Thrombosis in MPN with Thrombocythemia Is Associated with Higher Platelet Count At the Time of the Event: Data From the Czech Registry of Patients Treated with Anagrelide,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3857-3857
Author(s):  
Jiri Schwarz ◽  
Miroslav Penka ◽  
Petra Ovesna ◽  
Olga Cerna ◽  
Yvona Brychtova ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Thrombotic Event ◽  
Jak2 V617f ◽  
Protein C Deficiency ◽  
Thrombotic Risk ◽  
Female Ratio ◽  
Platelet Counts ◽  
Cell Counts ◽  
Registry Entry

Abstract Abstract 3857 Background: Recent studies of prognostic parameters in Ph- myeloproliferative neoplasms with thrombocythemia (MPN-t) indicate that WBC counts at diagnosis, rather than platelet (Plt) counts, determine the risk of thrombosis. We have studied these and other risk parameters in our patient cohort. Patients: 843 prospectively assigned patients from the Czech segment of the International registry of patients treated with anagrelide (ANG; Thromboreductin®) were studied. The male: female ratio was 2:3, the median age was 51 (0–96) years. The majority of patients (68.1%) was pretreated by other cytoreducing drugs. According to PVSG criteria, the diagnoses were the following: essential thrombocythemia – 569, primary myelofibrosis – 155, polycythemia vera – 92, or other – 27 patients. Data from the time of diagnosis, from the time of registry entry (at the start of ANG therapy) and from the time of the thrombotic event were evaluated. The median follow-up since registry entry was 33 (0–117) months and the follow-up comprised 2505 patient-years. All patients were treated with ANG and in 80% of follow-up reports, acetylsalicylic acid (ASA) was mentioned to be given in parallel. In 18% of entries (from registration and follow-up), administration of another cytoreducing drug (mainly hydroxyurea or interferon) in combination with ANG was noted. Results: Of 449 thrombotic events reported, 335 occurred in history (i.e. before registry entry) and 114 during follow-up. The numbers of arterial, venous, and microcirculatory events in history were 147, 124 and 64, respectively. Of the 114 thrombotic events in 88 patients during follow-up (3.79 events/100 patient-years), 45 were classified as major. There were 61 arterial, 16 venous and 37 microcirculatory events. ANG ± ASA therapy dramatically decreased the number of venous events (7.8-fold), while arterial and microcirculatory events were reduced 2.4-fold and 1.7-fold, respectively. At diagnosis, the strongest predictors of all thrombotic events jointly were JAK2 V617F mutation (P=0.001), hereditary or acquired thrombophilia (P<0.001), hypertension (P=0.006), smoking (P=0.02) and diabetes mellitus (P=0.04). Also previous thrombosis predicted a subsequent thrombotic event (P=0.002). Age >65 yrs was a less powerful predictor (P=0.08). WBC and hematocrit levels positively correlated with the thrombotic risk (P=0.002 and P=0.006, respectively), whereas Plt counts correlated inversely with all thrombotic events (P=0.012) but correlated positively with microcirculatory events (P=0.01). Some of the factors (age, hypertension, diabetes, and smoking) powerfully predicted rather arterial events, whereas others (f.V “Leiden” mutation, protein C deficiency, elevated f.VIII levels, presence of antiphospholipid antibodies) were connected preferentially with venous events. However, when full blood cell counts from the time of the thrombotic events were studied and compared to mean levels of all entries during follow-up, we could detect higher platelet counts at the time of the thrombotic event (454 vs 420 G/L, P=0.007), while we could not demonstrate any significance of the WBC counts at the time of the event. The correlation of the Plt count was marked in all types of events and was most conspicuous in microcirculatory events. Thrombotic events during follow-up were also associated with lack of ASA therapy: only 6/16 (37.5%) patients at the time of the venous event, 35/61 (57.4%) patients at the time of the arterial event and 11/37 (29.7%) patients at the time of the microcirculatory event received ASA therapy (whereas ASA administration was reported in 80.0% of follow-up entries). Conclusions: The current study indicates that during ANG ± ASA therapy, the incidence of thrombosis is very low in MPN-t and especially the rate of venous events is extraordinarily low. The predictors of the thrombotic events are similar as previously published by others. Above that, we have proven the usefulness of detection of the so-called thrombophilic states. However, in contrast with the prevailing current opinion, we have shown that higher platelet counts (and not WBC counts) are important at the time of thrombosis, albeit at diagnosis the Plt counts may inversely and WBC counts positively correlate with the thrombotic risk. This discrepancy may result from treatment: patients with higher Plt counts at diagnosis may receive more cytoreducing and/or antiaggregation therapy. Disclosures: Schwarz: AOP Pharmaceuticals: Consultancy.

