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

PRIMARY OBJECTIVES:

I. To determine if the administration of post-Induction age-adjusted intrathecal triple
therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance (IM)
high-dose methotrexate (IMHDM) backbone will improve 5-year disease-free survival (DFS) of
children with high-risk (HR) B-acute lymphoblastic leukemia (ALL) compared to age-adjusted
intrathecal (IT) methotrexate (MTX).

II. To determine, in a randomized fashion, if the cyclophosphamide + etoposide containing
regimen (Experimental Arm 1) will improve the 4-year DFS of children, adolescents, and young
adults with very high-risk (VHR) B-ALL compared to a modified MBFM-IMHDM regimen that
contains a second IM (Control Arm).

SECONDARY OBJECTIVES:

I. To determine the toxicity and tolerability of post-Induction age-adjusted ITT compared to
age-adjusted IT MTX in children with HR B-ALL.

II. To determine the toxicity and tolerability of Experimental Arm 1 compared to the Control
Arm in children, adolescents, and young adults with VHR B-ALL.

III. To determine whether a single-arm, modified Induction with limited anthracycline
exposure and post-Induction therapy regimen with MBFM-IMIDM and reduced vincristine
(vincristine sulfate)/steroid pulse frequency and enhanced supportive care in children with
Down syndrome (DS) and HR B-ALL will result in a >= 65% 5-year DFS and < 10% Induction
mortality.

IV. To determine the toxicity and tolerability of MBFM-IMIDM in children with DS and HR
B-ALL.

V. To estimate overall survival (OS) rates both overall and by regimen a) for HR B-ALL and
b) VHR B-ALL patients.

VI. To determine the incidence of osteonecrosis (ON), defined by magnetic resonance (MR)
imaging, and to characterize the natural history of clinically silent ON in children,
adolescents, and young adults 10 years of age and greater and to assess the role of drugs
(i.e., asparaginase and methotrexate) in addition to corticosteroids, in the risk for
development of ON.

VII. To determine if the prevalence of cognitive deficits measured by CogState, in children
(ages 6 to 11 years) with HR- and VHR B-ALL at 1 year off therapy, is significantly higher
than the normative population (> 14%) in the following domains: working memory, executive
function, visual motor, processing speed, and visual attention.

TERTIARY OBJECTIVES:

I. To determine if the reduction of minimal residual disease (MRD) from end-Induction to
end-Consolidation is greater for children, adolescents, and young adults with VHR B-ALL
receiving Experimental Arm 1 compared to the Control Arm.

OUTLINE:

INDUCTION THERAPY:

Patients without Down syndrome receive induction chemotherapy comprising cytarabine
intrathecally (IT) on day 1; vincristine sulfate intravenously (IV) over 1 minute on days 1,
8, 15, and 22; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22;
dexamethasone orally (PO) or IV twice daily (BID) on days 1-14 (patients under 10 years old)
or prednisone PO or IV BID on days 1-28 (patients at least 10 years old); pegaspargase IV
over 1-2 hours on day 4; and methotrexate IT on days 8 and 29 (plus days 15 and 22 for CNS3
patients). Treatment continues for 56 days in the absence of disease progression or
unacceptable toxicity.

CONSOLIDATION THERAPY: Patients are randomized to 1 of 2 treatment arms.

ARM I HR B-ALL CONSOLIDATION (C): Patients receive consolidation therapy comprising
cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 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, methotrexate IT on days 1, 8, 15, and 22; vincristine sulfate IV
over 1 minute on days 15, 22, 43, and 50; and pegaspargase IV over 1-2 hours on days 15 and
43. Patients with continuing clinical evidence of testicular leukemia undergo radiotherapy
(RT) QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues
for 56 days in the absence of disease progression or unacceptable toxicity.

ARM II HR B-ALL C: Patients receive Consolidation therapy as in Arm I HR B-ALL C. Patients
also receive ITT comprising methotrexate, hydrocortisone sodium succinate, and cytarabine on
days 1, 8, 15, and 22. Patients with testicular leukemia also undergo RT as in Arm I HR
B-ALL C.

