Cognitive Impairment in Pediatric ALL Survivors Even Without Brain RT

Even in the absence of cranial radiation therapy, survivors of childhood acute lymphoblastic leukemia (ALL) have decreased neurocognitive function years later. Certain chemotherapy agents in particular are associated with declines in function, according to results from a study (abstract 10001) presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting held May 29 to June 2 in Chicago.

“We do know that survivors who are treated with cranial radiation may suffer from cognitive impairment,” said Yin Ting Cheung, PhD, of St. Jude Children’s Research Hospital in Memphis. Recent studies have suggested that those treated solely with chemotherapy also have some related problems, especially with regards to executive function.

She discussed an analysis of 213 patients, with an average age of 6.6 years at diagnosis and an age of 13.8 years at evaluation. Most of the patients (57%) were considered low-risk.

The mean cumulative methotrexate dose was 15,665.3 mg/m², and the cumulative oral dexamethasone dose was 1,084.5 mg/m². Patients underwent functional MRI imaging and cognitive testing for the study.

“At more than 5 years post-diagnosis, survivors’ cognitive flexibility was half a standard deviation poorer than the normative sample,” Cheung said. Verbal fluency was also reduced, by about one-third of a standard deviation compared with normative samples.

The Z-score for cognitive flexibility was -0.55 (P < .0001); for verbal fluency, it was -0.38 (P < .0001). In total, 17.1% excess proportion of this population had cognitive flexibility impairment, and 14.4% excess proportion had verbal fluency impairment.

Methotrexate exposure was significantly associated with cognitive flexibility (P = .015) and verbal fluency (P = .007). Dexamethasone was not significantly associated with either (P = .10 and .68, respectively). Post-methotrexate homocysteine levels were also significantly associated with impairment.

There was complete neuroimaging data available for 146 of the survivors. Methotrexate exposure was positively correlated with activation in the frontal and anterior cingulate cortex, Cheung said, as well as in the putamen and caudate nucleus, which are associated with executive function.

She noted that these results could be confounded by the use of other chemotherapeutic agents, as some patients received multiple lines of therapy.

Sabine Mueller, MD, PhD, of the University of California, San Francisco, was the discussant for the session. She said that the decline in neurocognitive function is not surprising when one considers the complex factors that play a role in pediatric cancer survivors, from genetic factors to psychological status and many others.

She also noted the “pitfalls” of studying the effects of methotrexate, including differing routes of administration, as well as the fact that dose alone may not adequately reflect drug exposure.

“Pediatric leukemia survivors… are at risk for neurocognitive sequelae,” she said. “Future studies should focus on the identification of additional host factors such as genetic polymorphisms of potential candidate genes that might predict or influence neurocognitive function in pediatric cancer survivors.”