Influence of Platelet and White Blood Cell Counts until Major Thrombosis: Analysis from a Patient Registry in Essential Thrombocythemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2814-2814
Author(s):  
Veronika Buxhofer-Ausch ◽  
Michael Steurer ◽  
Siegfried Sormann ◽  
Ernst Schloegel ◽  
Wolfgang Schimetta ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Research Funding ◽  
Who Classification ◽  
Thrombotic Event ◽  
Youden Index ◽  
Thrombotic Risk ◽  
Cox Regression Analysis ◽  
Platelet Counts ◽  
Cell Counts ◽  
The Impact

Abstract Retrospective studies could not proof a correlation of elevated platelet counts at diagnosis with thrombotic events. However, randomized and prospective clinical studies on platelet lowering therapies justify recommendations for the normalization of platelet counts as an appropriate endpoint for treatment in high-risk essential thrombocythemia (ET). Furthermore, there is increasing evidence that leukocytosis is an important risk factor for arterial thrombosis, especially in WHO classified ET. Leukocytosis is even more pronounced in prefibrotic primary myelofibrosis (PMF) compared to WHO classified ET. Patient cohorts that were diagnosed prior to the WHO classification likely consist of a mixture of ET and prefibrotic PMF. Some authors suppose interplay between white blood cells (WBC) and platelets in patients with myeloproliferative diseases. The current study considers the Austrian cohort of a European registry, which was established to document the efficacy of the platelet-lowering therapeutic anagrelide in myeloproliferative neoplasms. Out of 845 patients, only those with a confirmed diagnosis of ET according to the PVSG classification until 2001 or according to the WHO classification thereafter were included in the analysis. Median follow up of the 620 included patients is 3.1 years (range 1.21-5.73 years), corresponding to 2428 patient years. 418 patients (67%) were females and the median age at study entry was 62 years (range 51-72 years). Thirty four patients (5.5%) experienced at least one major arterial or venous event until data analysis corresponding to 1.40 events per 100 patient years. The influence of platelet and WBC counts on thrombotic risk was assessed by correlating the first major thrombotic event with the median of all blood counts recorded during the course of the disease until an event or until end of observation. The median platelet counts until the first event occurred and until end of observation (in patients without an event) were 595.8 G/l (range 495.0-743.0 G/l) and 500.0 G/l (range 410.5-619.5 G/l), respectively, and thus were substantially different (p= 0.008). The median WBC counts until the first event occurred and until end of observation (in patients without an event) were statistically not different but might indicate a trend with 9.60 G/l (range 8.70-10.95 G/l) and 8.42 G/l (range 7.05-10.70 G/l), respectively (p=0.084). By using the calculated (Youden index) cut offs of 574.5 G/L for platelets and 8.48 G/L for WBC counts, respectively, the Cox regression analysis revealed a clear influence of platelets (p= 0.008) as well as WBC counts (p= 0.011) above the cut offs until the time to a major event. Interestingly, in this analysis, the influence of higher platelet counts on major thrombotic events was more pronounced than that of higher WBC counts. The frequency of major events per 100 patient years was highest when both platelet and WBC counts ranged above the calculated cut offs and was substantially different from the frequency when both, platelet and WBC counts ranged below the cut offs (3.05 vs. 1.4, p<0.001). In conclusion, our data add evidence to the impact of elevated platelet as well as elevated WBC counts on the time until a thrombotic event and on the frequency of thrombosis in ET. Moreover, we suspect a particular interaction between platelets and WBC which might not only be the result of simple addition of risk but might rather be based on biological interplay. We speculate that this interaction depends on particular cell counts of platelets and WBC which will need to be defined. Disclosures Buxhofer-Ausch: AOP Orphan: Research Funding. Gisslinger:AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy.

