Germline polymorphisms can affect response to treatment in people with polycythemia vera (PV). A diplotype in IFNL4 is significantly linked to molecular response, which suggests that interferon alpha (IFNα) may directly affect JAK2V617F burden, according to research published in Blood.

IFNα-based therapies produce durable molecular responses in some patients, while others have a limited response. Using data from the PROUD-PV (ClinicalTrials.gov Identifier: NCT01949805) and CONTINUATION-PV (CONTI-PV; ClinicalTrials.gov Identifier: NCT02218047) studies, the authors assessed the effects of common germline polymorphisms on hematologic response and molecular response.

A germline variation at the interferon lambda 4 (IFNL4) locus has affected IFNα therapy response and viral clearance in patients with hepatitis C. The authors performed genome-wide association studies on 122 patients treated with ropeginterferon alfa-2b (ropeg) and focused on the role IFNL4 polymorphisms may have on response. After a 36 month follow-up, the investigators noted that longitudinal data on hematologic and molecular responses did not result in significant genome-wide associations.

“These results indicate that all patients with PV may be eligible for ropeg therapy independent of their genetic makeup,” the authors wrote.


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The authors also performed analysis on 4 IFNL4 variants that have an effect on treatment response in hepatitis C patients: 2 noncoding tagging single-nucleotide polymorphisms (tagSNPs), rs8099917 and rs12979860, and 2 coding diplotype variants, rs368234815 and rs117648444. The variants had no effect on hematologic response, but they did affect molecular response.

The authors examined 5 patients with the rs368234815/rs117648444 diplotype and categorized them based on IFNL4 functional status. Functional IFNL4 seems to reduce the durability of patients’ molecular response. Patients with no IFNL4 had a stronger molecular response compared with patients with the IFNL-P70 protein variant (89.3% vs 42.3%; odds ratio, 10.80; P =3.91 x 10-4).

The authors suggest that the influence of IFNL4 diplotype status on molecular response may be due to the effect of ropeg treatment on JAK2V617F burden, the mutation that drives most cases of PV.

“As deep [molecular response] is indispensable when aiming for curative therapy, it will be important to investigate whether increased treatment duration can overcome the dampening effect of functional IFNL4 on [molecular response],” the authors wrote. Future research may further evaluate the role of genetic predisposition on response to IFNα therapy for PV.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Jäger R, Gisslinger H, Fuchs E, et al. Germline genetic factors influence outcome of interferon alpha therapy in polycythemia vera. Blood. Published August 19, 2020. doi:10.1182/blood.2020005792