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Clinical Trial
. 2021 Jan 21;137(3):387-391.
doi: 10.1182/blood.2020005792.

Germline genetic factors influence the outcome of interferon-α therapy in polycythemia vera

Roland Jäger  1 , Heinz Gisslinger  2 , Elisabeth Fuchs  3 , Edith Bogner  3 , Jelena D Milosevic Feenstra  4 , Jakob Weinzierl  1 , Fiorella Schischlik  3 , Bettina Gisslinger  2 , Martin Schalling  2 , Michael Zörer  5 , Kurt Krejcy  5 , Christoph Klade  5 , Robert Kralovics  1   3
Affiliations
Clinical Trial

Germline genetic factors influence the outcome of interferon-α therapy in polycythemia vera

Roland Jäger et al. Blood. .

Abstract

Interferon-α (IFN-α)-based treatments can induce hematologic and molecular responses (HRs and MRs, respectively) in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have been implicated in differential drug responses. We addressed the effect of common germline polymorphisms on HR and MR after treatment of PV in the PROUD-PV and CONTINUATION-PV studies in a total of 122 patients who received ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over a 36-month follow-up did not reveal any associations at the level of genome-wide statistical significance. Furthermore, we performed targeted association analyses at the interferon lambda 4 (IFNL4) locus, well known for its role in hepatitis C viral clearance and recently reported to influence HR during treatment of myeloproliferative neoplasms. We did not observe any association of IFNL4 polymorphisms with HR in our study cohort; however, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair, including the protein-coding variants rs368234815/rs117648444) on MR (P = 3.91 × 10-4; odds ratio, 10.80; 95% confidence interval, 2.39-69.97) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of patients with PV based on IFNL4 functionality may allow for optimizing patient management during IFN-α-based therapy.

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Conflict of interest statement

Conflict-of-interest disclosure: R.K. has received honoraria from and served on the advisory board of AOP Orphan Pharmaceuticals AG; has received honoraria from Pharma Essentia; and has equity ownership in MyeloPro Diagnostics and Research GmbH. H.G. has been a consultant to and received honoraria and research funding from AOP Orphan Pharmaceuticals AG; has received honoraria from Novartis, Celgene, and Janssen-Cilag; has been a consultant to Roche, MyeloPro Diagnostics and Research GmbH; and has received personal fees from PharmaEssentia. M.Z., K.K., and C.K. are employed by AOP Orphan Pharmaceuticals AG. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Germline genetic variation within the protein-coding region of IFNL4 affects MR during IFN-α treatment of PV. (A) Genomic organization of the IFNL locus on human chromosome 19q13.2. (B) An association plot derived from GWAS performed for MR after a 12-month follow-up of ropeg treatment (n = 102 patients). The plot is representative of all GWAS performed on both HR and MR data after a 12-, 18-, 24-, 30-, and 36-month follow-up. (C) Longitudinal P values for the association of the IFNL4 tagSNP rs12979860 with response to ropeg over a 36-month follow-up (FU). (D) Fraction (%) of MRs in the 3 main functional categories: patients who produced no functional IFNL4 (no IFNL4), those who produced impaired IFNL4-S70 (IFNL4-S70 alone+IFNL4-S70/P70), and those who produced fully functional IFNL4-P70 alone. Numbers within the bars represent total patients in the categories. (E) JAK2V617F mutant allele burden changes (absolute change from baseline value) at a 36-month follow-up in patients stratified according to IFNL4 diploid functional status. N, no IFNL4; S, IFNL4-S70; P, IFNL4-P70.
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Comment in

  • IFN: Jekyll and Hyde.
    Plo I, Vainchenker W. Plo I, et al. Blood. 2021 Jan 21;137(3):291-293. doi: 10.1182/blood.2020008560. Blood. 2021. PMID: 33475740 No abstract available.

References

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