Chronic Myeloprolipherative Neoplasms (MPNs) and Splanchnic Venous Thrombosis(SVT): Incidence and Risk Factors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5057-5057
Author(s):  
Bruno Martino ◽  
Caterina Alati ◽  
Patrizia Cufari ◽  
Iolanda Vincelli ◽  
Francesca Ronco ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Venous Thrombosis ◽  
Thrombotic Event ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Thrombotic Risk ◽  
Prothrombotic Risk Factors ◽  
V617f Mutation

Abstract Abstract 5057 There is evidence in literature of the clinical and pathogenetic role of JAK2 V617F mutation in MPN, while its contribute as an additional thrombotic risk factor in MPN patients is still under discussion. The jak2 mutation has been identified as occult marker in several patients with splanchnic venous thrombosis (SVT); morover, 45% of patients with Budd-Chiari syndrome (BCS) and 34% of patients with portal vein thrombosis (PVT) have associated MPN. On the other hand, the majority of BCS patients without MPN present additional congenital or acquired thrombosis risk factors. The aim of the present study is to evaluate the incidence of SVT in MPN patients. We also evaluated the presence of other prothrombotic risk factors in MPN patients, in addition to the JAK-2 mutation. Out of the 460 Ph1 negative MPN patients observed in our center from January 2000 to January 2010 and retrospectively evaluated, 9 patients (7 females and 2 males; 2%) presented SVT. Six cases had Essential Thrombocythemia (ET), 2 Primary Myelofibrosis (PMF), and 1 Polycitemia Vera (PV). Five of the 6 cases with ET were females. Among the entire population of ET, SVT incidence was 3%. All the 9 patients diagnosed of SVT were JAK2 V617F positive and they were treated with antiaggregant and anticoagulation therapy; 6 received hydrossiurea. Seven patients had SVT before MPN diagnosis, 2 of them had splenectomy at diagnosis for surgical decision. In these patients developing SVT before MPN diagnosis no other major thrombotic event occurred during follow-up. The remaining 2 MPNs patients presented asymptomatic SVT diagnosed by imaging techniques routinely performed during MPN follow up. Interestingly, 75% of MPNs patients with SVT demonstrated at least one prothromobtic risk factor, such as factor V Leiden, Protein C deficiency, hyperhomocystinemia and 50% had 2 or more associated defects. MPNs patients without SVT (396) had a lower prevalence of prothrombotic risk factors and developed venous thrombosis in different anatomical sites: in these cases white blood cell count, platelets values and the presence of JAK2 V617F mutation correlate with the development of the thrombotic event. Conclusion. Even though SVT has a low incidence in MPNs patients, according to the results of the present retrospective study we suggest the potential benefit of searching for additional prothrombotic risk factors in the whole MPN population in order to prevent and/or properly treat this complication. Disclosures: No relevant conflicts of interest to declare.

Cytoreductive Therapeutic Approach in the Essential Thrombocythemia (ET) Patients of the Registro Italiano Trombocitemia (RIT): Preliminary Data

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5248-5248
Author(s):  
Luigi Gugliotta ◽  
Alessia Tieghi ◽  
Anna Candoni ◽  
Monia Lunghi ◽  
Gianluca Gaidano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Thrombocythemia ◽  
Therapeutic Approach ◽  
Jak2 V617f ◽  
Bone Marrow Biopsies ◽  
Thrombotic Risk ◽  
Significant Difference ◽  
Cytoreductive Treatment ◽  
Wbc Count

