Non-Inferiority of Anagrelide Compared to Hydroxyurea in Newly Diagnosed Patients with Essential Thrombocythemia: The ANAHYDRET-Study.

The ANAHYDRET study group involving 27 centers in 11 countries, sponsored by the AOP Orphan Pharmaceuticals, initiated a prospective randomized single blind multicenter phase III trial in order to compare efficacy and tolerability of anagrelide with hydroxyurea in high risk ET patients diagnosed according to the WHO classification. The study was designed as a non-inferiority trial as the limited number of treatment naïve ET patients available and the expected low number of ET related events following treatment with a cytoreductive therapy would not have allowed the conduct of a conventional superiority trial. At the stage of final analysis 258 patients with high risk ET previously untreated, were randomized to receive anagrelide (n=122, median age 58,1 years, rage 19–90 years; 46 male, 76 female) or to receive hydroxyurea (n=136, median age 56,4 years, range 22–83 years, 47 male, 89 female). Anagrelide, a novel non-immediate release formulation, was started with a dose of 1mg/day and hydroxyurea was initiated using a dose of 1500mg/day. Confirmatory proof of non inferiority of anagrelide after 6 months therapy (short term objective) was achieved based on predefined equivalence criteria for the course of platelet and white cell counts, hemoglobin levels, (difference of +/− 10% within CI 95%), and for the rate of ET related events (Odds ratio >0,404, medium sized difference corresponding to Cohens’s standardized difference of 0.5). Neutrophile counts remained unchanged in the anagrelide arm but were significantly reduced by hydroxyurea. There was no difference in the number of patients with at least 1 adverse event between the anagrelide treated group (73%) and the hydroxyurea treated group (73%). Five patients were discontinued in each group because of adverse events. However, the results showed an advantage of anagrelide over hydroxyurea concerning leukopenia and flue like symptoms while the angrelide treated patients had more frequently tachycardia, palpitations and headache. The final data analysis after 12 months therapy revealed that non- inferiority of anagrelide compared to hydroxyurea with regard to the platelet lowering effect, hemoglobin levels and ET related symptoms was maintained (p<0,025). During the entire study period of 12 months, 8 major ET related complications occurred in the anagrelide arm (2 myocardial infarctions, 1 coronary arterial disease, 1 peripheral arterial disease, 1 mesenteric vein thrombosis and 3 bleedings) and also 8 major events were seen in the hydroxyurea arm (1 myocardial infarction, 1 peripheral arterial disease, 1 stroke, 1 pulmonary embolism, 2 deep vein thromboses and 2 bleedings). Twenty two minor ET related events occurred in the anagrelide arm as compared to 23 such events in the hydroxyurea arm. The frequency of adverse events and withdrawals remained balanced in both treatment arms at the stage of final analysis after 12 months therapy. In addition, all these parameters will also be analysed with respect to the JAK2 mutation. In summary the study provides evidence for non-inferiority of anagrelide compared to hydroxyurea in the treatment of ET diagnosed according to the WHO classification.