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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.

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Summary. Background:Little information is available on the long‐term clinical outcome of cerebral vein thrombosis (CVT).

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Kiladjian: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Klade:AOP Orphan Pharmaceuticals AG: Employment. Illés:Takeda, Seattle: Research Funding; Janssen, Celgene, Novartis, Takeda, Roche, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Krejcy:AOP Orphan Pharmaceuticals AG: Employment. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. Kralovics:Pharma Essentia: Honoraria; MyeloPro Diagnostics and Research: Equity Ownership; AOP Orphan Pharmaceuticals AG: Honoraria, Other: Advisory board; Qiagen: Honoraria; Novartis: Honoraria. Gisslinger:Celgene GmbH: Honoraria; Pharma Essentia: Other: Personal fees; Roche Austria GmbH: Consultancy; Janssen-Cilag: Honoraria; Novartis Pharma GmbH: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Honoraria, Research Funding; Myelopro GmbH: Consultancy.

Background:Interferon-alpha (IFN) is being used in myeloproliferative neoplasms (MPNs) since years and remains the only known treatment with disease-modifying potential. Ropeginterferon alfa-2b (Ropeg) is a novel mono-pegylated IFN, with reduced dosing frequency and improved tolerability. Here, we report 3 years clinical data from the phase III PROUD/CONTI-PV trials with an additional emphasis on the first comprehensive, prospective, randomized, controlled genomic profiling including not only JAK2V617F, but longitudinal targeted sequencing to identify non-JAK somatic mutations and chromosomal aberrations.

Background:Interferon-alpha (IFNa) based therapies have been successfully used in myeloproliferative neoplasms (MPN) for over thirty years. Ropeginterferon alfa-2b (Ropeg) is a novel mono-pegylated IFNa, which is administered once every 2 weeks, or monthly during long-term maintenance. Ropeg is developed in polycythemia vera (PV), and 12-month data from the randomized controlled phase III PROUD-PV study comparing Ropeg with hydroxyurea (HU) have been presented. Here we report 2 years treatment data obtained from the follow-up phase III CONTI-PV study.

Gisslinger: AOP Orphan Pharmaceuticals AG, Novartis, Celgene, Baxalta: Consultancy, Honoraria, Research Funding. Klade:AOP Orphan: Employment. Georgiev:Alnylam Pharmaceuticals: Consultancy. Illes:University of Debrecen faculty of medicine department of hematology: Employment. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Research Funding; AOP Orphan: Research Funding.

Recent studies of prognostic parameters in Ph- myeloproliferative neoplasms with thrombocythemia (MPN-t) indicate that WBC counts at diagnosis, rather than platelet (Plt) counts, determine the risk of thrombosis. We have studied these and other risk parameters in our patient cohort.843 prospectively assigned patients from the Czech segment of the International registry of patients treated with anagrelide (ANG; Thromboreductin®) were studied. The male: female ratio was 2:3, the median age was 51 (0–96) years. The majority of patients (68.1%) was pretreated by other cytoreducing drugs. According to PVSG criteria, the diagnoses were the following: essential thrombocythemia – 569, primary myelofibrosis – 155, polycythemia vera – 92, or other – 27 patients. Data from the time of diagnosis, from the time of registry entry (at the start of ANG therapy) and from the time of the thrombotic event were evaluated. The median follow-up since registry entry was 33 (0–117) months and the follow-up comprised 2505 patient-years. All patients were treated with ANG and in 80% of follow-up reports, acetylsalicylic acid (ASA) was mentioned to be given in parallel. In 18% of entries (from registration and follow-up), administration of another cytoreducing drug (mainly hydroxyurea or interferon) in combination with ANG was noted.Of 449 thrombotic events reported, 335 occurred in history (i.e. before registry entry) and 114 during follow-up. The numbers of arterial, venous, and microcirculatory events in history were 147, 124 and 64, respectively. Of the 114 thrombotic events in 88 patients during follow-up (3.79 events/100 patient-years), 45 were classified as major. There were 61 arterial, 16 venous and 37 microcirculatory events. ANG ± ASA therapy dramatically decreased the number of venous events (7.8-fold), while arterial and microcirculatory events were reduced 2.4-fold and 1.7-fold, respectively.At diagnosis, the strongest predictors of all thrombotic events jointly were JAK2 V617F mutation (P=0.001), hereditary or acquired thrombophilia (P<0.001), hypertension (P=0.006), smoking (P=0.02) and diabetes mellitus (P=0.04). Also previous thrombosis predicted a subsequent thrombotic event (P=0.002). Age >65 yrs was a less powerful predictor (P=0.08). WBC and hematocrit levels positively correlated with the thrombotic risk (P=0.002 and P=0.006, respectively), whereas Plt counts correlated inversely with all thrombotic events (P=0.012) but correlated positively with microcirculatory events (P=0.01). Some of the factors (age, hypertension, diabetes, and smoking) powerfully predicted rather arterial events, whereas others (f.V “Leiden” mutation, protein C deficiency, elevated f.VIII levels, presence of antiphospholipid antibodies) were connected preferentially with venous events.However, when full blood cell counts from the time of the thrombotic events were studied and compared to mean levels of all entries during follow-up, we could detect higher platelet counts at the time of the thrombotic event (454 vs 420 G/L, P=0.007), while we could not demonstrate any significance of the WBC counts at the time of the event. The correlation of the Plt count was marked in all types of events and was most conspicuous in microcirculatory events. Thrombotic events during follow-up were also associated with lack of ASA therapy: only 6/16 (37.5%) patients at the time of the venous event, 35/61 (57.4%) patients at the time of the arterial event and 11/37 (29.7%) patients at the time of the microcirculatory event received ASA therapy (whereas ASA administration was reported in 80.0% of follow-up entries).The current study indicates that during ANG ± ASA therapy, the incidence of thrombosis is very low in MPN-t and especially the rate of venous events is extraordinarily low. The predictors of the thrombotic events are similar as previously published by others. Above that, we have proven the usefulness of detection of the so-called thrombophilic states. However, in contrast with the prevailing current opinion, we have shown that higher platelet counts (and not WBC counts) are important at the time of thrombosis, albeit at diagnosis the Plt counts may inversely and WBC counts positively correlate with the thrombotic risk. This discrepancy may result from treatment: patients with higher Plt counts at diagnosis may receive more cytoreducing and/or antiaggregation therapy.Schwarz: AOP Pharmaceuticals: Consultancy.