Abstract Background: the Registro Italiano Trombocitemia, that is a GIMEMA project, has been activated to registry Italian Essential Thrombocythemia (ET) patients, to improve the diagnosis appropriateness (WHO criteria), to verify the prognostic value of the clinical and biological parameters, to evaluate the compliance to the therapeutical Italian guidelines (1), and to create a network for activation of new studies. Objective: this analysis is mainly devoted to describe the ET patients registered in the RIT and to evaluate the therapeutic approach adopted in the 102 participating hematological centers. Material and methods: two thousand and fifteen ET patients have been registered after the written informed consent was obtained, and data validation by various expert panels is in progress. This preliminary report considers 1785 patients, diagnosed mainly (1078, 60.4%) since the publication in the year 2004 of the ET therapy Italian guidelines (1). Results: the patients, 678 (38%) males and 1107 (62%) females, showed at diagnosis: age 60.3 ± 16.8 years with higher values in males than in females (61.7 ± 15.3 vs. 59.4 ± 17.7, p&lt;0.05), being the patients below 40 years 14% and those over 70 years 33% of cases; PLT count (109/L) 846 ± 309 with lower values in males than in females (813 ± 261 vs. 866 ± 334, p&lt;0.002), and with values 1001–1500 and over 1500 in 16% and 4% of cases, respectively; WBC count (109/L) 9.1 ± 2.9, without difference by sex, and with values 12–15 in 10% and over 15 in 3% of cases; Hgb (g/dL) 14.2 ± 1.6 with higher values in males than in females (14.8 ± 1.5 vs. 13.8 ± 1.5, p&lt;0.001), and with values over 16.5 in 8.5% of males and 2.7% of females, respectively; splenomegaly in 488 (27%), echo-documented in 324 cases (18%); history of hemorrhage and thrombosis in 90 (5%) and 325 (19%) of cases, respectively; disease-related symptoms in 41% and general thrombotic risk factors in 93% of cases, respectively. The WHO 2001 diagnostic criteria were reported for 33% of cases observed before the year 2004 and for 53 % of cases observed since the year 2004. Detailed data at diagnosis were reported as follows: bone marrow biopsy in 1087 cases (61%) with a frequency of 51% and 68% before and since the year 2004, respectively; bcr-abl study in 1045 cases (59%); cytogenetics in 828 cases (46%) with karyotype abnormalities in 27 patients (3%). The JAK2 V617F mutation, searched in 574 cases (32%), was observed in 320 of them (56%). The patient follow-up was 4.5 ± 4.5 years with a total of 5245 pt-yrs. During the follow-up the hemorrhagic events were 5.7% (1.3/100 pt-yrs), being the major events 1.9% (0.4/100 pt-yrs); the thrombotic complications were 14.9 % (3.3/100 pt-yrs), resulting the major arterial 9.4% (2.1/100 pt-yrs), the major venous 3.5% (0.8/100 pt-yrs) and the minor thrombosis 2% (0.4/100 pt-yrs). An antiplatelet treatment, almost always with low dose aspirin, was performed in 75% of the patients, without significant difference in the cases diagnosed before and since the 2004. A cytoreductive treatment was done with use of Hydroxyurea (HU, 64%), Interferon alpha (IFN, 16%), Anagrelide (ANA, 15%), Busulfan (BUS, 4%), and Pipobroman (PIPO, 2 %). In the ET patients diagnosed since the year 2004 respect those diagnosed before, it was observed a decrease in the use of all the cytoreductive drugs, particularly BUS (−62%), IFN ((−62%), and ANA ((−68%). The use of the cytoreductive drugs was related to the patient mean age (years): BUS (76), PIPO (72), HU (67), ANA (53), IFN (48). In the patients diagnosed since the 2004 as compared with those before 2004, the mean age of the treated patients increased for BUS (from 69 to 81 yrs, p&lt;0.001) and for HU (from 64 to 69 yrs, p&lt;0.001) while it decreased for IFN (from 49 to 46 yrs, p&lt;0.05). Conclusion: in the analyzed patients of the ET Italian registry the diagnosis appropriateness resulted improved in the cases observed since the year 2004 respect those observed before, with an increase of bone marrow biopsies from 51% to 68% of patients. Moreover, in accord with the ET therapy Italian guidelines, the use of the cytoreductive drugs was less frequent in the patients diagnosed since the year 2004 than before (particularly for BUS, IFN, and ANA) and the more safe molecules IFN and ANA were preferentially deserved to the younger patients.

Outcomes of Patients with Myelodysplastic Syndromes/Myeloproliferative Neoplasms with Emphasis On MDS/MPN-Unclassified

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5025-5025
Author(s):  
Charikleia Kelaidi ◽  
Varnavas Constantinou ◽  
George Papaioannou ◽  
Niki Stavroyianni ◽  
Chrysanthi Vadikoliou ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
Univariate Analysis ◽  
Jak2 V617f ◽  
Female Ratio ◽  
Wbc Count

