Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations

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 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). (Completed effective March 19, 2018) 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). (Completed effective February 15, 2017)

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. (Completed effective March 19, 2018) 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. (Completed effective February 15,
2017) III. To determine whether a single-arm, modified Induction with limited anthracycline
exposure and post-Induction therapy regimen with MBFM-interim maintenance intermediate dose
methotrexate (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 describe the outcomes for children and young adults with Philadelphia chromosome
(Ph)-like B-ALL and a predicted TKI-sensitive mutation treated with dasatinib plus
MBFM-IMHDM.

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

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

VII. 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. (Completed accrual July 2016) VIII. To determine if the prevalence of
cognitive deficits measured by CogState, in children (ages 6 to < 13 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.

EXPLORATORY 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. (Closed effective October 20, 2017)

OUTLINE:

INDUCTION THERAPY:

Patients without Down syndrome receive induction chemotherapy comprising cytarabine
intrathecally (IT) on day 1 (and twice weekly thereafter for CNS2 patients [except for days 8
and 29]); 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 for CNS1 and CNS2 patients (plus days 15 and 22
for CNS3 patients). Treatment continues for 35 days in the absence of disease progression or
unacceptable toxicity.

Participants are stratified to 1 of 3 disease groups: HR B-ALL, VHR B-ALL and PH-like B-ALL a
predicted TKI-sensitive mutation.

GROUP I - HR B-ALL: Patients are randomized to 1 of 2 treatment arms. (RANDOMIZATION CLOSED
03/19/2018)

CONSOLIDATION THERAPY (C):

ARM A HR B-ALL 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 B 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. (CLOSED 03/19/2018)

INTERIM MAINTENANCE THERAPY (IM) ARM A HR B-ALL 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 B 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. (CLOSED 03/19/2018)

DELAYED INTENSIFICATION THERAPY (DI):

ARM A HR B-ALL DI: Patients receive DI therapy comprising vincristine sulfate IV over 1
minute on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID on days 1-7 and 15-21;
doxorubicin hydrochloride IV over 1-15 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 B HR B-ALL DI: Patients receive ITT on days 1, 29, and 36 and DI therapy as in Arm I HR
B-ALL DI. (CLOSED 03/19/2018)

MAINTENANCE THERAPY (M):

ARM A 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 B 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. (CLOSED
03/19/2018)

GROUP II: VHR B-ALL: Patients are randomized to 1 of 3 treatment arms. (RANDOMIZATION CLOSED
02/15/2017)

CONSOLIDATION THERAPY PART I: In all arms, patients receive cyclophosphamide IV over 30-60
minutes on day 1; cytarabine IV over 1-30 minutes 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 1): 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. (CLOSED 02/15/2017)

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

INTERIM MAINTENANCE THERAPY PART 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 THERAPY 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 1-15 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 THERAPY 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 1-30 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 1): 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. (CLOSED 02/15/2017)

ARM C VHR B-ALL DI (EXPERIMENTAL ARM 2): 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 THERAPY PART 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.

GROUP III: PH-LIKE PREDICTED TKI-SENSITIVE KINASE MUTATION:

CONSOLIDATION THERAPY: Patients receive dasatinib PO QD on days 1-56, 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 on days 1-14 and 29-42, 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, 22, 43 and 50, and pegaspargase IV over 1-2 hours on days 15 and 43. Treatment continues
for 56 days in the absence of disease progression or unacceptable toxicity.

INTERIM MAINTENANCE THERAPY I: Patients receive dasatinib PO QD on days 1-63, 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.

DELAYED INTENSIFICATION THERAPY: Patients receive dasatinib PO QD on days 1-56, vincristine
sulfate IV over 1 minute on days 1, 8, 15, 43, and 50, dexamethasone PO or IV on days 1-7 and
15-21, doxorubicin hydrochloride IV over 1-15 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 day 29, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, and
thioguanine PO on days 29-42. Treatment continues for 56 days in the absence of disease
progression or unacceptable toxicity.

