Ropeginterferon alfa-2b, nejnovější přípravek ze skupiny pegylovaných forem interferonu, prokázal jako jediný z dostupných léčivých přípravků schopnost dosáhnout nejen hematologické, ale i molekulární odpovědi u vysokého procenta pacientů s pravou polycytemií. V randomizovaných multicentrických studiích PROUD-PV a CONTINUATION-PV byla prokázána dlouhodobá superiorita tohoto přípravku v účinnosti, ale i bezpečnosti ve srovnání s hydroxyureou. Na základě těchto předností byla terapie ropeginterferonem alfa-2b zařazena do první linie terapie pacientů s pravou polycytemií nízkého rizika i podle nejnovějších doporučení European Leukemia Net z roku 2021.

Ropeginterferon alfa-2b, the newest form of pegylated interferon, evinced as the only one with potential to achieve hematological and molecular response in substantial proportion of patients with polycythaemia vera. Multicentric randomized studies PROUD-PV and CONTINUATION-PV have shown its long-term superiority in the efficacy and safety when comparing with hydroxyurea. Based on these benefits the newest 2021 European Leukemia Net guidelines recommend ropeginterferon alfa-2b as first line therapy of patients with low-risk polycythemia vera.

• Keywords
• studie PROUD‐PV, studie CONTINUATION‐PV, Ropeg-IFN,
• MeSH
• Cell Aggregation genetics   drug effects   MeSH
• Hematologic Tests MeSH
• Interferon alpha-2 adverse effects   therapeutic use   MeSH
• Humans MeSH
• Multicenter Studies as Topic MeSH
• Mutation MeSH
• Myeloproliferative Disorders MeSH
• Polycythemia Vera * diagnosis   complications   therapy   MeSH
• Polyethylene Glycols therapeutic use   MeSH
• Randomized Controlled Trials as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Practice Guideline MeSH

Úvod: Ropeginterferon alfa-2b (RopegIFN) prokázal účinnost a bezpečnost u pacientů s pravou polycytémií v multicentrických randomizovaných studiích PROUD-PV a CONTINUATION-PV. Během 4.–5. roku terapie byl prokázán jednoznačný benefit terapie RopegIFN ve srovnání s nejlepší dostupnou terapií, a to jak ve smyslu dosažení kompletní hematologické remise onemocnění, tak i výrazného snížení mutační alelické zátěže JAK2V617F. Materiál a metodika: Retrospektivní neintervenční analýza byla provedena u celkem 14 pacientů s Ph negativními myeloproliferacemi (Ph-MPN) léčených RopegIFN na Interní hematologické a onkologické klinice (IHOK) v období od května 2020 do července 2022. Hodnocena byla data týkající se délky terapie, dávkování, efektu a tolerance terapie. Výsledky: Medián délky terapie v souboru byl 266 dní. Léčeno bylo celkem 14 pacientů, z toho 11 s pravou polycytémií (79 %), 2 s esenciální trombocytémií (14 %) a 1 se sekundární myelofibrózou po pravé polycytémii (7 %). Medián dávky RopegIFN byl 150 μg. Dosažení kompletní hematologické remise bylo u 11 pacientů (79 %). Terapie byla během doby sledování ukončena u 2 pacientů (14 %). Nežádoucí účinky byly zaznamenány u 6 pacientů (43 %), tromboembolická příhoda byla dokumentována u jednoho pacienta (7 %). Závěr: Naše analýza prvotních zkušeností s terapií RopegIFN potvrdila jeho velmi dobrý efekt na kontrolu hematokritu a zároveň výbornou toleranci u pacientů s Ph-MPN.