Abstract Abstract 5025 Background: Data on outcomes of patients (pts) with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), especially MDS/MPN-unclassified (MDS/MPN-U), are scarce. Patients/methods: We retrospectively studied pts followed in our center, with MDS/MPN according to WHO 2008 criteria. Because of overlap characteristics of MPN and MDS, pts with systemic mastocytosis associated with MDS (SM/MDS) were also included. Pts with previous MDS or MPN were excluded. Response and disease progression were defined according to IWG 2006 criteria. Results: Twenty-five pts with MDS/MPN were included. Median age was 70 y (range 19–79). Male/female ratio was 1.77/1. Diagnosis was CMML-1 N=7, CMML-2 N=7, JMML N=1, MDS/MPN-U N=8, systemic mastocytosis (SM)/MDS N=2, with one additional pt with CMML subsequently developing SM. At diagnosis, median WBC count was 18.8 G/L (range 3–120), ANC 15.5 G/L (0.6–70), monocytes 1.9 G/L (0.1–16), left shift 16% (0–28), Hb 11.2 g/dL (6–17), platelets 99 G/L (10–680), peripheral and bone marrow (BM) blasts 5% (0–17) and 7% (2–19), respectively (resp.). 25% of pts had platelets count ≥400 G/L. Splenomegaly, B-symptoms and BM fibrosis were present in 23%, 57% and 27% of pts, resp. Karyotype was fav, int and unfav in 55%, 36% and 9% of pts, with −7, +8, del(12)(p11), del(12)(q14;q21), +10, +21, and previously unreported t(9;12)(q13;q13) in 3, 6, and 1 pt each, resp., while +21 and i(17)(q10) appeared during disease progression other than AML transformation. IPSS was low/int-1 and int-2/high in 50% and 50% of pts, resp. JAK2 V617F and CKIT D816V mutations were detected in 2/6 pts and 2/2 SM/MDS pts, resp. 70% and 29% of pts were transfused at diagnosis with PRBC and platelets, resp. Treatment included erythropoiesis stimulating agents (ESAs), low dose chemotherapy, intensive chemotherapy (IC) and azacitidine (AZA) in 40%, 36%, 16% and 48% of pts resp. Response rate to ESAs, IC and AZA was 60%, 14% and 14% resp. Response rate to AZA in CMML-1 pts was 33%. Dasatinib yielded no response in 1 SM/MDS pt with CKIT D816V. 3-year cumulative incidence of AML and median overall survival (OS) in pts with CMML-1, CMML-2 and MDS/MPN-U were 20%, 40% and 0 (P=0.059) and 39, 8, and 20 mo (P=0.50), resp. The pt with JMML died from AML transformation 3 months after diagnosis. 2/3 pts with SM/MDS died from disease progression w/o AML at a median of 10 mo after diagnosis. Median survival after disease progression other than AML transformation was 35, 15 and 14 mo in pts with CMML-1, CMML-2 and MDS/MPN-U, resp. (P=0.88). Cause of death was disease progression other than AML, AML transformation and unrelated to disease in 50%, 50%, and 0 and 80%, 0 and 20% of cases in CMML and MDS/MPN-U, resp. (P=0.10). Percentage of circulating blasts ≥5% was the only independent factor affecting risk of AML transformation in the overall population (P=0.0004). Diagnosis other than CMML-1, WBC ≥30 G/L, % of circulating blasts ≥5% and IPSS high/int-2 were associated with worse survival in univariate analysis (P=0.06, 0.03, 0.04 and 0.08, resp.). No predictive factor of OS was found in multivariate analysis. Conclusion: MDS/MPN are heterogeneous disorders with respect to disease progression and AML transformation. MDS/MPN-U tended to differ from CMML-1 by shorter survival after disease progression other than AML, and from CMML-2 by lower risk of AML transformation. Mortality of pts with MDS/MPN-U was mainly attributed to disease progression without AML transformation. Alternatively to hypomethylating agents, therapeutic options in pts with MDS/MPN-U could include JAK2 inhibitors. Disclosures: No relevant conflicts of interest to declare.

Risk Factors for Thrombosis Vary According to Age in Patients with Essential Thrombocythemia: a Retrospective Analysis of 1090 Patients from the “Gruppo Laziale SMPC Ph Negative “,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3854-3854
Author(s):  
Marco Montanaro ◽  
Roberto Latagliata ◽  
Michele Cedrone ◽  
Nicoletta Villivà ◽  
Raffaele Porrini ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Thrombotic Event ◽  
Age Groups ◽  
Thrombotic Risk ◽  
Mutational Status ◽  
Group A ◽  
Group B