INTERIM MAINTENANCE THERAPY II: Patients dasatinib PO QD on days 1-56, vincristine sulfate IV
over 1 minute days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or
10-15 minutes (diluted) on days 1, 11, 21, 31 and 41, methotrexate IT on days 1 and 31, and
pegaspargase IV over 1-2 hours days 2 and 22.

MAINTENANCE THERAPY: Patients receive dasatinib PO QD on days 1-84, vincristine sulfate IV
over 1 minute on days 1, 29 and 57, prednisone PO BID or IV on days 1-5, 29-33 and 57-61,
methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 (omit on days when MTX
[IT] is given), mercaptopurine PO on days 1-84, methotrexate IT on day 1 (also day 29 of
course 1 and 2, for patients who did not receive CNS radiation). Treatment repeats every 12
weeks for 2 years (females) or 3 years (males) in the absence of disease progression or
unacceptable toxicities.

Participants with Down syndrome are assigned to DS HR B-ALL:

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 (patients under 10 years
old) or prednisone PO BID (patients at least 10 years old) 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 2-3, 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 1-15 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 (females) or 3 years
(males) in the absence of disease progression or unacceptable toxicities.

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

Inclusion Criteria:

- Patients must be enrolled on APEC14B1 and consented to Eligibility Screening on the
Part A consent form 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

- Organ function requirements for patients with Ph-like ALL and a predicted
TKI-sensitive mutation: patients identified as Ph-like with a TKI-sensitive kinase
mutation must have assessment of organ function performed within 3 days of study entry
onto the dasatinib arm of AALL1131

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70mL/min/1.73
m^2 or a serum creatinine based on age/gender as follows:

- Age: Maximum Serum Creatinine (mg/dL)

- 1 to < 6 months: 0.4 (male) 0.4 (female)

- 6 months to < 1 year: 0.5 (male) 0.5 (female)

- 1 to < 2 years: 0.6 (male) 0.6 (female)

- 2 < 6 years: 0.8 (male) 0.8 (female)

- 6 to < 10 years: 1.0 (male) 1.0 (female)

- 10 to < 13 years: 1.2 (male) 1.2 (female)

- 13 to < 16 years: 1.5 (male) 1.4 (female)

- > 16 years: 1.7 (male) 1.4 (female)

- Direct bilirubin =< 3 x upper limit of normal (ULN) for age, and

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 10 x
upper limit of normal (ULN) for age

- Shortening fraction >= 27% by echocardiogram, or ejection fraction >= 50% by gated
radionuclide study

- Patients must have an electrocardiogram (EKG) fewer than 6 days prior to
enrollment on the dasatinib arm; patients who have had cardiac assessments by
echocardiogram or radionuclide scan at the beginning of induction do not need to
have these repeated prior to study entry; correct QT interval (QTc) < 450 msec on
baseline electrocardiogram as measured by the Friderica or Bazett formula

- No major conduction abnormality (unless a cardiac pacemaker is present)

- No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% at
sea level if there is clinical indication for determination

- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled; however, drugs that induce CYP3A4/5 (carbamazepine, oxcarbazepine,
phenytoin, primidone, phenobarbital) should be avoided

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

- Patients must be aged 6 to 13 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

- Effective March 19, 2018, patients enrolled on AALL0932, without Down syndrome,
meeting the following criteria will NOT be eligible to continue on AALL0932 or 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 bone
marrow (BM) MRD < 0.01%

- With favorable cytogenetics (ETV6-RUNX1 or double trisomies 4+10), with any day 8
PB MRD and day 29 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

- Effective Amendment 6, patients enrolled on AALL0932, without Down syndrome, meeting
the following criteria will NOT be eligible to continue on AALL0932 or the VHR stratum
of AALL1131:

- 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 BCR-ABL1 fusion are not eligible for post-induction therapy on this
study but may be eligible to enroll in a 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 since fetal toxicities and teratogenic
effects have been noted for several of the study drugs

- 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