INTERIM MAINTENANCE THERAPY:

ARM I HR B-ALL INTERIM MAINTENANCE (IM): Patients receive IM therapy comprising vincristine
sulfate IV over 1 minute on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours
on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46;
methotrexate IT on days 1 and 29; and mercaptopurine PO on days 1-56. Treatment continues
for 63 days in the absence of disease progression or unacceptable toxicity.

ARM II HR B-ALL IM: Patients receive ITT on days 1 and 29 and IM therapy as in Arm I HR-ALL
IM. Treatment continues for 63 days in the absence of disease progression or unacceptable
toxicity.

DELAYED INTENSIFICATION THERAPY:

ARM I HR B-ALL DELAYED INTENSIFICATION (DI): Patients receive DI therapy comprising
vincristine sulfate IV over 1 hour on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID
on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-60 minutes on days 1, 8, and 15;
methotrexate IT on days 1, 29, and 36; pegaspargase IV over 1-2 hours on days 4 and 43;
cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on
days 29-32 and 36-39; and thioguanine PO QD on days 29-42. Treatment continues for 56 days
in the absence of disease progression or unacceptable toxicity.

ARM II HR B-ALL DI: Patients receive ITT on days 1, 29, and 36 and DI therapy as in Arm I HR
B-ALL DI.

MAINTENANCE (M) THERAPY:

ARM I HR B-ALL M: Patients receive maintenance therapy comprising vincristine sulfate IV
over 1 minute on days 1, 29, and 57; methotrexate IT on day 1 (also day 29 of courses 1-4);
prednisone PO BID on days 1-5, 29-33 (may receive methylprednisolone IV if PO is not
tolerated), and 57-61; mercaptopurine PO QD on days 1-84; and methotrexate PO on days 8, 15,
22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2 years
(females) or 3 years (males) in the absence of disease progression or unacceptable toxicity.

ARM II HR B-ALL M: Patients receive ITT on day 1 (also day 29 of courses 1-4) and
maintenance therapy as in Arm I HR B-ALL M. Treatment repeats every 12 weeks for 2 years
(females) or 3 years (males) in the absence of disease progression or unacceptable toxicity.

VERY HIGH-RISK B-ALL: Patients are randomized to 1 of 3 treatment arms.

CONSOLIDATION THERAPY PART I: In all arms, patients receive cyclophosphamide IV over 30-60
minutes on day 1; cytarabine IV or SC on days 1-4 and 8-11; mercaptopurine PO QD on days
1-14; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 patients);
vincristine sulfate IV over 1 minute on days 15 and 22; and pegaspargase IV over 1-2 hours
on day 15. Patients with continuing clinical evidence of testicular leukemia undergo RT QD,
5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 28
days in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY PART II:

ARM A VHR B-ALL C (CONTROL ARM): Patients receive consolidation therapy comprising
cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on
days 29-32 and 36-39; mercaptopurine PO QD on days 29-42; vincristine sulfate IV over 1
minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues
for 28 days in the absence of disease progression or unacceptable toxicity.

ARM B VHR B-ALL C (EXPERIMENTAL ARM): Patients receive consolidation therapy comprising
cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 60-120 minutes on
days 29-33; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over
1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression
or unacceptable toxicity.

ARM C VHR B-ALL C: Patients receive clofarabine IV over 2 hours on days 29-33 and
consolidation therapy as in Arm B VHR B-ALL C. (Closed as of 9/12/2014)

INTERIM MAINTENANCE I: In all arms, patients receive vincristine sulfate IV over 1 minute on
days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43;
leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO QD on
days 1-56; and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the
absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION PART I: In all arms, patients receive vincristine sulfate IV over 1
minute on days 1, 8, and 15; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin
hydrochloride IV over 1-60 minutes on days 1, 8, and 15; methotrexate IT on day 1; and
pegaspargase IV over 1-2 hours on day 4. Treatment continues for 28 days in the absence of
disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION PART II:

ARM A VHR B-ALL DI (CONTROL ARM): Patients receive DI therapy comprising cyclophosphamide IV
over 30-60 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and
36-39; thioguanine PO QD on days 29-42; methotrexate IT on days 29 and 36; vincristine
sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43.
Treatment continues for 28 days in the absence of disease progression or unacceptable
toxicity.

