Interestingly, prognostic studies demonstrated an independent role of leukocytosis to predict future cardiovascular events in so‐called low risk ET and this could be another group for primary prophylaxis with low‐dose aspirin.[30], [31] and [32] The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea (HU) and interferon-alpha (IFN-alpha). HU is an antimetabolite that prevents

DNA synthesis and was introduced in the therapy of PV and ET by the Polycythemia Vera Study Group (PVSG). These investigators assumed this drug to be not leukemogenic and in a paper summarizing their long-term experience in 51 PV patients followed for a median of 8.6 years, they reported an incidence Trichostatin A in vivo of leukemia of 9.8% (vs 3.7% in the historical phlebotomized controls) but less myelofibrosis (7.8% vs 12.7%), fewer total deaths (39.2% vs 55.2%) and less thrombotic events.33 In the ECLAP Proteasome inhibition study, HU alone was not found to enhance the risk of leukemia in comparison with patients treated with phlebotomy only (hazard ratio: 0.86; 95% CI: 0.26–2.88; p = 0.8); however, the risk was significantly increased by exposure to radiophosphorus, busulphan or pipobroman (hazard ratio: 5.46; 95% CI: 1.84–16.25; p = 0.002). In addition, the use of HU in patients already treated with alkylating

agents or radiophosphorus also enhanced the leukemic risk (hazard ratio: 7.58; 95% CI: 1.85–31; p = 0.0048).34 A randomized clinical trial did not find significant differences in the rate of leukemic transformation in PV patients treated with HU or pipobroman, an alkylating CYTH4 agent with a mechanism

of action that also involves metabolic competition with pyrimidine basis.35 However, different results were observed by prolonging the observation time. In a recent long-term analysis of the above mentioned study comparing HU to pipobroman in 292 PV patients (median follow-up: 16.3 years), median survival was 20.3 years in HU arm and 15.4% in pipobroman arm. Cumulative incidence of AML/MDS at 10, 15 and 20 years was 6.6%, 16.5% and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (p = 0.004).36 A similar trend was observed by Gangat et al.37 who reported a rate of AML of 2.4%, 4%, 11.6% and 16.7% in PV patients given no chemotherapy, HU only, one single cytotoxic drugs or two or more cytotoxic agents, respectively. Recently, in a nationwide cohort of 11,039 MPN patients, a nested case–control study including 162 AML and MDS patients and 242 matched controls was conducted in Sweden.38 Results indicate that the risk of AML/MDS was not significantly enhanced by HU given as a sole therapy. Of note, 25% of the patients who developed leukemia were never exposed to cytotoxic therapy supporting the notion of a major role for intrinsic MPN‐related factors in leukemogenesis of MPN.