The efficacy of HU in preventing thrombosis in high-risk ET patients was demonstrated in a seminal randomized clinical trial.16 One hundred Selisistat and fourteen patients were randomized to long-term treatment with HU (n = 56) or to no cytoreductive treatment (n = 58). During a median follow-up of 27 months, two thromboses were recorded in the HU-treated group (1.6% pt-yr) compared with 14 in the control group (10.7% pt-yr; p = 0.003). Some long-term follow-up studies revealed that a proportion of ET patients treated with HU developed acute leukemia, particularly when given before or after alkylating

agents or radiophosphorus.[39] and [40] In other studies, however, the use of this drug as the only cytotoxic treatment was rarely associated with secondary malignancies. In an analysis of 25 ET patients younger than 50 years and treated with HU alone for high risk of thrombosis, no case of leukemic or neoplastic transformation occurred after a median follow up of 8 years (range: 5–14 years).41 In clinical practice, the starting dose of HU selleck chemicals is 15–20 mg/kg/day until response is obtained,

according to ELN criteria (Table 2 and Table 3).42 Thereafter, a maintenance dose should be administered to keep the response without reducing leukocyte count values below 2500 × 109/L. Supplemental phlebotomy should be performed if needed in PV patients. Complete hemogram should be recorded every 2 weeks during the first 2 months, then every month and, in steady state in responding patients, every 3 months. In regard to HU toxicity, a recent large multicenter retrospective study of patients with MPN (3411 MPN patients treated with HU diagnosed in the contributing centers in the period from 1980 to 2010) has estimated the frequency and the clinical relevance of unacceptable side effects (fever, pneumonitis, and cutaneous or mucosal lesions) during treatment with HU.43 Due to the large subjectivity of reporting, the authors deliberately excluded from the analysis gastrointestinal toxicities, even if they were considered as drug-related in

patients’ and/or physicians’ opinion. Results indicate that clinically relevant toxicities attributed to HU, in accordance with the criteria of “intolerance” established by the ELN consensus conference,44 occur in a small either proportion of patients even after long exposure time. The rate of 5% discontinuation in this study is lower than the 10.6% found in the HU plus aspirin group (n = 404) of the Primary Thrombocythemia-1 (PT-1) trial.17 However, in the latter study no detailed information about causes of discontinuation was reported, and it is possible that also gastrointestinal side effects were included. Patients who develop severe HU-related toxicities represent a category of subjects in need of alternative therapies and nonleukemogenic drugs such as anagrelide or IFN-alpha should be considered.