Final Results of the ANAHYDRET-Study: Non-Inferiority of Anagrelide Compared to Hydroxyurea in Newly Diagnosed WHO-Essential Thrombocythemia Patients

Abstract

Abstract Background: Both anagrelide and hydroxyurea effectively lower platelet counts in essential thrombocythemia (ET) and other thrombocythemic myeloproliferative neoplasms. Anagrelide has a selective inhibitory effect on megakaryopoiesis and platelet production in contrast to hydroxyurea, which is a nonspecific, myelosuppressive compound inhibiting megakaryopoiesis as well as granulopoieses and erythropiesis. Based on the superiority of hydroxyurea+aspirin over anagrelide+aspirin in ET patients in the PT1-trial, guidelines for cytoreductive therapy favor hydroxyurea as first line therapy for ET. However, the diagnosis of ET in the PT1-trial was made according to the PVSG cassification and it remains questionable if these recommendations can be applied to ET patients diagnosed according to the WHO classification. Patients and methods: In this prospective randomized single blind international multicenter phase III study efficacy and tolerability of anagrelide and hydroxyurea monotherapies were compared 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. After informed consent 258 treatment naïve, high risk patients with ET were randomized to receive either anagrelide (n=122) or hydroxyurea (136). The patients characteristics were equally distributed within both arms with a median age of 58,1 years, range 19–90 years; 46 male, 76 female in the anagrelide arm vs. a median age of 56,4 years, range 22– 83 years, 47 male, 89 female in the hydroxyurea arm. Anagrelide (Thromboreductin) was started with a dose of 1mg/day and hydroxyurea was initiated using a dose of 1500mg/day. Results: A central blinded pathologic review of 236 bone marrow biopsies revealed a high reproducibility of the ET diagnosis by applying the WHO classification: 194 (82.2%) of patients were classified as ET, 16 patients (6,8%) were reclassified as PMF-0 and 16 patients (6,8%) were considered to be early PVs with an ET-like clinical phenotype. Confirmatory proof of non-inferiority was achieved after a mean observation time of 2,1 years (comprising 539 patient years) based on predefined equivalence criteria for platelet counts, course of hemoglobin levels and white cell count during therapy, and for the rate of ET related events. In the anagrelide arm 75,4% of the patients received a complete response of platelet counts (<450×109/l) compared to 81,7% in the hydroxyurea arm. Neutrophile counts remained unchanged in the anagrelide arm but were significantly reduced by hydroxyurea. No significant differences were observed for the rates of major and minor clinical complications in the anagrelide group (4,29%, and 16,8%, resp.) compared to hydroxyurea (4,25%, and 12,8%, resp.). During the whole study period 11 major ET related complications occurred in the anagrelide group (5 arterial events, 2 venous thrombotic complications and 4 bleedings) and 12 major events were seen in the hydroxyurea arm (5 arterial events, 5 venous thrombositic events and 2 bleedings). 43 minor ET related events occurred in the anagrelide arm as compared to 36 such events in the hydroxyurea arm. Adverse drug reactions or poor response were reasons for discontinuations of the study drug in 19 patients treated with anagrelide and in 10 patients treated with hydroxyurea. Transformations to myelofibrosis were not reported during the whole study period. The JAK2 mutation status was evaluated in 189 patients with 101 JAK2 positive (53,4%) and 88 (46,6%) JAK2 negative patients. The impact of this mutation on thrombotic events in both arms will be presented at the meeting. Conclusion: The final analysis of the study provides evidence for non-inferiority of anagrelide compared to hydroxyurea in the treatment of ET diagnosed according to the WHO classification. Therefore it can be speculated that in these cases a thromboreductive therapy represented by anagrelide may be sufficient in order to prevent thrombotic complications whereas in other thrombocythemic MPN patients a cytoreductive treatment (e.g. with hydroxyurea) may be necessary.