ARM B VHR B-ALL DI (EXPERIMENTAL ARM): Patients receive DI therapy comprising
cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 60-120 minutes on
days 29-33; methotrexate IT on days 29 and 36; vincristine sulfate IV over 1 minute on days
43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in
the absence of disease progression or unacceptable toxicity.

ARM C VHR B-ALL DI: Patients receive clofarabine IV over 2 hours on days 29-33 and DI
therapy as in Arm II B VHR B-ALL DI. (Closed as of 9/12/2014)

INTERIM MAINTENANCE II: In all arms, patients receive vincristine sulfate IV over 1 minute
and methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11,
21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days
1 and 31. Treatment continues for 56 days in the absence of disease progression or
unacceptable toxicity.

MAINENTANCE THERAPY: Patients with CNS3 disease at diagnosis undergo RT QD over 4 weeks (10
fractions total). In all arms, patients receive vincristine sulfate IV over 1 minute on days
1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61 (may receive
methylprednisolone IV if PO is not tolerated); methotrexate PO on days 8, 15, 22, 29, 36,
43, 50, 57, 64, 71, and 78 (except on methotrexate IT days); mercaptopurine PO QD on days
1-84; methotrexate IT on day 1 (also day 29 of courses 1 and 2 for CNS patients who did not
undergo RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in
the absence of disease progression or unacceptable toxicities.

INDUCTION THERAPY: All patients receive cytarabine IT on day 1; vincristine sulfate IV over
1 minute on days 1 and 8, dexamethasone PO or IV BID (patients under 10 years old) or
prednisone PO BID (patients at least 10 years old) on days 1-14 (may receive
methylprednisolone IV if PO is not tolerated), pegaspargase IV over 1-2 hours on day 4;
methotrexate IT on day 8; and leucovorin calcium PO on days 10-11. Treatment continues for
14 days in the absence of disease progression or unacceptable toxicity.

Rapid early responders (RER): Patients receive induction therapy comprising vincristine
sulfate IV over 1 minute on days 15 and 22; dexamethasone PO BID or prednisone PO BID on
days 15-28; methotrexate IT on day 29 (also days 15 and 22 for CNS3 patients); and
leucovorin calcium PO on days 31-32 (also days 17-18 and 24-25 for CNS3 patients). Treatment
continues for 14 days in the absence of disease progression or unacceptable toxicity.

Slow early responders (SER): Patients receive daunorubicin hydrochloride IV over 1-15
minutes on day 15 and Induction therapy as RER patients. Treatment continues for 14 days in
the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY: All patients receive cyclophosphamide IV over 30-60 minutes on days 1
and 29; cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39;
mercaptopurine PO QD on days 1-14 and 29-42; vincristine sulfate IV over 1 minute on days
15, 22, 43, and 50; pegaspargase IV over 1-2 hours on days 15 and 43; methotrexate IT on
days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 patients); and leucovorin calcium PO on
days 3-4, 10-11, 17-18, and 24-25. Patients with continuing clinical evidence of testicular
leukemia undergo RT QD, 5 days a week, for approximately 2½ weeks (12 fractions total).
Treatment continues for 56 days in the absence of disease progression or unacceptable
toxicity.

INTERIM MAINTENANCE THERAPY: Patients receive vincristine sulfate IV over 1 minute on days
1, 15, 29, and 43; intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and
43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO QD
on days 1-56; and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the
absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION THERAPY: Patients receive vincristine sulfate IV over 1 minute on
days 1, 8, 15, 43, and 50; dexamethasone PO BID or IV on days 1-7 and 15-21; doxorubicin
hydrochloride IV over 1-60 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on
days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO QD on days
29-42; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; methotrexate IT on
days 1, 29, and 36; and leucovorin calcium PO on days 3-4, 31-32 and 38-39.

MAINTENANCE THERAPY: Patients with CNS3 disease undergo RT QD, 5 days a week, for 2 weeks
(10 fractions total). Patients receive vincristine sulfate IV over 1 minute on day 1;
prednisone PO BID or IV on days 1-5 (may receive methylprednisolone IV if PO not tolerated);
methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO QD
on days 1-84; and methotrexate IT on day 1 (also day 29 of courses 1-4 for CNS3 patients who
did not undergo RT). Treatment repeats every 12 weeks for 2 years in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 10 years.

