NEW YORK – A genetic variant common among the Aymara Indigenous community in the Andean mountains in South America is linked with better response to a drug used to treat polycythemia vera and essential thrombocythemia, two types of blood cancer, researchers reported Tuesday.
The variant, present in the NFKB1 gene, could serve as a biomarker to guide treatment decisions, provide insight into disease prognosis, and potentially be a target for new therapies, researchers presented in a late-breaking abstract at the American Society of Hematology's annual meeting in San Diego.
The treatment in the study was PharmaEssentia's Besremi (ropeginterferon-alfa-2b), an interferon drug designed to reduce blood cell production. The US Food and Drug Administration approved Besremi in 2021 for adults with polycythemia vera; the drug hasn't been approved for essential thrombocythemia, though it is being studied in a Phase III trial.
"People who inherit [the genetic variant] … are much more likely to achieve complete remission" after treatment with this drug, said Josef Prchal, a physician-scientist at the Huntsman Cancer Institute and a professor of hematology at the University of Utah Health in Salt Lake City, who is the senior author of the abstract, during a press briefing.
In the study, investigators analyzed genetic profiles, gene expression, and clinical outcomes among 30 patients with polycythemia vera and 15 patients with essential thrombocythemia. Both polycythemia vera and essential thrombocythemia are part of a group of rare blood cancers known as myeloproliferative neoplasms. Researchers homed in on patients with these blood cancers and one of three genotypes of the NFKB1 rs230511 variant: C/C, C/T, and T/T.
In prior research detailed in a paper that has been accepted by Nature Communications but not yet been published, Prchal and colleagues estimated that nearly 90 percent of people in the Aymara community have the C/T or T/T genotype, compared to about 30 percent of people with European, Asian, or Hispanic ancestry. Prchal described this as an evolutionary selected variant that seemingly helps the Aymara, as a population living at a high altitude, tolerate the lower oxygen pressure.
The research team previously identified other variants in populations living at high altitudes, such as in Tibet.
Meanwhile, investigators in that study also found that the NFKB1 gene regulates inflammation, a characteristic of many conditions including myeloproliferative neoplasms. Typically, this gene correlates with increased inflammation; however, investigators found that the T allele had a protective effect by suppressing inflammatory gene expression when under inflammatory stress.
In the study presented at the late-breaking abstract session Tuesday, investigators assessed an association between NFKB1 genotype and the likelihood of achieving a return to normal blood counts after treatment with Besremi. They also studied the expression of genes involved in inflammation and other molecular pathways related to polycythemia vera and essential thrombocythemia.
Prchal and colleagues found that the C/T genotype was more prevalent among patients who achieved complete hematological response after treatment compared to those who did not achieve that treatment outcome. This suggested to researchers that the NFKB1 haplotype might impact therapy efficacy and serve as a potential biomarker of response in patients with these conditions.
Among patients with complete hematological response, 58.6 percent had the C/T genotype, 6.9 percent had the T/T genotype, and 34.5 percent had the C/C genotype. For patients who did not achieve this outcome, one-third of patients were C/T, 22.2 percent were T/T, and 44.4 percent were C/C. Additional research is needed into differences between the C/T and T/T genotypes, and whether this information could be used to further inform treatment decisions, researchers said.
Investigators suspect that patients with the T allele may tolerate treatment better on account of experiencing reduced inflammatory gene expression. Investigators found that the presence of the T allele correlated with decreased inflammatory activity compared to patients without the variant. In addition to chronic inflammation, patients with polycythemia vera and essential thrombocythemia are also at risk of blood clots, but the C/T genotype was associated with decreased prothrombotic activity, as well.
"These novel insights offer valuable implications for both of our understanding of inflammatory and prothrombotic processes and may also lead to novel [polycythemia vera] and [essential thrombocythemia] therapies," researchers wrote in the abstract.
To measure inflammatory and prothrombotic activity, investigators assessed the expression of relevant genes, for example, prothrombotic genes such as F3, THBD, SELP, and SERPINE1. They found that many of these transcripts were significantly lower for patients with the C/T genotype compared to those with the C/C genotype.
Now, the research team wants to establish in a larger cohort of patients whether these findings on inflammatory and other biomarkers correlate with the expected clinical symptoms, that is, whether patients with the T allele have a decreased risk of blood clots and other poor outcomes.
Investigators are also interested in studying the implications of this variant in other conditions characterized by inflammation, such as in autoimmune diseases.
An area they're planning to study next is graft-versus-host disease (GVHD), a complication of allogeneic transplants driven by inflammation. They're curious whether patients with this particular genetic variant are likely to not experience GVHD or have less severe symptoms.
"We speculate … if you inherit [this gene], you will do much better after transplantation," Prchal said. But "it remains to be proven," he added.