Previous research indicates that patients undergoing blood or marrow transplantation (BMT) are exposed to potentially neurotoxic treatment. “In a previous study, my colleagues and I found that cognitive impairment is prevalent in patients who had hematologic malignancies and were treated with BMT, up to 3 years after BMT, and those with cognitive impairment were less likely to return to work,” explains Smita Bhatia, MD, MPH. With significant interindividual variability in risk for cognitive impairment in this patient population, suggesting a role for genetic susceptibility, Dr. Bhatia and colleagues tested the hypothesis that individual single nucleotide polymorphisms (SNPs) and gene-level variants are associated with cognitive impairment in patients with hematologic malignancies treated with BMT and that inclusion of these SNPs improves risk prediction beyond that offered by clinical and demographic characteristics.

Considering Genes

For a study published in the Journal of Clinical Oncology, Dr. Bhatia and colleagues performed neuropsychological testing on patients prior to treatment with BMT through 3 years after. “Our team hypothesized that chemotherapy and/or radiation induce oxidative stress resulting in DNA damage and telomere shortening, which could result in neurodegeneration and present as cognitive impairment,” adds Dr. Bhatia. The researchers developed a list of biologically plausible SNPs to determine susceptibility. Germline DNA was collected before BMT treatment and genotyped. The team genotyped 68 SNPs identified during the discovery phase and then using tested machine-learning techniques to identify gene markers and develop risk prediction models. The complex analyses were led by Noha Sharafeldin, MD, MSc, PhD.

The Results

Older age (odds ratio [OR], 4.6), male sex (OR, 3.3), and lower cognitive reserve (OR, 4.6) were associated with the highest risk of cognitive impairment (Table). Dr. Bhatia highlights that patients who received total body irradiation were also at an increased risk when compared with those who did not. Additionally, cognitive impairment following BMT was associated with five SNPs on DNA repair genes (rs13006837, rs293796, rs12534423, rs4725015, and rs7087131), one SNP on the BBB gene (rs10808071), and one SNP on the telomere homeostasis gene (rs1713436), indicating associations of SNPs in DNA repair genes with processing speed and working memory.

“Our study provides useful insights regarding the utility of collecting genetic data in clinical practice to predict post-BMT cognitive impairment,” emphasizes Dr. Bhatia. “The combination of genetics, demographics, and clinical make-up can identify BMT recipients at highest risk for cognitive impairment. We can use this information in the future to work closely with BMT recipients at highest risk for cognitive impairment in order to institute cognitive remediation.”

Upon further analysis, the team determined the median time between patients receiving BMT treatment and developing cognitive impairment to be 2 years (interquartile range, 1 to 7 years). No demographic or clinical characteristics were independently associated with learning or memory severity. Because of previous reports of fatigue being associated with cognitive decline in patients treated with allogeneic BMT, the team included fatigue as a variable when predicting risk of cognitive impairment. However, they did not find that fatigue was independently associated with cognitive impairment.

Continuing Research

“Our results suggest that incorporating identified genetic factors significantly enhanced the risk prediction of cognitive impairment and improved the accuracy, as assessed by the C-statistic,” notes Dr. Bhatia. “This study represents the first step toward identification of BMT survivors at high risk for cognitive impairment, informing personalized management of cognitive outcomes in patients undergoing BMT. In the future, we would like to develop a diagnostic assay that would be incorporated into a risk prediction tool, which would create a ‘personal risk score’ for cognitive impairment. Patients at high risk also could benefit from specific interventions to improve cognition.”

Author