Hydroxyurea and Anagrelide Combination Therapy in Patients with Chronic Myeloproliferative Diseases Resistant or Intolerant to Monotherapy

Abstract

Furthermore, AG has no myelotoxic or leukemogenic potential to add to that of HU. Based on these considerations, we reviewed the records of patients with PV or ET treated in our institution and analyzed the characteristics of those treated with HU plus AG in order to assess the feasibility of the combination in terms of efficacy and safety. We identified 16 cases in which a combination of HU and AG had been used at some point of their course between June 2003 and February 2008. Diagnosis was made according to the WHO criteria for ET, PV and idiopathic myelofibrosis (IM). Thirteen patients were investigated for a JAK2V617F mutation and 8 of them were positive. Patient characteristics are shown in table 1 . Eight patients had ET, 7 had PV and 1 had IM. All of them had thrombocytosis. Thirteen had been using HU, at a median precombination daily dose of 1,285 mg (calculated by dividing the total weekly dose by 7), range 500– 2,428 mg. Three were using AG at a median dose of 1.5 mg. These doses are derived from the last 30-day patient schedule before changing to a combined regimen. All patients were also given an anti-platelet (anti-PLT) agent, either salicylic acid 100 mg (13/16), clopidogrel (2/16) or dipyridamol (1/16). We did not discontinue anti-PLT therapy after normalization of PLTs. The optimal management of essential thrombocythemia (ET) and polycythemia vera (PV) is still a matter of continuous research. ET can be managed with low-dose aspirin in patients of low vascular risk or with cytoreductive therapy plus aspirin in the high-risk group, whereas in the intermediate-risk group, cardiovascular risk factors should be considered [1, 2] . The myelosuppressive agent of choice is hydroxyurea (HU), with interferon(IFN) and anagrelide (AG) being second-line choices, especially for young patients due to their lack of leukemogenicity. Phlebotomy plus low-dose aspirin is the initial therapy for PV [3] , while cytoreduction is useful for controlling thrombocytosis, splenomegaly and in patients intolerant to venesection. The use of cytoreduction with either HU, IFN or AG is advocated in high vascular risk patients [4] . There are considerable side effects with either of these therapies which can lead to dose reductions and thus interfere with their efficacy. An interesting approach to overcome dose-limiting toxicities or resistance would be to combine 2 drugs at lower doses than those needed for each drug separately to be effective [2] . HU and AG could be ideal partners for patients with thrombocytosis because they do not have an overlapping toxicity profile. Received: September 5, 2008 Accepted after revision: November 5, 2008 Published online: January 8, 2009