristine IV on day 1; oral
mercaptopurine once daily on days 1-14; oral dexamethasone twice daily on days 1-5; and
TIT twice weekly for 2 weeks. Patients also receive E. coli asparaginase* OR
pegasparaginase* as above beginning on day 1 and continuing for up to 30 weeks.
Patients proceed to consolidation II after day 21.

NOTE: *Patients are either randomized to receive E. coli asparaginase or pegasparaginase OR
are assigned to receive E. coli asparaginase. Patients continue to receive E. coli
asparaginase or pegasparaginase during consolidation II therapy.

- CNS therapy (HR and VHR patients): Patients receive vincristine, mercaptopurine,
dexamethasone, and TIT as in the SR group. Patients also receive dexrazoxane
hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1. HR
patients also receive E. coli asparaginase OR pegasparaginase as above beginning on day
1 and continuing for up to 30 weeks. VHR patients continue to receive E. coli
asparaginase OR pegasparaginase as per consolidation I treatment. Patients proceed to
consolidation II after day 21.

Patients with WBC > 100,000/mm³, T-cell disease, and/or CNS-3 at diagnosis or CNS-2 at end
of remission induction therapy also undergo cranial radiation therapy daily for 8 or 10
days.

- Consolidation II (SR patients): Patients receive vincristine IV on day 1; oral
dexamethasone twice daily on days 1-5; and oral mercaptopurine once daily on days 1-14.
Treatment repeats every 21 days until E. coli asparaginase or pegasparaginase is
completed. Patients also receive MTX IV or IM 1 day after each E. coli asparaginase or
pegasparaginase dose and TIT every 9 weeks for 6 doses and then every 18 weeks
thereafter.

- Consolidation II (HR and VHR patients): Patients receive vincristine, dexamethasone,
and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride
IV over 15 minutes followed by DOX IV over 15 minutes on day 1. Treatment repeats every
21 days until E. coli asparaginase or pegasparaginase is completed. Patients also
receive MTX IV or IM as in the SR group and TIT every 9 weeks for 6 doses and then
every 18 weeks thereafter OR TIT every 18 weeks.

- Continuation therapy: After completion of all consolidation therapy, all patients
receive vincristine IV on day 1; oral dexamethasone twice daily on days 1-5; oral
mercaptopurine once daily on days 1-14; and MTX IV or IM on days 1, 8, and 15.
Treatment repeats every 21 days for up to 2 years after achieving CR. Patients continue
to receive TIT as in consolidation II for up to 2 years after achieving CR.

Patients complete dietary questionnaires at the time of diagnosis, at day 32, and 12 months
after diagnosis.

Quality of life is assessed periodically.

After completion of study therapy, patients are followed periodically for 3 years and then
annually thereafter.

PROJECTED ACCRUAL: A total of 544 patients will be accrued for this study.