OBJECTIVES: Bleeding and thrombotic events are common complications symptoms in myeloproliferative diseases with thrombocythemia (MPD-T). The increased platelet count need not be the only cause of them. In the current study we have evaluated prospectively collected data of 421 Czech patients from an international registry of patients treated with anagrelide (ANG) with the aim to check whether JAK2 V617F mutation or additional thrombophilic states predispose to thrombosis in MPD-T. PATIENTS: The initial diagnoses (recorded largely according to PVSG criteria) were the following: essential thrombocythemia – 333 (79.1 %), idiopathic myelofibrosis – 40 (9.5%), polycythemia vera – 35 (8.4 %) and chronic myeloid leukemia – 8 (1.9%). The age at diagnosis and at database entry has rankged between 40 – 60 years in more than 50% of patients (mean: 51.0 years). The male/female ratio was 37.5: 62.5%. A large proportion of patients (77.7%) had been already pretreated with thromboreducing drugs: overall, 55 patients had received ANG, 84 had had interferon-alpha, 208 had been treated with hydroxyurea and 59 patients had received another drug. More than one line of previous thromboreductive therapy was recorded in 155 (36.8%) patients. Following registration, 18.0% was receiving another thromboreducing drug in addition to ANG. The median platelet value was 1015 G/l at diagnosis, and 658 G/l (range 140–3325) at database entry. The treatment goal was achieving 600/400 G/l platelets in low-/high-risk patients. High-risk patients had either previous thrombosis, an additional thrombophilic state (mostly inherited; “thrombophilia+”), or JAK2 gene V617F mutation. RESULTS: Pretreated and unpretreated patients responded to ANG equally well. High-risk patients had lower platelet counts at 3–6–9–12–36 months – 488–400–387–376–323 G/l (n=118) than good-risk ones – 523–441–384–423–455 G/l (n=98) at the given above time points. The mean ANG dose at 3 months was only 1.8 mg/day (median, 1.5 mg/d), whereas onwards, the mean dose was quite stable within 2.2–2.3 mg/day interval (median, 2.0 mg/d). At the time of database entry, 75 (17.8%) patients had a history of a thrombotic event, and 35 (8.3%) had had hemorrhage. During the follow-up after entering the registry, only 11 (3.5%) patients had thrombosis (6 had a major and 5 a minor one). Likewise, there have been very few patients with a bleeding event reported: 2 patients experienced a major and 4 patients a minor event (altogether 1.9% of patients). 282 patients had the JAK2 mutation evaluated. Half of them (51.4% patients) carried the mutation (hetero-/homozygous). Of the 145 patients with the mutation, 40 (27.6%) had thrombosis (before or after registration). Thrombosis was significantly more rare in 137 patients without the mutation, in 11 cases only (8.0%; P = 0.017, Fisher’s test, CI 95%). Of 78 evaluable patients with thrombosis, 20 (25.6%) were thrombophilia+, whereas of 343 patients without thrombosis, a thrombophilia+ state was demonstrated only in 48 cases (14.0%; P = 0.016). CONCLUSIONS: Our analysis has shown that high-risk MPD-T patients treated with ANG do not achieve the desired level of thromboreduction quite late: after 3–6 months of ANG treatment. However, during ANG treatment, relatively very few hemorrhagic or thrombotic complications were observed. The results confirmed in a large patient cohort that JAK2 mutation or additional thrombophilic states are major risk factors of thrombosis in MPD-T.