Inclusion Criteria:

- Patients must be enrolled on AALL08B1 prior to enrollment on AALL1131

- White Blood Cell Count (WBC) Criteria

- Age 1-9.99 years: WBC >= 50 000/uL

- Age 10-30.99 years: Any WBC

- Age 1-30.99 years: Any WBC with:

- Testicular leukemia

- CNS leukemia (CNS3)

- Steroid pretreatment

- Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health
Organization [WHO] classification) (also termed B-precursor acute lymphoblastic
leukemia); patients with Down syndrome are also eligible

- Eligibility criteria for the Incidence and Natural History of Osteonecrosis study

- Patients must be 10 years of age or greater at the time of B-ALL diagnosis,
enrolled on AALL1131

- Patients with Down syndrome are not eligible

- Eligibility criteria for the Longitudinal, Computerized Assessment of Neurocognitive
Functioning study

- Patients must be aged 6 to 11 years at time of B-ALL diagnosis, enrolled on
AALL1131

- Patients must be English-, French- or Spanish-speaking (languages in which the
assessment is available)

- Patients must have no known history of neurodevelopmental disorder prior to
diagnosis of B-ALL (e.g., Down syndrome, Fragile X, William's Syndrome, mental
retardation)

- Patients must have no significant visual impairment that would prevent computer
use and recognition of the visual test stimuli

- Eligibility criteria for the National Cancer Institute (NCI) standard risk patients
from AALL0932 enrolling on this study at the end of Induction:

- Patients enrolled on AALL0932, without Down syndrome, meeting the following criteria
will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the HR
B-ALL stratum of this study at the end of Induction:

- Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with
day 8 peripheral blood (PB) minimal residual disease (MRD) >= 1% and day 29 BM
MRD < 0.01%

- With favorable cytogenetics (ETV6-RUNX1 or double trisomies 4+10), with any day
8 PB MRD and day 29 bone marrow (BM) MRD >= 0.01%

- Both NCI standard risk (SR) and HR patients without Down syndrome and with
testicular disease at diagnosis, who do not meet other VHR criteria, will be
eligible for the HR stratum

- Patients enrolled on AALL0932, without Down syndrome, meeting the following criteria
will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the
VHR B-ALL stratum of this study at the end of Induction:

- Intrachromosomal amplification of chromosome 21 (iAMP21)

- Mixed-lineage leukemia (MLL) rearrangement

- Hypodiploidy (n < 44 chromosomes and/or a deoxyribonucleic acid [DNA] index <
0.81)

- Induction failure (M3 BM at day 29)

- Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with
day 29 BM MRD >= 0.01%

- Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria
will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS
HR B-ALL stratum of this study at the end of Induction:

- Day 29 MRD >= 0.01%

- MLL rearrangement

- Hypodiploidy (n < 45 chromosomes and/or DNA index < 0.81)

- DS HR B-ALL patients initially enrolled on AALL0932 or this study who have Induction
failure (M3 BM day 29) or Philadelphia chromosome (BCR-ABL1) will not be eligible for
post-Induction therapy on either trial (AALL0932 or AALL1131)

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

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

Exclusion Criteria:

- With the exception of steroid pretreatment or the administration of intrathecal
cytarabine, patients must not have received any prior cytotoxic chemotherapy for
either the current diagnosis of B-ALL or any cancer diagnosed prior to the initiation
of protocol therapy on AALL1131; patients cannot have secondary B-ALL that developed
after treatment of a prior malignancy with cytotoxic chemotherapy; patients receiving
prior steroid therapy may be eligible for AALL1131

- Patients with breakpoint cluster region (BCR)-v-abl Abelson murine leukemia viral
oncogene homolog 1 (ABL1) fusion (not eligible for post-Induction therapy on this
study; non-DS patients may be eligible to enroll in AALL1122 or successor Children's
Oncology Group [COG] Philadelphia positive [Ph+] ALL trial by day 15 Induction)

- DS HR B-ALL patients with Induction failure or BCR-ABL1

- Female patients who are pregnant are ineligible

- Lactating females are not eligible unless they have agreed not to breastfeed their
infant

- Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained

- Sexually active patients of reproductive potential are not eligible unless they have
agreed to use an effective contraceptive method for the duration of their study
participation