Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia in Children and Adolescents

There are a standard set of risk factors which are used to decide how strong treatment should
be for a child with ALL. These risk factors include the child's age when the leukemia is
diagnosed, how high the white blood cell count (WBC) is in the blood, whether or not leukemia
cells are seen in the spinal fluid (referred to as Central Nervous System or CNS status), and
whether or not the leukemia has certain abnormalities in their chromosomes (genetic material
in the cell). Another risk factor is the amount of leukemia in the marrow that can be
measured by a special laboratory test called "MRD" (Minimal Residual Disease) after the first
month of treatment.

Over the last several years, new factors have been identified which help predict how well a
child's leukemia may respond to treatment. These new risk factors include additional
abnormalities in the genes of the leukemia cell, as well the amount of leukemia (MRD level)
at second time point (about 2-3 months after starting treatment).

In this trial, the investigators will use the new risk factors along with old risk factors to
decide how strong the treatment will be. The goal is to better identify those participants
who might benefit from stronger treatment in order to improve their chance for cure. The
investigators also hope to better identify participants who have a high chance of being cured
with standard treatment in order to reduce their chance of side effects while maintaining the
chance of cure.

This trial also aims to study the dosing of a drug called pegaspargase. Pegaspargase is a
chemotherapy drug that is an important part of ALL treatment but it is also can cause many
side effects. With the standard dose of pegaspargase, levels of the drug in the blood are
higher than may be necessary to effectively treat leukemia.

On this research study, the investigators will be comparing the standard dose of pegaspargase
with a new way of dosing the drug based on levels of the drug that we can measure in the
blood. With the new way of doing, treatment will begin with a lower dose. If the levels are
high, the dose will be decreased one more time; however, if at any time the levels are too
low, dosing will be switched back up to the standard dose. The goal of this research study is
to learn whether this new way of dosing (starting at a lower dose and changing the dose based
on drug levels in the blood) will decrease side effects but still be as effective as the
standard dosing of the drug.

Inclusion Criteria:

1. Confirmed diagnosis of acute lymphoblastic leukemia. Diagnosis should be made by bone
marrow aspirate or biopsy demonstrating ≥ 25% involvement by lymphoblasts, with flow
cytometry or immunohistochemistry confirming B-precursor or T-ALL phenotype.

-- For patients with circulating blasts in the peripheral blood, flow cytometry
confirmation of B-ALL or T-ALL phenotype is sufficient for registration onto the
study. Bone marrow aspirate and/or biopsy should be performed as soon as feasible,
preferably prior to the initiation of any therapy.

2. Prior Therapy: No prior therapy is allowed except for the following:

- Corticosteroids: Short courses of corticosteroid (defined as ≤ 7 days of
corticosteroids within the 4-weeks preceding registration) are allowed prior to
registration.

--- Participants who have been on corticosteroids chronically (defined as more
than 7 days of corticosteroids within the 4-weeks preceding registration or more
than 28 days of corticosteroids over the preceding 6 months) are not eligible.

- IT cytarabine: A single dose of intrathecal cytarabine (at the time of the
diagnostic lumbar puncture) is allowed prior to registration. If patient has
received IT cytarabine prior to registration, Day 1 IT cytarabine should not be
administered.

- Emergent Radiation Therapy: Emergent radiation to the mediastinum or other
life-threatening masses is allowed prior to registration.

3. Age: 365 days to < 22 years

4. Direct bilirubin < 1.4 mg/dL (23.9 micromoles/L).

5. Ability of parent or guardian to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

1. Mature B-cell (Burkitt's) ALL (defined by the presence of surface immunoglobulin
and/or the t(8;14)(q24;q32), t(8;22), or t(2;8) translocation and/or c-myc-gene
rearrangement).

2. World Health Organization diagnostic criteria of mixed phenotype acute leukemia (MPAL)
or leukemia of ambiguous lineage

3. Any chemotherapy or radiotherapy for previous malignancy are not eligible.

4. Treatment in past with any anti-neoplastic agent, including methotrexate,
6-mercaptopurine, 6-thioguanine, vincristine cyclophosphamide, cytarabine (except for
IT cytarabine), or any anthracycline, for any reason (eg, rheumatologic or autoimmune
condition).

5. Currently receiving any investigational agents.

6. Known HIV-positivity

7. Uncontrolled intercurrent illness including, but not limited to ongoing infection with
vital sign instability (hypotension, respiratory insufficiency), life-threatening
acute tumor lysis syndrome (eg, with renal failure), symptomatic congestive heart
failure, cardiac arrhythmia, intracranial or other uncontrolled bleeding, or
psychiatric illness/social situations that would limit compliance with study
requirements.

8. Pregnant women are excluded from this study because many of the agents used on this
protocol have potential for teratogenic and/or abortifacient effects. Because there is
an unknown but potential risk of adverse events in nursing infants secondary to
treatment of the mother with these chemotherapy agents, breastfeeding should be
discontinued if the mother is enrolled.

9. History of a previous malignancy. Exception: Individuals with a previous malignancy
treated with surgery only (no chemotherapy or radiotherapy) more than 5 years prior to
registration may be enrolled.