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In the first study of its kind, researchers identified genetic factors that can lead to a decrease in cognitive ability after a blood or bone marrow transplant. In the first study of its kind, researchers at the University of Alabama at Birmingham have identified genetic factors associated with cognitive impairment related to blood and bone marrow transplants. That information can better pinpoint patients at the highest risk for cognitive issues compared to using demographic or clinical characteristics alone. These findings were published in the Journal of Clinical Oncology on Feb. 21.
Blood or bone marrow transplants are potentially lifesaving treatments for patients with leukemia, myeloma, lymphoma and other hematologic malignancies; but these treatments can bring long-lasting side effects, including cognitive impairment that leaves patients unable to resume work or normal activities.
Identifying the patients at a higher risk for cognitive decline allows clinicians to consider other treatment options or to begin interventions that are aimed at enhancing cognition.
Up to 36 percent suffer from ‘chemo brain’
Blood cancers account for 10 percent of all new cancer diagnoses, according to the Leukemia and Lymphoma Society. The society estimates that 179,000 people in the United States were diagnosed with a blood cancer in 2019.
A 2018 study by the same UAB research team found that patients who received cells transplanted from others, called an allogeneic BMT, have a significantly higher risk of cognitive impairment.
“That study found that 36 percent of patients who had allogeneic transplants had cognitive issues for up to three years after the transplant,” said Noha Sharafeldin, M.D., Ph.D., an assistant professor in the School of Medicine’s Division of Hematology and Oncology.
In the current study, Sharafeldin and colleagues wanted to identify single nucleotide polymorphisms, known as SNPs, that could explain why some patients are affected by chemo brain and others are not. SNPs are a common type of genetic variation in the population that can help explain individual variance in disease susceptibility.
Sharafeldin is first author in both studies and a researcher in UAB’s Institute for Cancer Outcomes and Survivorship, which is led by Smita Bhatia, M.D., who studies the long-term impacts of BMT on survivors’ health. Bhatia is senior author on both papers.
“Patients use the phrase ‘chemo brain,’” said Sharafeldin, who is also an associate scientist with the O’Neal Comprehensive Cancer Center. “It’s not dementia, but mild to moderate cognitive impairment. They feel foggy, become forgetful. They say they’re not keeping up with appointments and medications. It hinders their ability to function in the workplace.”
Understanding accelerated aging
The combination of cancer and high-intensity treatments like BMT, which involve chemotherapy and radiation therapy, can lead to accelerated aging in many patients.
“One of the hallmarks of accelerated aging is premature occurrence of health conditions that are typically seen in older people,” Sharafeldin said.
Little is known about the relationship between genetics and cognitive ability in cancer patients, even though the link has been demonstrated in several studies outside the oncology realm, including in Alzheimer’s disease.
The researchers started with a list of possible SNPs, hypothesizing that chemotherapy and/or radiation could damage DNA and shorten telomeres, the structures that shorten as cells age. These changes could result in neurodegeneration and cognitive impairment, as could failures of DNA repair genes and other genes that maintain the blood-brain barrier, which pump toxicity out of brain cells.
Machine learning
The researchers identified nearly 1,000 SNPs in 68 genes among 277 patients who had undergone allogeneic or autologous BMT between 2005 and 2011. These patients had contributed pre-BMT samples, and they were able to test their model by checking its predictions against the patients’ results on cognitive tests up to three years after treatment.
Using machine learning techniques, the researchers built a risk prediction model that featured the SNP and gene-level signals that correlated the most with cognitive impairment. These included SNPs on DNA repair genes, SNPs on genes linked to blood-brain barrier maintenance and genes linked to telomere balance. They tested this model by predicting outcomes for nearly 550 patients from the BMT Survivor Study, which examines outcomes for patients who received the treatment between 1974 and 2014. The study includes information on self-reported problems post-BMT that were identified by the patients’ health care providers. It was supported by Bhatia’s $6.38 million National Cancer Institute grant that studies the long-term impacts of BMT on survivors’ health.
“The cost of SNP testing technologies is declining steadily,” Sharafeldin noted. “What we envision is a custom array with a few selected SNPs that can help us in the clinic in addition to the other information we already collect. Incorporating SNPs in a risk prediction model can enable a more informed clinical decision-making process.”
“A better understanding of post-BMT health care needs could result in targeted strategies that yield better quality of survival and reduced utilization of health care resources,” Bhatia added. “That is what drives all of our efforts in the Institute for Cancer Outcomes and Survivorship.”
This research was supported in part by the Leukemia and Lymphoma Society. In addition to Sharafeldin and Bhatia, authors include Joshua Richman, M.D., Ph.D., Yanjun Chen, M.S., Purnima Singh, Ph.D., and Liton Francisco from UAB; Alysia Bosworth, Sunita Patel, Ph.D., F. Lennie Wong, Ph.D., and Stephen Forman, M.D., from City of Hope in Duarte, California; and Xuexia Wang, Ph.D., from the University of North Texas.