Abstract Abstract 3854 Increasing age is a well-recognised risk factor for thrombotic events in patients with Essential Thrombocythemia (ET): however, few data exist on the role of other clinical and biological features in different age groups. To address this issue, we analysed retrospectively 1090 ET patients (M/F 403/687, median age 63 years, IR 17 – 96) diagnosed at 11 Hematological Institutions in the Lazio region from 1980 to 2010 and with a median period of follow-up of 84 months (IR 1 – 371). Based on the commonly adopted age threshold, 480 patients (44 %) were < 60 years (Group A) and 610 (56 %) were ≥ 60 years (Group B). Clinical and biological features as well as cardiovascular risk factors analyzed for the impact on the thrombotic risk in the two age groups are reported in the Table.Group A < 60 yearsGroup B ≥ 60 yearsPutative risk factorsRisk ratio (95% CI)P valueRisk ratio (95% CI)P valueM/F167/3132.68 (1.03–6.94)0.0029236/3741.12 (0.17–2.59)0.73WBC median (range) x 109/l8.9 (4.29–22.35)0.387 (0.149–1,004)0.06458.9 (1.2–57.7)0.79 (0.41–1.47)0.445PLTS median (range) x 109/l837 (451–3582)0.37 (0.258–1.70)0.66802 (450–3104)0.52 (0.28–0.99)0.0052Hb median, g/dL (range)14.1 (6.0–18.4)0.86 (0.33–2.24)0.76914.0 (7.0–17.8)0.87 (0.45–1.67)0.674*JAK-2 mutational status: wild type/mutated (%)53.2/46.81.57 (0.50–4.87)0.4434.1/65.90.498 (0.17–1.48)0.209Previous thrombotic events: n° (%)· All events72 (15)2.18 (0.59–7.96)0.12149 (24.4)3.01 (1.38–6.57)0.0004· within 24 months from diagnosis48 (10)1.43 (0.19–10.4)0.7464 (10.5)0.506 (0.18–1.39)0.189· within 60 months from diagnosis60 (12.5)NA0.5191 (14.9)0.323 (0.11–0.95)0.023Cardiovascular risk factors: Y/N %○ Arterial hypertension41.7/58.31.68(0.64–4.36)0.2880.7/19.30.96 (0.36–2.57)0.935○ Diabetes10.2/89.81.11 (0.23–5.15)0.8925.0/75.01.09 (0.38–3.11)0.86○ Smoking attitude45.6/54.42.78 (1.01–7.65)0.06758.3/41.71.04 (0.35–3.09)0.94○ Hyperlipidemia31.0/69.03.11(0.917–10.592)0.03951.6/48.42.31 (0.70–7.55)0.203 In Group A, 39 patients (8.1%) had at least one thrombotic event during follow-up; there were 20 (51.3%) arterial thrombosis and 19 (48.7%) venous thrombosis. In Group B, 63 patients (10.3%) had at least one thrombotic event during follow-up; there were 38 (69.4%) arterial thromboses and 25 (39.6%) venous thromboses. In group A univariate analysis for thrombosis-free survival performed by Kaplan-Meier method, disclosed a significant impact of male gender (p=0.0029, CI 1.03–6.94, HR 2.68), > 2 cardiovascular risk factors (p=0.0002, CI 1.87 – 190, HR 18.94) and isolated hyperlipidemia (p=0.039, CI 0.917 – 10.59, HR 3.11), while previous thrombotic events had no significant impact (p=0.27). By contrast, the presence of a previous thrombotic event was the only feature with a significant impact on thrombotic risk in Group B (p=0.0004, CI 1.38 – 6.55, HR 3.01). WBC and PLTS values at different cut-off levels as well as JAK-2 mutational status did not have any impact on thrombosis in either age groups. However, in group B, we observed a trend (p=0.052, CI 0.28–0.99, HR 0.52) towards a protective effect of higher PLTS values (> 800 × 109/l). In conclusion, our data seem to reinforce the need of a different thrombotic risk assessment in distinct age groups: in particular, younger patients could benefit from early recognition and treatment of well-known cardiovascular risk factors. Disclosures: No relevant conflicts of interest to declare.

Leukocytosis Can Predict Thrombotic Events in Myelofibrosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5191-5191
Author(s):  
Laura Coutinho Vassalli ◽  
Emilia Carolina Malafaia ◽  
Maria L. Chauffaille ◽  
Daniella Kerbauy
Keyword(s):  
Polycythemia Vera ◽  
Blood Cells ◽  
Myeloproliferative Neoplasms ◽  
Thrombotic Event ◽  
White Blood Cells ◽  
Jak2 V617f ◽  
The Other ◽  
Jak2 V617f Mutation ◽  
Increased Risk ◽  
V617f Mutation

