Brain Function in Young Patients Receiving Methotrexate for Acute Lymphoblastic Leukemia

OBJECTIVES:

I. Determine the neuropsychological function in children with acute lymphoblastic leukemia
treated with either high-dose methotrexate or escalating-dose methotrexate in the absence of
cranial radiation and nelarabine.

II. Identify host polymorphisms that predict an increased risk of neurocognitive dysfunction
or acute neurotoxicity in these patients.

III. Correlate neuropsychological outcome measures and the occurrence of acute neurotoxicity
with host polymorphisms in these patients.

IV. Measure concentrations of 5-methyltetrahydrofolate, homocysteine, Ado,
S-adenosylmethionine, S-adenosylhomocysteine, and other potentially relevant compounds in
serum and cerebrospinal fluid during interim maintenance therapy with low- or high-dose
methotrexate regimens, respectively, and correlate these endpoints with the occurrence of
acute neurologic toxicity and long-term neurocognitive dysfunction in these patients.

V. Determine whether or not diffusion tensor imaging will identify areas of selective
vulnerability in CNS and provide an imaging modality that predicts and/or correlates with
neuropsychological outcome.

OUTLINE: This is a prospective, cohort, multicenter study.

Patients complete neurocognitive tests to assess thinking, memory, attention, and
concentration. The baseline test is administered during the consolidation phase of
chemotherapy and further tests are done at 1 year from baseline and 1 year after* the
completion of study therapy.

Patients undergo blood and cerebrospinal fluid collection periodically for biomarker,
genotypic polymorphisms, and pharmacokinetic analysis. Patients undergo MRI diffusion-tensor
imaging to correlate imaging with neuropsychological outcomes.

NOTE: * Within 8 months to 24 months after the completion of study therapy for patients on
AALL0232.

Inclusion Criteria:

- Diagnosis of acute lymphoblastic leukemia

- Enrolled on COG-AALL0434 (Cohort #1 only) or COG-AALL0232 (Cohorts #1 and #2)

- Patients must have received either high-dose methotrexate or escalating-dose
methotrexate during interim maintenance.

- No CNS-3 disease

- Patients must enroll within 8-24 months after completion of therapy on COG-AALL0232
and no evidence of relapsed or secondary malignancy

- No known significant neurodevelopmental disability unrelated to cancer diagnosis
including, but not limited to, any of the following:

- Down syndrome

- Fragile X mental retardation

- Autism

- Pervasive developmental disability

- Seizure disorder

- Attention-deficit hyperactivity disorder or specific learning disability (e.g.,
dyslexia) allowed

- No sensory impairment (e.g., pre-existing uncorrectable vision impairment or
deafness)

- No cranial radiation therapy