Pegaspargase and Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia (Closed to Accrual 4-22-2011)

PRIMARY OBJECTIVES:

I. To demonstrate that biweekly intravenous (IV) pegaspargase beginning with Consolidation
and ending with completion of delayed intensification (DI) in combination with
hemi-augmented BFM therapy (hABFM) is feasible and safe in children with high risk (HR)
acute lymphoblastic leukemia (ALL).

OUTLINE: Patients are stratified according to risk assignment (high-risk [HR]-average [day
29 minimal residual disease (MRD) < 0.01%] vs HR-high [MRD >= 0.01%, presence of central
nervous system [CNS]3 leukemia, testicular disease, myeloid/mixed lineage leukemia [MLL]
rearrangement, hypodiploidy, or steroid therapy within the past month]). Patients are
assigned to 1 of 2 treatment groups.*

(Note: *Amendment 2 [4-22-2011] requires changes in the regimens. See the changes below,
after Maintenance therapy.)

INDUCTION THERAPY: All patients receive cytarabine intrathecally (IT) on day 1; vincristine
sulfate IV on days 1, 8, 15, and 22; prednisone IV or orally (PO) twice daily (BID) on days
1-28; daunorubicin hydrochloride IV over 15 minutes on days 1, 8, 15, and 22; methotrexate
IT on days 8 and 29*; and pegaspargase IV over 1-2 hours on day 4.

(Note: *Patients with CNS3 disease [white blood cells [(WBC)] >= 5/uL and positive for
blasts on cytospin] also receive methotrexate IT on days 15 and 22.)

CONSOLIDATION THERAPY (begins on day 36 of induction therapy):

GROUP A (HR-AVERAGE): Patients receive cyclophosphamide IV over 1 hour on days 1 and 29;
cytarabine IV over 15 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39;
mercaptopurine PO once daily (QD) on days 1-14 and 29-42; vincristine sulfate IV on days 15,
22, 43, and 50; methotrexate IT on days 1, 8, 15*, and 22*; and pegaspargase IV over 1-2
hours on days 15 and 43.

GROUP B (HR-HIGH): Patients receive cyclophosphamide, cytarabine, mercaptopurine,
vincristine sulfate, and methotrexate as in Group A. Beginning on day 1, patients also
receive pegaspargase IV over 1-2 hours every 2 weeks. Patients with CNS3 disease undergo
cranial radiotherapy QD for 10 days and patients with testicular disease undergo testicular
radiotherapy QD for 12 days, beginning on day 1 of consolidation.

(Note: *Patients with CNS3 disease [WBC >= 5/uL and positive for blasts on cytospin] do not
receive methotrexate IT on days 15 and 22.)

Interim maintenance (IM) therapy (begins on day 57 of consolidation):

GROUP A: Patients receive vincristine sulfate IV on days 1, 11, 21, 31, and 41; methotrexate
IV over 10-15 minutes on days 1, 11, 21, 31, and 41; methotrexate IT on days 1 and 31; and
pegaspargase IV over 1-2 hours on days 2 and 22.

GROUP B: Patients receive vincristine sulfate and methotrexate as in Group A. Beginning on
day 1, patients also receive pegaspargase IV over 1-2 hours every 2 weeks.

DI therapy (begins on day 57 of IM):

GROUP A: Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone
IV or PO BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 15 minutes on days 1,
8, and 15; cyclophosphamide IV over 1 hour on day 29; cytarabine IV over 15 minutes or SC on
days 29-32 and 36-39; thioguanine PO on days 29-42; methotrexate IT on days 1, 29, and 36;
and pegaspargase IV over 1-2 hours on days 4 and 43.

GROUP B: Patients receive vincristine sulfate, dexamethasone, doxorubicin hydrochloride,
cyclophosphamide, cytarabine, thioguanine, and methotrexate as in Group A. Beginning on day
1, patients also receive pegaspargase IV over 1-2 hours every 2 weeks.

MAINTENANCE THERAPY (MT; begins on day 57 of DI): All patients receive vincristine sulfate
IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61; mercaptopurine PO
on days 1-84; methotrexate IT on day 1; and methotrexate PO BID on days 8, 15, 22, 29*, 36,
43, 50, 57, 64, 71, and 78.

In both groups, MT repeats every 12 weeks until total duration of therapy is 2 years from
the start of IM for female patients and 3 years from the start of IM for male patients.
Patients in Group B who did not undergo radiotherapy to the brain during consolidation
therapy undergo prophylactic cranial radiotherapy (CR) daily for 8 days.

([Note: *Patients in Group A also receive methotrexate IT on day 29 of courses 1-4 [no oral
methotrexate]).

REVISED MT (RMT): The regimen is the same as standard MT, but 2 of the doses of IT
methotrexate are omitted (day 29 of courses 3 and 4).

Inclusion Criteria:

- Patients must be eligible for and enrolled on AALL03B1 or the successor
classification study

- Patients must have newly diagnosed high-risk B-precursor acute lymphoblastic leukemia
(ALL)

- WBC criteria

- Age 1.00-9.99 years: WBC >= 50,000/uL

- Age 10.00 - 30.99 years: Any WBC

- Prior steroid therapy: Any WBC

- Patients with testicular leukemia: Any WBC

- 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; the CNS status must be determined
based on a sample obtained prior to administration of any systemic or intrathecal
chemotherapy, except for steroid pretreatment; systemic chemotherapy must begin
within 72 hours of this intrathecal therapy

- Patients receiving prior steroid therapy are eligible for study; the dose and
duration of previous steroid therapy should be carefully documented

- All patients and/or their parents or legal guardians must sign a written informed
consent

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

Exclusion Criteria:

- Pregnant female patients are ineligible; pregnancy tests with a negative result must
be obtained in all post-menarchal females; males and females of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive method; lactating females must agree that they will not breastfeed a
child while on this study

- Patients with Down syndrome (DS) are ineligible since excessive toxicities and death
have been noted for those enrolled on AALL0232 receiving the prednisone/Capizzi
methotrexate (PC) arm of treatment, which is the backbone regimen for the current
study