Abstract Thrombotic events are the main complication of Philadelphia-negative chronic myeloproliferative neoplasms (MPN). In polycythemia vera (PV) and essential thrombocythemia (ET), risk factors for thrombosis are well established, such as age greater than 60 years and previous thrombosis. However, the role of JAK2 V617F mutation and leukocytosis at diagnosis as risk factor for thrombosis is still controversial. Our aim was to identify factors related to the risk for thrombotic events in the studied population.This study is a retrospective non-interventional cohort. All of the analyses were performed using the database of 142 patients with MPN regularly followed at the Hematology Division (at UNIFESP-SP) from 1992 to 2014. Diagnosis was established according to WHO criteria. We analyzed the JAK2 V617F mutation, hemoglobin (g/dL), hematocrit (%), white blood cells (x109/L) and platelets (x109/L) at the diagnosis and DIPSS-Plus risk score (International Working Group for Myelofibrosis Research and Treatment, 2009). These variables were associated with thrombotic event at any time.Of the 142 patients, 54 had diagnosis of PMF, 28 of PV, 33 of ET and 27 of post-essential thrombocythaemic myelofibrosis (post ET MF) or post-polycythaemic myelofibrosis (post-PV MF). This last group was included in myelofibrosis group for statistical purposes. Thrombotic events were more frequent in PV patients (39.2%), followed by ET (33.3%), and PMF (20.9%). From those which JAK2 mutation was obtained, it was positive in 92.4% of PV patients, 62% of PMF and 50% of ET. In none of the three groups, the presence of JAK2 V617F mutation was related to increased risk of thrombosis. In myelofibrosis, leukocytosis was higher among thrombotic patients (median of 13.7 in thrombotic group versus 9.7x 109/L; p 0.0379). None of the other parameters, hemoglobin, hematocrit, platelets and DIPSS-Plus were statistically significant. In ET, the hemoglobin level at diagnosis was significantly higher in the presence of thrombosis (mean of 14.57 in thrombotic group against 13.03 g/dL in the non-thrombotic one, p 0.0428). The other parameters, hematocrit, white blood cells and platelets were not relevant. The median WBC in the thrombotic group was 9.4 and in the non-thrombotic one 9.3 x109/L. Finally, in polycythemia vera, none of the variables were related to thrombosis. Among the studied population, leukocytosis was increased in patients with thrombotic event in MF. Thus, monitoring leukocyte count in MF is essential to predict thrombosis risk and should be further studied in order to define therapeutic goals in these patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Epidemiology of Patients with Classical Philadelphia-Chromosome Negative Myeloproliferative Neoplasms at a Single Academic Medical Center in Singapore

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5478-5478
Author(s):  
Priscella Shirley Chia ◽  
Vanessa CL Chong ◽  
Ting Yuan Tay ◽  
Eng Soo Yap ◽  
Wee Joo Chng ◽  
...  
Keyword(s):  
Southeast Asia ◽  
Ethnic Groups ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Local Population ◽  
Philadelphia Chromosome ◽  
Leukemic Transformation ◽  
Female Ratio ◽  
Platelet Counts ◽  
The Mean

