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Concept: Anagrelide

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Evaluation of Xagrid® Efficacy and Long-term Safety, a Phase IV, prospective, non interventional study performed in 13 European countries enrolled high risk essential thrombocythemia patients treated with cytoreductive therapy. Primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: anagrelide (Xagrid®) (n=804), other cytoreductive therapy (n=2666), anagrelide + other cytoreductive therapy (n=141). Median age was 56 vs 70 years for anagrelide vs other cytoreductive therapy. Event rates (patients with events/100 patient years) were, for total thrombosis 1.62 vs 2.06, venous thrombosis 0.15 vs 0.53. Anagrelide was more commonly associated with hemorrhage (0.89 vs 0.43), especially with anti-aggregatory therapy (1.35 vs 0.33) and myelofibrosis (1.04 vs 0.30). Other cytoreductive therapies were more associated with acute leukemia (AL) (0.28 vs 0.07) and other malignancies (1.29 vs 0.44). Post-hoc multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age ≥65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age ≥65, time since diagnosis, and platelet count increase. Safety analysis reflected published data and no new safety concerns for anagrelide were found. Live births occurred in 41/54 pregnancies (76%). (ClinicalTrials.gov #NCT00567502).

Concepts: Scientific method, Blood, Observational study, Platelet, Multivariate statistics, Essential thrombocytosis, Phase IV, Anagrelide

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Anagrelide is an established therapy for essential thrombocythemia. Common adverse effects have been linked to peak plasma concentrations of anagrelide and its 3OH metabolite. Our study was performed to investigate the pharmacokinetics (PK) of a novel anagrelide extended-release (AER) formulation and its active metabolites. Thirty healthy volunteers were randomized to receive either 2 mg AER (under fasting and fed conditions) or 2 mg commercially available reference product (CARP) in an open-label, 3-way crossover trial with washout periods of 6 days. Plasma concentrations of anagrelide and its active metabolites were assessed by tandem mass spectrometry. The PK differed significantly between all treatment periods. Bioavailability of AER was 55% of the CARP under fasting conditions and 60% under fed conditions. Cmax , AUCt, and AUC∞ were significantly higher and Tmax and T1/2 were significantly shorter after the CARP compared with AER. Food had a significant impact on the PK of AER, increasing the Cmax , Tmax , and AUCt while reducing the T1/2 , plateau, and mean residence time. Both formulations were well tolerated, with a trend toward more frequently occurring adverse events after the CARP. The PK of AER and the CARP differed significantly in all parameters. Food enhanced the bioavailability of AER.

Concepts: Pharmacology, Clinical trial, Nutrition, Mass spectrometry, Food, Pharmacokinetics, Tandem mass spectrometry, Anagrelide

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To evaluate the reduction of thrombotic events (TE) in patients with essential thrombocythaemia (ET) treated with anagrelide versus hydroxyurea + aspirin (HU+ASA).

Concepts: Essential thrombocytosis, Anagrelide

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New treatment options for polycythemia vera (PV) have recently become available. This article reviews current treatment strategies for PV with a focus on anagrelide and ruxolitinib. Areas covered: The current treatment of PV is directed towards reducing the risk of additional thrombotic events. In addition to phlebotomy and aspirin, patients who are believed to have high-risk disease also receive cytoreductive therapy. Hydroxyurea (HU) and PEG-IFN are most commonly used first-line treatments. The use of anagrelide in PV is limited to situations where patient develops thrombohemorrhagic episodes in the setting of extreme thrombocytosis. The role of ruxolitinib in treatment of PV has not been fully established but based on a recently completed Phase III trial it will likely serve as a second-line option for patients with systemic symptoms. Expert opinion: HU and PEG-IFN are frontline therapies for patients with high-risk PV. Anagrelide use should be restricted to patients with clinical consequences of extreme thrombocytosis. Ruxolitinib is a treatment option for patients who fail frontline therapies. However, long-term effects and toxicities are not yet fully known.

Concepts: Clinical trial, Patient, Therapy, The Current, Antineoplastic drugs, Polycythemia vera, Anagrelide, Hydroxycarbamide

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Anagrelide represents a treatment option for essential thrombocythemia, although its place in therapy remains controversial.

Concepts: According to Jim, Essential thrombocytosis, Anagrelide

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To identify switch modalities used when initiatingsecond- or third-line anagrelide for essential thrombocythemia (ET), assess whether anagrelide is initiatedconsistently with Summary of Product Characteristics (SPC)recommendations, and determine whether different observedswitch regimens have anyrelationship with maintenance, platelet response,or tolerability.

Concepts: Essential thrombocytosis, Anagrelide

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This study investigates whether the response criteria proposed by the European LeukemiaNet (ELN) to evaluate cytoreductive therapies in essential thrombocythemia (ET) correlate with clinically relevant outcomes in patients receiving anagrelide. We evaluated 154 ET patients treated with anagrelide (upfront in 87) for a median of 2.9 years. Complete response (CR), partial response, and no response were observed in 56, 30.5, and 13.5 % patients, respectively. Only 38 patients (25 %) achieved a sustained CR. Overall, the aggregated time on CR and without CR was 200.1 and 333.6 person-years, respectively. The incidence rate of thrombosis and hemorrhage was independent of the CR status. The only factor associated with shorter survival after anagrelide start was the patient’s age, whereas achieving a CR with anagrelide had no predictive value for subsequent survival. In conclusion, CR according to the ELN definition is not associated with any measurable clinical benefit in ET patients treated with anagrelide.

Concepts: Epidemiology, Patient, Medical statistics, Incidence, The Europeans, Clinical death, Employee benefit, Anagrelide

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EXELS is an ongoing phase IV non-interventional study; 3643 high-risk patients with essential thrombocythemia (ET) were recruited across 13 European countries. We report patient characteristics and cytoreductive treatment patterns of ET across Europe. Hydroxycarbamide (HC; 64.3%) and anagrelide (22.0%) were the two main cytoreductive treatments prescribed. The proportions of patients taking either HC or anagrelide varied across countries, as did the number of patients receiving anti-aggregatory therapy in addition to cytoreductive treatment. This real-world evidence demonstrates that, generally, treatment patterns of ET across Europe adhere to expert recommendations, with some notable variations between countries.

Concepts: European Union, Patient, Europe, Essential thrombocytosis, Phase IV, Anagrelide