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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.

The various plectin isoforms are among the major crosslinking elements of the cytoskeleton. The importance of plectin in epithelia is convincingly supported by the severe skin blistering observed in plectin-deficient humans and mice. Here, we identified plectin 1a (> 500 kDa), a full length plectin variant containing the sequence encoded by the alternative first exon 1a, as the isoform most prominently expressed in human and mouse keratinocytes. In skin sections and cultured keratinocytes, plectin 1a was shown to colocalize with hemidesmosomal structures. In contrast, a second isoform expressed in epithelia, plectin 1c, differing from 1a merely by a short N-terminal sequence, colocalized with microtubules. Expression of plectin 1a, but not of its N-terminal fragment alone, or of a third alternative full length isoform (plectin 1), restored the reduced number of hemidesmosome-like stable anchoring contacts in cultured plectin-null keratinocytes. Our results show for the first time that different isoforms of a cytolinker protein expressed in one cell type perform distinct functions. Moreover, the identification of plectin 1a as the isoform defects in which cause skin blistering in plectin-related genetic diseases, such as epidermolysis bullosa simplex MD and epidermolysis bullosa simplex Ogna, could have implications for the future development of clinical therapies for patients.

Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, composed of mainly one isoform, resulting in longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design Efficacy and safety data are being collected in the follow-up extension stage of the study (collecting the data of both Phase I and Phase II portions of the study), after the maximum tolerated dose (MTD) of ropeginterferon alfa-2b, administered subcutaneously every 14 to 28 days, has been defined earlier. Patients with confirmed diagnosis of PV, age ≥18 years, both naïve and cytoreductively pre-treated were eligible. After establishing the MTD, an extended cohort of 25 additional patients has been planned to be recruited. Complete hematological response (CR) is defined by hematocrit (Hct)400*109/L) platelet count, or reduction of phlebotomy requirements by at least 50%. Complete molecular response has been defined as reduction of any molecular abnormality to undetectable levels; partial molecular response as: reduction ≥ 50% in patients with < 50% mutant allele burden, or a reduction ≥ 25% in patients with > 50% mutant allele burden. The present analysis was focused on long-term tolerability and safety in correlation with the dose of ropeginterferon alfa-2b in PV. Results Data on treatment as by July, 24, 2015, are covered by the current analysis. Baseline characteristics of the study cohort during short-term treatment were already presented earlier (Gisslinger et al, ASH 2013). The full analysis set and efficacy set were composed of 51 and 47 patients, respectively. Currently, the median reported treatment duration is 138 weeks, 33 patients completed their follow up for two years, 19 for three years. Starting with the week 10, Hct-level, platelet- and WBC-counts could be constantly maintained within normal range in the majority of patients. In a group of patients with the mean administered dose of 300 µg, n=11) group of 8 (73%) and 3 (27%) respectively. However, no statistical significance can be observed if correlation between the dose and response status was analyzed. 30 patients are still being treated in the study. Similarly, no association between the dose and occurrence of adverse events in the study could be observed. Complete molecular response as best individual response was observed more frequently in the high dose group 4 (36%) compared to 8 (23%) in the low dose group, while partial molecular responses were equally frequent in both dose groups (in 6/55% and 20/57%, respectively). 21 patients discontinued the study, 18 being treated with AOP2014 doses corresponding to low, and 3 to the high dose arms, corresponding to the drop-out rate of 50% and 27% in the respective arms. Interestingly, all discontinuations in the high dose group occurred within the first year of treatment (at weeks 16, 18 and 32), while the drop-outs in the low dose group (6 patients, 33%) discontinued the study after completion of their first year of treatment. Conclusions Efficacy and safety profile remain in line with expectations from other (pegylated) interferons. Overall response rate of >80% with cumulative CRs in 45-50%, accompanied by phlebotomy independence, normalization of hematological parameters and spleen size reduction in majority of patients have been observed. Significant and sustained JAK2 allelic burden decrease, starting from week 28 of treatment, was seen. No significant difference between the two mean dose levels regarding response rates or adverse events even during long-term treatment and observation could be observed. These finding are to be further verified in a larger prospective setting. Disclosures Gisslinger: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Janssen Cilag: Honoraria, Speakers Bureau. Buxhofer-Ausch:AOP Orphan: Research Funding. Thaler:AOP Orphan: Research Funding. Schlögl:AOP Orphan: Research Funding. Gastl:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Research Funding. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Willenbacher:COMET Center ONCOTYROL: Research Funding; AOP Orphan: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Zörer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Pfizer: Honoraria, Research Funding; GSK: Research Funding; Boehringer-Ingelheim: Honoraria; AOP Orphan: Research Funding; Celgene: Consultancy; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ratiopharm: Research Funding; Sanofi Aventis: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Roche, Celgene: Honoraria, Research Funding.

Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, consisting predominantly of only one isoform, leading to longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design The PEGINVERA study (NCT01193699) is the phase I/II single arm dose escalation study with cohort extension after defining the MTD. 51 patients with PV who could be either cytoreduction therapy naive or pre-treated were included. Ropeginterferon alfa-2b was administered subcutaneously in a dose range of 50-540 µg every two weeks. Main objectives were definition of the maximum tolerated dose as well as observation long term safety and efficacy in terms of normalization of blood parameters and molecular abnormalities. The option to switch to an "once every four weeks" schedule has been implemented by the amended protocol for patients who responded well to the treatment and participated in the study for longer than one year. The dose of the study drug had to remain unchanged after the switch, resulting in a decrease of the overall exposure to the drug. Outcomes of this switch are presented here. Results 44 patients (period A, median exposure duration 37 weeks, mean monthly dose 505 µg), eligible for the analysis, i.e. being treated in the maintenance setting, were dosed every two weeks based on the Phase II dosing rules prior the amendment. 33 patients (period B, median exposure duration 12 weeks, mean monthly dose 432 µg) were dosed every two weeks beyond the first year and, showing benefit from treatment, have been assessed as eligible for the switch. 28 patients (period C, median exposure duration 93 weeks) were then switched to dosing once every four weeks (mean monthly dose 203 µg). Blood parameters were normalized and remained stable following one year of treatment and could be maintained after the switch (hematocrit, median in % - period A: 42.7, period B: 42.9, period C: 42.8; WBC, median in G/l - period A: 5.6, period B: 5.3, period C: 5.8; platelets, median in G/l - period A: 252, period B: 217, period C: 210). Spleen length stayed stable within the normal range following the switch in the majority of patients (mean, in cm - period A: 11.6, period B: 8.8, period C: 11.1). Complete hematological response could be maintained in 57% of patients in period A, in 38% of patients in period B and in 50% of patients in period C, while for partial hematological responders the results were 71%, 54% and 57%, respectively. Molecular response improved continuously over time, being maintained at the best individual level in 38% of period A patients, compared to 53% of period B and 69% of period C patients. Comparison of patient discontinuations between the arms revealed the following rates: 5(11%) in the period A, 5(15%) in the period B and 3(11%) in the period C, while the mean numbers of adverse events per patient treatment week was 0.15, 0.27 and 0.09 respectively. There were no new drug-related SAEs occurring in the period C. Conclusions This explorative data re-confirm the feasibility to administer ropeginterferon alfa-2b once every four weeks, while efficacy was maintained compared to the biweekly application schedule. Reduced injection frequency is not associated with a lack or loss of response, but clearly improves tolerability. Finally, continuous reduction of the JAK2 allelic burden indicates that duration of interferon treatment rather than the absolute dose level is an important variable inducing molecular responses. The here presented findings support the idea that interferon alpha effects in PV are pleiotropic, such as induction of immune-surveillance, which may be sufficiently maintained also at lower ropeginterferon alfa-2b levels. Disclosures Buxhofer-Ausch: AOP Orphan: Research Funding. Gisslinger:Geron: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Sanofi Aventis: Consultancy. Thaler:AOP Orphan: Research Funding. Schlögl:AOP Orphan: Research Funding. Gastl:AOP Orphan: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria; Novartis: Honoraria; AOP Orphan Pharmaceuticals: Honoraria, Research Funding. Willenbacher:AOP Orphan: Research Funding. Zörer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Celgene: Consultancy; Pfizer: Honoraria, Research Funding; Roche, Celgene: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Ratiopharm: Research Funding; AOP Orphan: Research Funding.