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Researchers seek a way to predict cognitive deficits in children treated for ALL


 

Researchers are attempting to determine, early in the treatment process, which children with acute lymphoblastic leukemia (ALL) have an increased risk of neurocognitive deficits after chemotherapy.

Peter D. Cole, MD Rutgers Cancer Institute of New Jersey

Dr. Peter D. Cole

The goal of the researchers’ project (5R01CA220568-02) is to determine if gene variants and biomarkers associated with oxidative stress, neuroinflammation, and folate physiology correlate with cognitive decline during and after chemotherapy. Ideally, certain variants and biomarkers will reveal patients who might benefit from interventions to prevent or even reverse cognitive deficits.

Peter D. Cole, MD, of Rutgers Cancer Institute, New Brunswick, N.J., and colleagues are conducting this research in patients from the DFCI-16-001 trial (NCT03020030). This multicenter, phase 3 study is enrolling patients (aged 1-21 years) with B- or T-cell ALL who then receive a multidrug chemotherapy regimen.

Dr. Cole and colleagues are analyzing a subset of patients from the trial, looking for relationships between chemotherapy-induced neurocognitive changes, gene variants, and changes in biomarkers detected in cerebrospinal fluid (CSF).

“We’re looking at a broad panel of target gene variants that are associated with either drug metabolism, defenses against oxidative stress, neuroinflammation, or folate physiology,” Dr. Cole said in an interview.

This includes variants Dr. Cole and colleagues identified in a previous, retrospective study of ALL survivors. The researchers found that survivors who were homozygous for NOS3 894T, had a variant SLCO2A1 G allele, or had at least one GSTP1 T allele were more likely to exhibit cognitive deficits (J Clin Oncol. 2015 Jul 1;33[19]:2205-11).

The researchers are also analyzing CSF samples, looking for changes in tau protein, homocysteine, homocysteic acid, the adenosylmethionine to adenosylhomocysteine ratio, and other biomarkers of oxidative stress, neuroinflammation, and folate physiology. The CSF is collected at five time points: the start of chemotherapy, day 18, the start of first consolidation, the end of first consolidation, and 7 weeks later in second consolidation.

Cognitive testing

While Dr. Cole is leading the genetic and biomarker analyses, Stephen A. Sands, PsyD, of Memorial Sloan Kettering Cancer Center in New York, is leading the cognitive testing.

Dr. Stephen A. Sands, of Memorial Sloan Kettering Cancer Center in New York

Dr. Stephen A. Sands

The researchers are evaluating patients for cognitive decline using computerized tests from a company called Cogstate. The tests are designed to assess functions such as processing speed, attention, visual learning, and working memory. The tests are administered on an iPad and involve tasks like identifying features of playing cards and finding the correct way through a maze.

The patients – aged 3 years and older – undergo cognitive testing at six time points: baseline, which is any time between days 8 and 32 of induction (except within 72 hours after sedation or anesthesia); at first consolidation; the end of central nervous system therapy; 1 year into chemotherapy; the end of chemotherapy; and 1 year after chemotherapy ends.

In a prior study, Cogstate testing proved reliable for detecting neurocognitive changes in patients undergoing treatment for ALL (Support Care Cancer. 2017;25[2]:449-57). In the current study, the researchers are supplementing Cogstate test results with Wechsler IQ tests administered 1 year after patients complete chemotherapy.

Dr. Sands noted that Cogstate tests provide benefits over the Wechsler “paper-and-pencil” tests. One benefit is that Cogstate tests can be given more often without inducing practice effects (J Clin Exp Neuropsychol. 2006 Oct;28[7]:1095-112). Another is that Cogstate tests can be administered by anyone with a bachelor’s degree who has undergone the appropriate training, while Wechsler IQ tests must be given by psychologists.

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