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Nicola Cascavilla,1 Valerio De Stefano,2 Fabrizio Pane,3 Alessandro Pancrazzi,4 Alessandra Iurlo,5 Marco Gobbi,6 Francesca Palandri,7 Giorgina Specchia,8 A Marina Liberati,9 Mariella D’Adda,10 Gianluca Gaidano,11 Rajmonda Fjerza,4 Heinrich Achenbach,12 Jonathan Smith,13 Paul Wilde,13 Alessandro M Vannucchi41Division of Hematology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy; 2Institute of Hematology, Catholic University, Rome, Italy; 3Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy; 4Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; 5Oncohematology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; 6IRCCS AOU San Martino, Genova, Italy; 7Department of Specialistic, Diagnostic and Experimental Medicine, St Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; 8Unit of Hematology with Transplantation, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy; 9Ospedale Santa Maria, Terni, Italy; 10Division of Hematology, Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Italy; 11Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; 12Research and Development, Shire GmbH, Eysins, Switzerland; 13Shire Pharmaceutical Development Ltd, Basingstoke, United KingdomAbstract: A JAK2(V617F) mutation is found in approximately 55% of patients with essential thrombocythemia (ET), and represents a key World Health Organization diagnostic criterion. This hypothesis-generating study (NCT01352585) explored the impact of JAK2(V617F) mutation status on treatment response to anagrelide in patients with ET who were intolerant/refractory to their current cytoreductive therapy. The primary objective was to compare the proportion of JAK2-positive versus JAK2-negative patients who achieved at least a partial platelet response (≤600×109/L) after anagrelide therapy. Of the 47 patients enrolled, 46 were included in the full analysis set (JAK2-positive, n=22; JAK2-negative, n=24). At 12 months, 35 patients (n=14 and n=21, respectively) had a suitable platelet sample; of these, 74.3% (n=26) achieved at least a partial response. The response rate was higher in JAK2-positive (85.7%, n=12) versus JAK2-negative patients (66.7%, n=14) (odds ratio [OR] 3.00; 95% confidence interval [CI] 0.44, 33.97). By using the last observation carried forward approach in the sensitivity analysis, which considered the imbalance in patients with suitable samples between groups, the overall response rate was 71.7% (n=33/46), with 77.3% (n=17/22) of JAK2-positive and 66.7% (n=16/24) of JAK2-negative patients achieving at least a partial response (OR 1.70; 95% CI 0.39, 8.02). There was no significant change in median allele burden over 12 months in the 12 patients who achieved a response. In conclusion, the overall platelet response rate was high in both JAK2-positive and JAK2-negative patients; however, a larger study would be required to confirm the differences observed according to JAK2(V617F) mutation status.Keywords: essential thrombocythemia, mutation, JAK2, anagrelide, treatment response, allele burden

Emicizumab is a humanized recombinant bispecific antibody, bridging together activated factor IX (FIXa) and factor X (FX), thus mimicking the activity of FVIII in vivo. Emicizumab is designed for long-term prophylaxis in patients with severe hemophilia A with and without inhibitors. This approach provides constant protection, with significant reduction in bleeding rate and improved quality of life. However, protection provided by emicizumab is not absolute, and clotting factor concentrates (FVIII, rFVIIa, aPCC) may be necessary for post-traumatic bleeding or surgery, with a potential thrombotic risk or difficulty in preventing bleeding. Real world evidence is still scanty, especially for managing major surgery. In this study, 75 surgeries were managed in 28 patients (27 major procedures in 15 patients and 48 minor procedures in 20 patients. In 17 patients without inhibitors, 30 minor surgeries were carried out by using FVIII in 5, with only a bleeding event, which was successfully treated with FVIII concentrate. Six major surgeries were uneventfully performed with FVIII concentrate. Eleven PWHA and high-titer inhibitors underwent 39 surgical procedures (18 minor and 21 major surgeries). Minor surgeries were mostly performed without prophylaxis with rFVIIa, with only a single bleeding complication. All 21 major surgeries were covered with a homogeneous protocol using rFVIIa. In four instances, bleeding complications occurred, treated with rFVIIa. Of them, a single patient only failed to respond and died because of an uncontrollable bleeding from a large ruptured retroperitoneal pseudotumor. Surgery in patients with emicizumab can be safely carried out with the use of appropriate replacement therapy protocols.