Background: Ropeginterferon alfa-2b demonstrated efficacy and safety in patients with polycythaemia vera in the PROUD-PV and CONTINUATION-PV multicentric randomised studies. These studies reported the superior effect of ropeginterferon alfa-2b in attaining haematological and molecular remission during the fourth and fifth year of therapy. Patients and Methods: A total of 14 Ph-MPN patients treated with ropeginterferon alfa-2b at our Dept. of Internal Medicine – Haematology and Oncology were analysed from May 2020 to July 2022. Therapy duration, dosing, effect, and tolerance were evaluated. Results: Therapy median duration was 266 days. 14 patients in total were treated; 11 had polycythaemia vera (79%), 2 had essential thrombocythemia (14%), and one patient had secondary myelofibrosis post polycythaemia vera (7%). The median ropeginterferon alfa 2-b dose was 150 μg. Complete haematological remission was attained in 11 (79%) patients. Two patients (14%) had to discontinue treatment. During therapy, six patients (43%) suffered adverse events; only one patient (7%) developed a thromboembolic event. Conclusion: Our initial experience has confirmed the promising effect of ropeginterferon alfa 2-b on haematocrit control and its excellent tolerance among patients.

• Keywords
• Ph negativní myeloproliferativní onemocnění, ropeginterferon alfa‐2 b,
• MeSH
• Interferon alpha-2 pharmacology   therapeutic use   MeSH
• Interferons pharmacology   therapeutic use   MeSH
• Humans MeSH
• Myeloproliferative Disorders * drug therapy   MeSH
• Polycythemia Vera * drug therapy   MeSH
• Randomized Controlled Trials as Topic MeSH
• Retrospective Studies MeSH
• Check Tag
• Humans MeSH

The main goal of the present study was to evaluate the effects of different blood flow restriction (BFR) protocols (continuous and intermittent) on peak bar velocity (PV) and mean bar velocity (MV) during the squat exercise at progressive loads, from 40 to 90% 1RM. Eleven healthy men (age = 23.4 ± 3.1 years; body mass = 88.5 ± 12.1 kg; squat 1RM = 183.2 ± 30.7 kg; resistance training experience, 5.7 ± 3.6 years) performed experimental sessions once a week for 3 weeks in random and counterbalanced order: without BFR (NO-BFR), with intermittent BFR (I-BFR), and with continuous BFR (C-BFR). During the experimental session, the participants performed six sets of the barbell squat exercise with loads from 40 to 90% 1RM. In each set, they performed two repetitions. During the C-BFR session, the cuffs were maintained throughout the training session. During the I-BFR, the cuffs were used only during the exercise and released for each rest interval. The BFR pressure was set to ∼80% arterial occlusion pressure (AOP). Analyses of variance showed a statistically significant interaction for MV (p < 0.02; η2 = 0.18). However, the post hoc analysis did not show significant differences between particular conditions for particular loads. There was no significant condition × load interaction for PV (p = 0.16; η2 = 0.13). Furthermore, there were no main effects for conditions in MV (p = 0.38; η2 = 0.09) as well as in PV (p = 0.94; η2 = 0.01). The results indicate that the different BFR protocols used during lower body resistance exercises did not reduce peak bar velocity and mean bar velocity during the squat exercise performed with various loads.

• Publication type
• Journal Article MeSH

This study evaluated the effects of continuous and intermittent blood flow restriction (BFR) with 70% of full arterial occlusion pressure on bar velocity during the bench press exercise against a wide range of resistive loads. Eleven strength-trained males (age: 23.5 ± 1.4 years; resistance training experience: 2.8 ± 0.8 years, maximal bench press strength - 1RM = 101.8 ± 13.9 kg; body mass = 79.8 ± 10.4 kg), performed three different testing protocols in random and counterbalanced order: without BFR (NO-BFR); intermittent BFR (I-BFR) and continuous BFR (C-BFR). During each experimental session, subjects performed eight sets of two repetitions each, with increasing loads from 20 to 90% 1RM (10% steps), and 3 min rest between each set. In the C-BFR condition occlusion was kept throughout the trial, while in the I-BFR, occlusion was released during each 3 min rest interval. Peak bar velocity (PV) during the bench press exercise was higher by 12-17% in both I-BFR and C-BFR compared with NO-BFR only at the loads of 20, 30, 40, and 50% 1RM (p < 0.001), while performance at higher loads remained unchanged. Mean bar velocity (MV) was unaffected by occlusion (p = 0.342). These results indicate that BFR during bench press exercise increases PV and this may be used as an enhanced stimulus during explosive resistance training. At higher workloads, bench press performance was not negatively affected by BFR, indicating that the benefits of exercise under occlusion can be obtained while explosive performance is not impaired.

