Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial. We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed. After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events. In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007–006694-91.)

Background Prior thrombosis is a well-established risk factor for re-thrombosis in polycythemia vera and essential thrombocythemia but scarce data are available on the rate of re-thrombosis and the optimal strategy for prevention of recurrence. Design and Methods We retrospectively estimated the rate of recurrence in a multicenter cohort of 494 patients (poly-cythemia vera/essential thrombocythemia 235/259) with previous arterial (67.6%) or venous thrombosis (31%) or both (1.4%). First thrombosis was cerebrovascular disease in 191 cases, acute coronary syndrome in 106, peripheral arterial thrombosis in 44, and venous thromboembolism in 160. Microcirculatory events were not computed. Results Thrombosis recurred in 166 patients (33.6%), with an incidence of 7.6% patient-years. Sex, diagnosis (polycythemia vera or essential thrombocythemia), and presence of vascular risk factors did not predict recurrence, whereas age >60 years did (multivariable hazard ratio [HR], 1.67; 95% confidence interval [CI] 1.19–2.32). Increased leukocyte count at the time of the first thrombosis was a risk factor for recurrence in patients <60 years old (HR 3.55; 95% CI 1.02–12.25). Cytoreduction halved the risk in the overall cohort (HR 0.53; 95% CI 0.38–0.73) and the combination with antiplatelet agents or oral anticoagulants was more effective than administration of single drugs. Significant prevention of rethrombosis was independently achieved in patients with venous thromboembolism by both oral anticoagulants (HR 0.32; 95% CI 0.15–0.64) and antiplatelet agents (HR 0.42; 95% CI 0.22–0.77), in those with acute coronary syndrome by cytoreduction (HR 0.30; 95% CI 0.13–0.68), and in those with cerebrovascular disease by antiplatelet agents (HR 0.33; 95% CI 0.16–0.66). The overall incidence of major bleeding was 0.9% patient-years and rose to 2.8% in patients receiving both antiplatelet and anti-vitamin K agents. Conclusions In patients with polycythemia vera and essential thrombocythemia, cytoreduction protects against recurrent thrombosis, particularly after acute coronary syndrome. The contemporary use of oral anticoagulants (after venous thromboembolism) or antiplatelet agents (after cerebrovascular disease or venous thromboembolism) further improves the protective effect. Such findings call for prospective studies aimed at investigating whether strategies tailored according to the type of first thrombosis could improve prevention of recurrences.

The JAK-STAT signaling pathway plays a central role in signal transduction in hematopoietic cells, as well as in cells of the immune system. The occurrence in most patients affected by myeloproliferative neoplasms (MPNs) of driver mutations resulting in the constitutive activation of JAK2-dependent signaling identified the deregulated JAK-STAT signal transduction pathway as the major pathogenic mechanism of MPNs. It also prompted the development of targeted drugs for MPNs. Ruxolitinib is a potent and selective oral inhibitor of both JAK2 and JAK1 protein kinases. Its use in patients with myelofibrosis is associated with a substantial reduction in spleen volume, attenuation of symptoms and decreased mortality. With growing clinical experience, concerns about infectious complications, and increased risk of B-cell lymphoma, presumably caused by the effects of JAK1/2 inhibition on immune response and immunosurveillance, have been raised. Evidence shows that ruxolitinib exerts potent anti-inflammatory and immunosuppressive effects. Cellular targets of ruxolitinib include various components of both the innate and adaptive immune system, such as natural killer cells, dendritic cells, T helper, and regulatory T cells. On the other hand, immunomodulatory properties have proven beneficial in some instances, as highlighted by the successful use of ruxolitinib in corticosteroid-resistant graft vs. host disease. The objective of this article is to provide an overview of published evidence addressing the key question of the mechanisms underlying ruxolitinib-induced immunosuppression.

Background: After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome.Methods: A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis.Results: At 3 years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate‐2–risk/high‐risk category (Dynamic International Prognostic Score System), a platelet count <100 ×10⁹ per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5 months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib‐related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib‐unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2 months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9 months for those who discontinued in blast phase; P < .001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib‐related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome.Conclusions: The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies.

Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders. Key Points Whole-exome sequencing reveals the presence of recurrent somatic mutations of ETNK1 in patients with atypical chronic myeloid leukemia. ETNK1 mutations impair the catalytic activity of the enzyme, causing a decrease in the intracellular levels of phosphoethanolamine.

Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference [1], although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of "intolerance" to HU have been described;patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.