The presence of the NFKB1 rs230511 haplotype improves response to ropeginterferon alfa-2b (Besremi) in patients with polycythemia vera (PV) and essential thrombocythemia (ET), according to research presented at the 2024 ASH Annual Meeting. The study, led by Jihyun Song, PhD, from the University of Utah Huntsman Cancer Institute, suggests that NFKB1 rs230511 reduces inflammation and amplifies responses to ropeginterferon alfa-2b in PV and ET.
Study Details and Findings
The study included 30 patients with PV and 15 with ET. Researchers found that the NFKB1 rs230511 haplotype was more common among patients who experienced a complete hematologic response (CHR) to ropeginterferon alfa-2b treatment (58.6%) compared with those who did not (33.3%; P < .0001). CHR was defined as a white blood cell count of less than 10,000/uL, hematocrit levels less than 49%, and a platelet count of less than 400,000/uL. Patients with cytopenia were classified as not having a CHR.
Background on PV and ET
PV and ET are caused by mutations in hematopoietic stem cells. PV leads to high hemoglobin levels, while ET is marked by an increase in platelet count. While PV is often linked to gain-of-function mutations in JAK2, ET can be caused by mutations in JAK2, CALR, and/or MPL. Both disorders result in hyperactive JAK-STAT pathway signaling, which increases the expression of inflammatory genes. Chronic inflammation is a key feature of both PV and ET, increasing disease severity.
Role of NFKB1 in Inflammation
JAK inhibitors do not completely normalize elevated inflammation in PV and ET, suggesting that other pathways beyond the JAK-STAT pathway contribute to chronic inflammation. NFKB1 plays a central role in inflammation as a master regulator in PV and ET, as this pathway is activated in these diseases.
Ropeginterferon Alfa-2b and its Approval
Ropeginterferon alfa-2b was approved by the FDA in November 2021 for the treatment of adult patients with PV. The approval was based on the phase 1/2 PEGINVERA study (NCT01193699), which showed a CHR rate of 61% among patients treated with the interferon therapy (n = 51). Ropeginterferon alfa-2b is notable as the first agent approved for PV that patients can receive irrespective of their treatment history.
Genetic Variants and Inflammation
To identify genetic variants associated with high altitude adaptation, researchers analyzed data from Andean, Ethiopian, and Tibetan populations. They found that Andean individuals exhibited higher hemoglobin levels compared with sea level and high-altitude European populations. Whole transcriptome analysis of granulocytes from Aymaran and European individuals living at high altitude revealed that most dysregulated genes were involved in the inflammatory pathway, including the NF-KB pathway.
NFKB1 Splice Variants and Allele Expression
Whole transcriptional analysis identified three novel alternatively spliced transcripts of NFKB1 (AS- NFKB1). These AS- NFKB1 transcripts were observed at higher levels among the Aymaran individuals compared with the European individuals. The NFKB1 rs230511 allele was more common in Aymaran (87.8%) and Quechuan (76%) individuals compared to Tibetan (36.4%), Han Chinese (38.8%), European (33.4%), and Yoruban (0.9%) individuals.
Impact on Inflammatory Gene Expression
AS- NFKB1 and NFKB1 rs230511 were positively correlated with IL-6 and IFN-γ levels. NFKB1 splice variants reduced NFKB1 translocation compared with canonical NFKB1. Overexpression of NFKB1 splice variants induced inflammatory gene expression, and the NFKB1 variants decreased inflammatory gene expression under inflammatory stress from TNF treatment.
Clinical Implications
Patients who did not experience a CHR had the C/C and T/T genotypes at rates of 44.44% and 22.22%, respectively, while those who achieved a CHR had respective rates of 34.48% and 6.90%. Individuals with the C/T or T/T genotype also displayed significantly lower inflammatory gene expression compared with those with the C/C genotype.
These findings suggest that NFKB1 could serve as a biomarker for treatment response in PV and ET, with the presence of the NFKB1 rs230511 haplotype indicating a higher likelihood of achieving a complete hematologic response with ropeginterferon alfa-2b treatment.