Splanchnic vein thrombosis (SVT) is one of the vascular complications of myeloproliferative neoplasms (MPN). We designed a phase 2 clinical trial to evaluate safety and efficacy of ruxolitinib in reducing splenomegaly and improving disease-related symptoms in patients with MPN-associated SVT. Patients diagnosed with myelofibrosis (12 cases), polycythemia vera (5 cases) and essential thrombocythemia (4 cases) received ruxolitinib for 24 weeks in the core study period. Spleen volume was assessed by magnetic resonance imaging (MRI) and splanchnic vein circulation by echo-Doppler analysis. Nineteen patients carried JAK2V617F, one had MPLW515L, and one CALRL367fs*46 mutation. Eighteen patients had spleno-portal-mesenteric thrombosis, two had Budd-Chiari syndrome, and one had both sites involved; 16 patients had esophageal varices. Ruxolitinib was well tolerated with hematological toxicities consistent with those of patients without SVT and no hemorrhagic adverse events were recorded. After 24 weeks of treatment, spleen volume reduction ≥35% by MRI was achieved by 6/21 (29%) patients, and a ≥50% spleen length reduction by palpation at any time up to week 24 was obtained by 13/21 (62%) patients. At week 72, 8 of the 13 (62%) patients maintained the spleen response by palpation. No significant effect of treatment on esophageal varices or in splanchnic circulation was observed. MPN-related symptoms, evaluated by MPN-symptom assessment form (SAF) TSS questionnaire, improved significantly during the first 4 weeks and remained stable up to week 24. In conclusion, this trial shows that ruxolitinib is safe in patients with MPN-associated SVT, and effective in reducing spleen size and disease-related symptoms., (© 2016 Wiley Periodicals, Inc.)

The prognostic significance of bone marrow (BM) fibrosis grade in patients with primary myelofibrosis (PMF) is still debated. A fibrosis grade greater than 1 was shown to associate with higher risk of death, and addition of fibrosis grade to IPSS score resulted in a more accurate prediction of survival. The aim of this study was to analyze the prognostic impact of BM fibrosis in 490 patients with PMF, evaluated at diagnosis, molecularly annotated and with extensive follow-up information. We found that fibrosis grade 2 and greater on a 0-3 scale was associated with clinical characteristics indicative of a more advanced disease, such as anemia, leukopenia, thrombocytopenia, constitutional symptoms, larger splenomegaly and a higher IPSS risk category. Patients with higher grade of fibrosis were also more likely to have additional somatic mutations in ASXL1 and EZH2, that are prognostically adverse. Median survival was significantly reduced in patients with grade 2 and 3 fibrosis as compared with grade 1; this effect was maintained when analysis was restricted to younger patients. In multivariate analysis, fibrosis grade independently predicted for survival regardless of IPSS variables and mutational status; the adverse impact of fibrosis was noticeable especially in lower IPSS risk categories. Overall, results indicate that higher grades of fibrosis correlate with unique clinical and molecular aspects and represent an independent adverse variable in patients with PMF; these observations deserve confirmation in prospectively designed series of patients. Am. J. Hematol. 91:918-922, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Janus kinase 2 (JAK2) mutations define polycythemia vera (PV). Calreticulin (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations are specific to JAK2-unmutated essential thrombocythemia (ET) and primary myelofibrosis (PMF). We examined the effect of these mutations on long-term disease outcome. One thousand five hundred eighty-one patients from the Mayo Clinic (n = 826) and Italy (n = 755) were studied. Fifty-eight percent of Mayo patients were followed until death; median survivals were 19.8 years in ET (n = 292), 13.5 PV (n = 267; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4-2.2), and 5.9 PMF (n = 267; HR, 4.5; 95% CI, 3.5-5.7). The survival advantage of ET over PV was not affected by JAK2/CALR/MPL mutational status. Survival in ET was inferior to the age- and sex-matched US population (P < .001). In PMF (n = 428), but not in ET (n = 576), survival and blast transformation (BT) were significantly affected by mutational status; outcome was best in CALR-mutated and worst in triple-negative patients: median survival, 16 vs 2.3 years (HR, 5.1; 95% CI, 3.2-8.0) and BT, 6.5% vs 25% (HR, 7.6; 95% CI, 2.8-20.2), respectively. We conclude that life expectancy in morphologically defined ET is significantly reduced but remains superior to that of PV, regardless of mutational status. In PMF, JAK2/CALR/MPL mutational status is prognostically informative., (© 2014 by The American Society of Hematology.)

Patients with chronic immune thrombocytopenia treated with romiplostim may benefit from a higher starting dose when a rapid increase in count is needed, but it could be avoided in those with a prompt response to the standard dosage. We hypothesized that a platelet count ≥ 20 × 10(9)/l at baseline could distinguish subjects with such response from those with a delayed one during the early phase of treatment. Our work is a retrospective and single-institution analysis comparing the median platelet count, the median weekly dosage of romiplostim and the median number of weekly platelet counts < 50 × 10(9)/l between patients with a baseline ≥ 20 × 10(9)/l platelets (n=10, 2 splenectomized) and those with a lower one (n=8, 3 splenectomized) during the first month of treatment with romiplostim. The results show a higher median platelet count (79,5 vs 40,5 × 10(9)/l, p=0,002) and a lower median dose of romiplostim (1 vs 2 mcg/kg/week, p=0,01) in subjects with a baseline ≥ 20 × 10(9)/l platelets, who also had a trend of less weekly counts < 50 × 10(9)/l platelets (1 vs 2, p=0,054). These data suggest that patients with ≥ 20 × 10(9)/l platelets at baseline may achieve a prompt response with the standard dose of romiplostim, but further and larger data are needed in order to assess whether it can be considered in clinical practice.