• Publication type
• Journal Article MeSH

Interferon alfa (IFN‑α) je používán přes 30 let v léčbě myeloproliferativních onemocnění. IFN‑α prokázal schopnost in dukovat klinickou, hematologickou, molekulární a histopatologickou remisi, ale jeho toxicita zůstala limitací jeho širšího užití. Vývoj pegylovaných forem s lepší tolerancí přináší pacientům nové možnosti. Klinické studie fáze 3, ropeginterferon‑α versus hydroxyurea: PROUD‑PV a CONTINUATION‑PV, prokázaly dlouhodobou superioritu v efektivitě a bezpečnosti ve srovnání ropeginterferonu alfa‑2 b s hydroxyureou. Léčebné použití interferonů je nutnou součástí léčebného schématu u mladších rizikových pacientů v 1. linii, ale do současnosti žádný nepegylovaný i pegylovaný interferon neměl v SPC léčbu pacientů s pravou polycytémií. Jako první a jediný získal registraci Ropeginterferon alfa‑2 b (Besremi®) a je dostupný v Evropské unii i v ČR pro léčbu pacientů s pravou polycytémií bez symptomatické splenomegalie.

Interferon alfa (IFN‑α) has been used in the treatment of myeloproliferative disorders for more than 30 years. IFN‑α has been shown to induce clinical, hematological, molecular, and histopathological remission, but its toxicity has remained a limita‑tion of its more widespread use. The development of pegylated forms with a better tolerance has brought new options for patients. Phase III clinical trials, ropeginterferon‑α versus hydroxyurea: PROUD‑PV and CONTINUATION‑PV, have shown long‑term superiority in the efficacy and safety when comparing ropeginterferon alfa‑2 b with hydroxyurea. Therapeutic use of interferons is a necessary part of the treatment regimen in younger at‑risk patients in the first line, but until now, no SPC of a non‑pegylated or pegylated interferon included treatment of patients with polycythemia vera.Ropeginterferon alfa‑2 b (Besremi®) is the first and only one to have obtained registration and is available in the European Union as well as the Czech Republic for the treatment of patients with polycythemia vera without symptomatic splenomegaly.

• Keywords
• studie PROUD‑PV, studie CONTINUATION‑PV, ropeginterferon alfa‑2 b,
• MeSH
• Adult MeSH
• Interferon alpha-2 pharmacology   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Myeloproliferative Disorders * drug therapy   MeSH
• Randomized Controlled Trials as Topic MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH

BACKGROUND: The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment. METHODS: PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing). FINDINGS: Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3-201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4-169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia). INTERPRETATION: In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea. FUNDING: AOP Orphan Pharmaceuticals AG.

• MeSH
• Antiviral Agents therapeutic use   MeSH
• Equivalence Trials as Topic MeSH
• Interferon alpha-2 therapeutic use   MeSH
• Interferon-alpha therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Polycythemia Vera drug therapy   pathology   MeSH
• Polyethylene Glycols therapeutic use   MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Recombinant Proteins therapeutic use   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH

OBJECTIVES: The authors report the first acute clinical experience of atrial fibrillation ablation with PEF-both epicardial box lesions during cardiac surgery, and catheter-based PV isolation. BACKGROUND: Standard energy sources rely on time-dependent conductive heating/cooling and ablate all tissue types indiscriminately. Pulsed electric field (PEF) energy ablates nonthermally by creating nanoscale pores in cell membranes. Potential advantages for atrial fibrillation ablation include: 1) cardiomyocytes have among the lowest sensitivity of any tissue to PEF-allowing tissue selectivity, thereby minimizing ablation of nontarget collateral tissue; 2) PEF is delivered rapidly over a few seconds; and 3) the absence of coagulative necrosis obviates the risk of pulmonary vein (PV) stenosis. METHODS: PEF ablation was performed using a custom over-the-wire endocardial catheter for percutaneous transseptal PV isolation, and a linear catheter for encircling the PVs and posterior left atrium during concomitant cardiac surgery. Endocardial voltage maps were created pre- and post-ablation. Continuous and categorical data are summarized and presented as mean ± SD and frequencies. RESULTS: At 2 centers, 22 patients underwent ablation under general anesthesia: 15 endocardial and 7 epicardial. Catheter PV isolation was successful in all 57 PVs in 15 patients (100%) using 3.26 ± 0.5 lesions/PV: procedure time 67 ± 10.5 min, catheter time (PEF catheter entry to exit) 19 ± 2.5 min, total PEF energy delivery time <60 s/patient, and fluoroscopy time 12 ± 4.0 min. Surgical box lesions were successful in 6 of 7 patients (86%) using 2 lesions/patient. The catheter time for epicardial ablation was 50.7 ± 19.5 min. There were no complications. CONCLUSIONS: These data usher in a new era of tissue-specific, ultrarapid ablation of atrial fibrillation.

• MeSH
• Operative Time MeSH
• Electroporation methods   MeSH
• Endocardium surgery   MeSH
• Atrial Fibrillation surgery   MeSH
• Catheter Ablation methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Pericardium surgery   MeSH
• Prospective Studies MeSH
• Aged MeSH
• Pulmonary Veins surgery   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

AIMS: A challenge of pulmonary vein isolation (PVI) in catheter ablation for paroxysmal atrial fibrillation (PAF) is electrical reconnection of the PV. EFFICAS I showed correlation between contact force (CF) parameters and PV durable isolation but no prospective evaluation was made. EFFICAS II was a multicentre study to prospectively assess the impact of CF guidance for an effective reduction of PVI gaps. METHODS AND RESULTS: Pulmonary vein isolation using a radiofrequency (RF) ablation catheter with an integrated force sensor (TactiCathTM) was performed in patients with PAF. Operators were provided EFFICAS I-based CF guidelines [target 20 g, range 10-30 g, minimum 400 g s force-time integral (FTI)]. Conduction gaps were assessed by remapping of PVs after 3 months, and gap rate was compared with EFFICAS I outcome. At follow up, 24 patients had 85% of PVs remaining isolated, compared with 72% in EFFICAS I (P = 0.037) in which CF guidelines were not used. The remaining 15% of gaps correlated to the number of catheter moves at creating the PVI line, quantified as Continuity Index. For PV lines with contiguous lesions and low catheter moves, durable isolation was 81% in EFFICAS I and 98% in EFFICAS II (P = 0.005). At index procedure, the number of lesions was reduced by 15% in EFFICAS II vs. EFFICAS I. CONCLUSION: The use of CF with the above guidelines and contiguous deployment of RF lesions in EFFICAS II study resulted in more durable PVI in catheter ablation of PAF.

• MeSH
• Equipment Failure Analysis MeSH
• Surgery, Computer-Assisted instrumentation   methods   MeSH
• Equipment Design MeSH
• Adult MeSH
• Atrial Fibrillation diagnosis   surgery   MeSH
• Catheter Ablation instrumentation   methods   MeSH
• Humans MeSH
• Body Surface Potential Mapping instrumentation   methods   MeSH
• Stress, Mechanical MeSH
• Transducers, Pressure MeSH
• Heart Conduction System surgery   MeSH
• Pulmonary Veins surgery   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Controlled Clinical Trial MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH