Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To determine whether the substitution of three intensified phases of post-Induction
treatment for standard phases will improve the event free survival (EFS) of children with
SR-average acute lymphoblastic leukemia (ALL).

II. Determine whether the substitution of intensified Consolidation for standard
Consolidation will improve the EFS of children with SR-average ALL.

III. To determine whether the addition of four doses of percutaneous endoscopic gastrostomy
(PEG) asparaginase, given once every three weeks during Consolidation and Interim Maintenance
phases, will improve the EFS for children with SR-low ALL.

SECONDARY OBJECTIVES:

I. Identify potentially modifiable factors associated with impaired health related quality of
life (HRQOL) at different periods of therapy in the patients who are SR-average enrolled on
the standard risk ALL study.

II. Determine the critical time periods when future intervention studies to mitigate adverse
HRQOL outcomes should occur.

III. Correlate day 29 minimal residual disease (MRD) with EFS and overall survival (OS) of
patients treated with these regimens.

IV. Correlate early marrow response with day 29 MRD status. V. To improve outcome by
identifying additional high risk patients by Day 29 MRD for treatment with fully augmented
Berlin-Frankfurt-Munster (BFM).

VI. To examine the relative contributions of genetic factors and early treatment response to
outcome by comparing the outcome of patients with and without TEL-AML1 fusion or triple
trisomy and low levels of MRD at end Induction who are treated with identical therapy on the
standard arms of the SR-low and SR-average trials.

OUTLINE: This is a 2-part, partially randomized, multicenter study. Patients are stratified
according to early response to study induction therapy (rapid early response [standard risk
(SR)-low or SR-average acute lymphoblastic leukemia (ALL)] vs slow early response [SR-high
ALL]). After completion of induction therapy but before proceeding to part II therapy,
patients are assigned to 1 of 3 groups based on stratification.

PART I:

INDUCTION THERAPY: All patients receive cytarabine intrathecally (IT) on day 1; vincristine
IV on days 1, 8, 15, and 22; dexamethasone 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; and
methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease).
Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each
dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone
marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy
in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended
induction therapy. Patients with M3 bone marrow are removed from the study.

EXTENDED INDUCTION THERAPY: Patients receive dexamethasone IV or PO BID on days 1-14;
vincristine IV on days 1 and 8; pegaspargase IM on day 4, 5, or 6; and daunorubicin
hydrochloride IV over 15 minutes to 2 hours on day 1. Patients with M1 bone marrow and MRD <
1% after extended induction therapy proceed to therapy in part II. Patients with M2 or M3
bone marrow after extended induction therapy are removed from the study.

PART II:

GROUP 1 (SR-low ALL): Patients are randomized to 1 of 2 treatment arms.

ARM I:

STANDARD CONSOLIDATION THERAPY: Patients receive vincristine IV on day 1; mercaptopurine PO
on days 1-28; and methotrexate IT on days 1, 8, and 15. Patients with Down syndrome (DS)
receive leucovorin calcium (PO) at 48 and 60 hours after each dose of methotrexate IT.

STANDARD INTERIM MAINTENANCE THERAPY: Patients receive vincristine IV on days 1 and 29;
dexamethasone IV or PO BID on days 1-5 and 29-33; mercaptopurine PO on days 1-50;
methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, and 50; and methotrexate IT on day 29.
Patients with DS receive leucovorin calcium PO at 48 and 60 hours after each dose of
methotrexate IT.

STANDARD DELAYED INTENSIFICATION (DI) THERAPY: Patients receive vincristine IV on days 1, 8,
and 15; dexamethasone IV or PO BID on days 1-21; doxorubicin hydrochloride IV over 15 minutes
to 2 hours on days 1, 8, and 15; pegaspargase IM on day 4, 5, or 6; cyclophosphamide IV over
30 minutes on day 29; cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39;
thioguanine PO on days 29-42; and methotrexate IT on days 1 and 29. Patients with DS receive
dexamethasone IV or PO BID on days 1-7 and 15-21 and leucovorin calcium PO at 48 and 60 hours
after each dose of methotrexate IT.

ARM II:

EXPERIMENTAL CONSOLIDATION THERAPY: Patients receive vincristine, mercaptopurine,
methotrexate, and leucovorin calcium as in arm I and pegaspargase IM on days 1 and 22.

EXPERIMENTAL INTERIM MAINTENANCE THERAPY: Patients receive vincristine, dexamethasone,
mercaptopurine, methotrexate PO, and methotrexate IT as in arm I and pegaspargase IM on days
15 and 36.Standard DI therapy: Patients receive standard DI therapy as in arm I.

GROUP 2 (SR-average ALL): Patients are randomized to 1 of 4 treatment arms.

ARM I: Patients receive standard consolidation therapy, standard interim maintenance therapy,
and standard DI therapy as in group 1, arm I.

ARM II:

STANDARD CONSOLIDATION THERAPY: Patients receive standard consolidation therapy as in group
1, arm I. Augmented interim maintenance therapy: Patients receive vincristine IV and
methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase IM on days 2 and 22; and
methotrexate IT on days 1 and 31. Patients with DS receive leucovorin calcium PO at 48 and 60
hours after each dose of methotrexate IT. Augmented DI therapy: Patients receive vincristine
IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on days 1-21; doxorubicin
hydrochloride IV over 15 minutes to 2 hours on days 1, 8, and 15; pegaspargase IM on day 4,
5, or 6 AND day 43; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or SC on
days 29-32 and 36-39; thioguanine PO on days 29-42; and methotrexate IT on days 1, 29, and
36. Patients with DS receive dexamethasone on days 1-7 and 15-21 and leucovorin calcium PO at
48 and 60 hours after each dose of methotrexate IT.

