Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CAC) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first-and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.

BACKGROUND Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. METHODS We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. RESULTS The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P = 0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard- therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy. CONCLUSIONS In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera.

Neutralizing antierythropoietin antibodies and pure red-cell aplasia can develop in patients with the anemia of chronic renal failure during treatment with epoetin.

This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.

Ruxolitinib is a Janus kinase (JAK) (JAK1/JAK2) inhibitor that has demonstrated superiority over placebo and best available therapy (BAT) in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies. COMFORT-II was a randomized (2:1), open-label phase 3 study in patients with myelofibrosis; patients randomized to BAT could crossover to ruxolitinib upon protocol-defined disease progression or after the primary end point, confounding long-term comparisons. At week 48, 28% (41/146) of patients randomized to ruxolitinib achieved ⩾35% decrease in spleen volume (primary end point) compared with no patients on BAT (P<0.001). Among the 78 patients (53.4%) in the ruxolitinib arm who achieved ⩾35% reductions in spleen volume at any time, the probability of maintaining response was 0.48 (95% confidence interval (CI), 0.35–0.60) at 5 years (median, 3.2 years). Median overall survival was not reached in the ruxolitinib arm and was 4.1 years in the BAT arm. There was a 33% reduction in risk of death with ruxolitinib compared with BAT by intent-to-treat analysis (hazard ratio (HR)=0.67; 95% CI, 0.44–1.02; P=0.06); the crossover-corrected HR was 0.44 (95% CI, 0.18–1.04; P=0.06). There was no unexpected increased incidence of adverse events with longer exposure. This final analysis showed that spleen volume reductions with ruxolitinib were maintained with continued therapy and may be associated with survival benefits.

Interferon-␣ (IFN-␣) is a nonleukemogenic treatment of polycythemia vera (PV