Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 ؋ 10 9 /L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time- IntroductionPrimary myelofibrosis (PMF) is a Philadelphia-negative myeloproliferative neoplasm (MPN) whose diagnostic criteria have been recently updated. 1 Among MPNs, PMF has the most heterogeneous clinical presentation, which may encompass anemia, splenomegaly, leukocytosis or leukopenia, thrombocytosis or thrombocytopenia, and constitutional symptoms. The discovery of the activating mutation JAK2 (V617F) in more than 70% of patients with MPNs 2 led to the development of new biochemically selective JAK2 inhibitors. 3 These agents are currently being tested in clinical trials that usually include patients with long disease history.Advanced age, 4-7 anemia, 4-11 red blood cell transfusion need, 12 leukopenia, 8 leukocytosis, 8 thrombocytopenia, 9 peripheral blast count, 4,6 systemic symptoms, 6,10 degree of microvessel density, 13 and cytogenetic abnormalities 5,7,9,[14][15][16] were shown to be associated with poor outcome in patients with PMF. The presence of the JAK2 (V617F) mutation per se does not seem to imply worse survival, 17 although a low JAK2 (V617F) allele burden seems associated with poorer outcome. 18,19 Recently, Cervantes et al 17 on behalf of the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) developed a prognostic scoring system to estimate survival of PMF patients. This model uses 5 factors (age older than 65 years, hemoglobin level Ͻ 100 g/L [10 g/dL], white blood cell count Ͼ 25 ϫ 10 9 /L, peripheral blood blasts Ն 1%, and presence of constitutional symptoms) to identify 4 risk categories with different survival.Prognostic models for PMF developed so far are based on the evaluation of risk factors present at diagnosis. However, the acquisition of additional risk factors during the disease course may substantially modify the patients' outcome. A dynamic prognostic model that accounts for modifications of the risk profile after diagnosis may prove useful in clinical practice. On behalf of IWG-MRT, first we investigated whether the acquisition anytime during follow-up of one or more of the prognostic factors identified by Cervantes et al 17 predicts survival. Then, a new prognostic score based on a time-dependent risk evaluation was developed: the Dynamic International Prognostic Scoring System (DIPSS) for PMF. MethodsThe study was carried out through an international cooperation on behalf of the IWG-MRT. An ad hoc database was developed for data collection. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From Study designThe Institutional Rev...

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Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR-ABL1 by Q-RT-PCR does not equate to eradication of the disease. Digital-PCR (dPCR), able to detect 1 BCR-ABL1 positive cell out of 10 7 , has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q-RT-PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q-RT-PCR for 36 months. Patients losing molecular remission (two consecutive positive Q-RT-PCR with at least 1 BCR-ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow-up of 21.6 months. Fifty-two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not-relapsed patients, 40 (37.0% of total) regained Q-RT-PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013-1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class 45 to <65 years and 33% of patients 65 years [P(v 2 ) < 0.0001]. Relapse rates ranged between 100% (<45 years, dPCR1) and 36% (>45 years, dPCR-). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse.

Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with longterm therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P ‫؍‬ .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P ‫؍‬ .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with > 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit. (Blood. 2012;120(6):1202-1209)

Essential thrombocythemia (ET) may occur in women of childbearing age. To investigate the risk of pregnancy complications, we studied 103 pregnancies that occurred in 62 women with ET. The 2-tailed Fisher exact test showed that pregnancy outcome was independent from that of a previous pregnancy. The rate of live birth was 64%, and 51% of pregnancies were uneventful. Maternal complications occurred in 9%, while fetal complications occurred in 40% of pregnancies. The Mantel-Haenszel method showed that fetal loss in women with ET was 3.4-fold higher (95% confidence interval [CI]: 3-3.9; P < .001) than in the general population. Half of the women studied carried the JAK2 (617V>F) mutation, and a multivariate logistic regression model identified this mutation as an independent predictor of pregnancy complications (P ‫؍‬ .01). Neither the platelet count nor the leukocyte count was a risk factor. JAK2 ( IntroductionEssential thrombocythemia (ET) is a chronic myeloproliferative disorder with an increased risk of vascular complications. Despite these events, life expectancy of patients with ET is not significantly affected by the disease in any age category. 1 Patients with ET are predominantly women, and some of them are diagnosed at childbearing age. 2 Decision-making on pregnancy is therefore a common issue in the clinical management of young women with ET.There is limited information regarding the outcome of pregnancy in patients with ET, mainly from case reports. Papers reviewing published studies on pregnancies in patients with ET 3-5 report live birth rates of 50% to 70% and spontaneous abortion rates of 25% to 50%. Concerning risk factors, the study of Wright and Tefferi 6 on 43 pregnancies indicates that preconception platelet count and aspirin therapy do not predict the risk of abortion.The JAK2 (617VϾF) mutation has been recently identified in approximately half of patients with ET. 7-10 It has been suggested that the presence of the mutation in patients with ET characterizes a disease with a higher risk of vascular events. 9 To date, the relationship between JAK2 mutational status and the outcome of pregnancy in women with ET is unknown.We studied 103 pregnancies occurring in 62 patients with ET to investigate the risk of complications and to find predictors of pregnancy outcome. Patients, materials, and methods PatientsThis study includes 103 consecutive pregnancies that occurred in 62 patients with ET who were followed between 1980 and 2006 at the Division of Hematology of the Fondazione Policlinico San Matteo, University of Pavia; the Division of Internal Medicine of the University of Padova; and the Division of Hematology of the Niguarda Ca' Granda Hospital of Milan, Italy. The study was approved by the institutional ethics committee of Pavia, and the procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000. Samples for molecular analysis were obtained after patients provided written informed consent.Diagnostic criteria of ET were those in use at the time of the fi...

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Careful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd–Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.