ARM III:

INTENSIFIED CONSOLIDATION THERAPY: Patients receive cyclophosphamide IV over 30 minutes on
days 1 and 29; cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on
days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; pegaspargase IM on days 15
and 43; and methotrexate IT on days 1, 8, 15*, and 22*. Patients with DS receive leucovorin
calcium PO at 48 and 60 hours after each dose of methotrexate IT*.

NOTE: *Patients with CNS3 disease at diagnosis do not receive methotrexate on days 15 and 22
or leucovorin calcium.

STANDARD INTERIM MAINTENANCE THERAPY: Patients receive standard interim maintenance therapy
as in group 1, arm I.

STANDARD DI THERAPY: Patients receive standard DI therapy as in group 1, arm I.

ARM IV:

INTENSIFIED CONSOLIDATION THERAPY: Patients receive intensified consolidation therapy as in
group 2, arm III.

AUGMENTED INTERIM MAINTENANCE THERAPY: Patients receive augmented interim maintenance therapy
as in group 2, arm II.

AUGMENTED DI THERAPY: Patients receive augmented DI therapy as in group 2, arm II.

GROUP 3 (SR-high ALL): Patients receive the following therapy: Intensified consolidation
therapy: Patients receive intensified consolidation therapy as in group 2, arm III.

AUGMENTED INTERIM MAINTENANCE* THERAPY: Patients receive augmented interim maintenance
therapy as in group 2, arm II. Treatment repeats every 56 days for 2 courses.

NOTE: *As of Amendment #7, all SR-High patients currently receiving AIM 1 therapy should
complete this phase of therapy and proceed to ADI 1 therapy as originally planned including
Capizzi methotrexate during AIM 1. Upon completion of ADI 1, patients should receive a second
Interim Maintenance phase with high-dose methotrexate (IM HD) rather than Capizzi
methotrexate. Patients should then proceed to ADI 2 and then Maintenance.

AUGMENTED DI* THERAPY: Patients receive augmented DI therapy as in group 2, arm II. Treatment
repeats every 56 days for 2 courses**.

NOTE: *As of Amendment #7, all SR-High patients currently receiving ADI 1 therapy should
complete this phase of therapy as originally planned. Upon completion of ADI 1, patients
should receive a second Interim Maintenance phase with IM HD. Patients should then proceed to
ADI 2 and then Maintenance.

NOTE: **Patients with CNS3 disease at diagnosis also undergo cranial radiotherapy on days
29-33 and 36-40 during course 2 only; these patients do not receive methotrexate on day 36,
thioguanine, or leucovorin calcium.

MAINTENANCE THERAPY: All patients receive vincristine IV on days 1, 29, and 57; oral
dexamethasone twice daily on days 1-5, 29-33, and 57-61; oral methotrexate on days 8, 15, 22,
29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine on days 1-84; and methotrexate IT* on
day 1. Courses repeat every 84 days for a total of 2 years from the start of interim
maintenance therapy for female patients and 3 years from the start of interim maintenance
therapy for male patients.

NOTE: *SR-High or CNS3 patients should receive up to a maximum of 23 intrathecal treatments
for females and 26 intrathecal treatments for males.

After the completion of study treatment, patients are followed every 1-2 months for 2 years,
every 3 months for 1 year, and then every 6-12 months for 2 years.

Inclusion Criteria:

- Patients must be enrolled on AALL03B1 prior to enrollment on AALL0331

- Initial white blood cells (WBC) < 50,000/ul

- Newly diagnosed B-precursor acute lymphoblastic leukemia

- Standard-risk (SR) disease meeting 1 of the following criteria:

- SR-average by age and WBC

- No unfavorable features

- Rapid early responder (RER) by day 15

- CNS 1 or 2

- Minimal residual disease (MRD) negative on day 29

- Trisomies of 4, 10, and 17 or TEL-AML1 translocation and RER and CNS2 allowed

- SR-low by age and WBC

- No unfavorable features

- RER by day 15

- MRD negative on day 29

- CNS1

- Favorable cytogenetics-trisomies of 4, 10, and 17 or TEL-AML translocation

- SR-high

- Unfavorable features meeting ≥ 1 of the following criteria:

- MLL rearrangements and RER

- Steroid pretreatment

- CNS3

- Slow early responder by morphology or MRD

- Patients with Down syndrome are allowed

- Patients with overt testicular disease are not eligible for this study, but may be
eligible for AALL0232

- Patients shall have had no prior cytotoxic chemotherapy with the exception of steroids
and intrathecal cytarabine; intrathecal 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 central nervous system [CNS] status must be determined based on a sample
obtained prior to administration of any systemic or intrathecal chemotherapy, except
for steroid pretreatment

- Patients receiving prior steroid therapy may be eligible for AALL0331 study

- Patients with a contraindication to additional asparaginase therapy, following
Induction, are not eligible for the Standard Risk-Low study, and should be removed
from protocol therapy at the end of Induction

- Patients who are assigned to the standard risk-average group following Induction and
who meet the HRQOL

- Age at diagnosis >= 2 years (note that this is a more restrictive age range than for
the therapeutic component of the study)

- At least one parent with reading comprehension of English or Spanish languages for
which validated surveys exist

- Diagnosis at one of the institutions participating in this limited institution
correlative study

- A parent or legal guardian must sign a written informed consent/parental permission
for all patients

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met