Abstract Introduction: Myeloproliferative Neoplasms (MPNs) represents a disorder that involves abnormal proliferation of cells originating from the myeloid line. The proliferation of these cells can lead to complications that are at times fatal. Despite its potential to cause life threatening complications, there is little data on this disease in Southeast Asia. As Singapore is a multiracial country in Southeast Asia, there may be some disease characteristics exclusive to patients here due to its unique population composition. The data from this Southeast Asian cohort would be useful to determine disease homogeneity in Asian countries. Methods: A retrospective review of the MPN database from National University Hospital, Singapore (NUHS) revealed 320 patients who were clinically diagnosed with MPN from 2008 to 2017. This data included patients with Essential Thrombocythemia (ET), Polycythemia Rubra Vera (PRV), Primary Myelofibrosis (PMF), Myeloproliferative Neoplasm, unclassifiable (MPN-U) and Chronic Eosinophilic Leukemia (CEL) (Figure 1A) as per the 2017 WHO classification. For this analysis, we included only the classical Philadelphia chromosome negative MPN and focused on the epidemiology, transformation and overall survival rate. Results: There was a slight male predominance with a male to female ratio of 1.3:1. The ethnic groups within this cohort consisted of 65.8% ethnic Chinese, 20.7% Malay, 5.5% Indian and the rest were made up of other ethnic groups within the region such as Eurasians, Thai, Filipinos, Burmese, Indonesians, Bangladeshi, Vietnamese and Arabian patients. The mean age at diagnosis for this group was 60.5. The mean age was 59.2 years for ET, 61.2 for PRV and the mean age of PMF was the oldest at 63.8. The mean age of diagnosis for ET and PMF patients in our cohort was slightly older compared to the Korean cohort (55.4 and 59.5 years) (Byun, et al., 2016). The majority of this cohort was made up of ET patients (53.1%) followed by PRV (35.3%) and PMF (11.6%). 77.5% of these patients were JAK2 V617F mutation (JAK2) positive. The percentage of patients who were JAK2 positive for ET, PRV and PMF were 69.2%, 96.9% and 56.3% respectively. The percentage of JAK2 positive patients for the three subtypes were higher in our local population compared to the Chinese and Japanese cohorts. Only 120 patients were tested for Calreticulin Exon 9 (CALR) mutations as this molecular test was only available in our institution from 2015 onwards. ET patients make up 68.4% of CALR positive patients. It was noted that CALR positive patients had comparatively higher mean platelet counts of 925.2 than CALR negative patients with mean platelet counts of 691.7. This phenomenon is seen in both CALR positive ET and CALR positive MF patients. In the 10-year period, 25 patients were lost to follow up and 8 patients transferred their care to another institution. Overall, 27 patients were deceased, with a mean survival of 3.5 years. The death-to-case ratio was 11.5 per 100 cases. The death-to-case ratio for ET, PRV and PMF is 6.1 per 100, 8.2 per 100 and 31.3 per 100 respectively. During this period, only 6 patients had transformation. Three patients progressed to post-ET myelofibrosis and 3 had leukemic transformation. Those who had leukemic transformation were initially diagnosed with PRV (1 patient) and PMF (2 patients). All patients who had leukemic transformation were deceased and had a mean survival of 1.4 years from the transformation event. Conclusion: Whilst there were some observable differences between our data and existing Asian data, there is still insufficient information to determine disease homogeneity. This is partly due to the rapid growth of molecular knowledge in this field and the regular revision of the WHO diagnostic criteria of MPNs over the last decade or so. There needs to be coordinated efforts within the region to ensure that our patients have equal access to these diagnostic platforms and that they receive an accurate diagnosis. Disclosures Chng: Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Aslan: Research Funding; Merck: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses.

scholarly journals Expression of HMGA2 Collaborates with JAK2V617F to Progress Myeloproliferative Neoplasms

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 482-482
Author(s):  
Koki Ueda ◽  
Kazuhiko Ikeda ◽  
Kazuei Ogawa ◽  
Akiko Shichishima-Nakamura ◽  
Kotaro Shide ◽  
...  
Keyword(s):  
Disease Progression ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Extramedullary Hematopoiesis ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Epigenetic Modifiers ◽  
One Year

Abstract Myeloproliferative neoplasms (MPN) are characterized by chronic proliferation of myeloid cells, extramedullary hematopoiesis and occasional leukemic transformation. Mutations in JAK2, CALR and MPL have been established as drivers of myeloproliferative phenotype, but their roles in disease progression with clonal expansion remain unclear. In addition, studies have shown mutations in epigenetic modifiers including TET2, DNMT3A, ASXL1 and EZH2, and aberrant expressions of microRNAs in MPN, but downstream of these changes is also largely unknown. Recently, we showed high expression of HMGA2 mRNA partly correlated with reduced microRNA let-7 in granulocytes of patients with MPN, including 100% patients with primary myelofibrosis (MF) and 20% polycythemia vera and essential thrombocythemia (Harada-Shirado et al, Brit J Haematol, 2015). In mice, loss of epigenetic modifiers such as BMI1 and EZH2, along with the Arf/Ink4a knockout (Oguro et al, J Exp Med, 2012) or the JAK2 V617F (Sashida et al, ASH, 2013), leads to overexpression of HMGA2 with accelerating MPN. We have generated transgenic (Tg) mice of Hmga2 cDNA with truncated 3'UTR (ΔHmga2) lacking binding sites of let-7 thatrepresses expression of HMGA2 (Ikeda et al, Blood, 2011). Δ Hmga2 mice overexpress HMGA2 and develop MPN-like disease, and represent a clonal advantage in competitive repopulations with serial bone marrow (BM) transplants (BMT). Here, to clarify if HMGA2 affect JAK2 V617F+ hematopoiesis, we crossed Δ Hmga2+/- mice with JAK2 V617F+/- Tg mice (Shide et al, Leukemia, 2008). Δ Hmga2-/-JAK2 V617F-/- wild type (WT), Δ Hmga2+/-JAK2 V617F-/- (Δ Hmga2 -Tg), Δ Hmga2-/-JAK2 V617F+/- (JAK2 V617F-Tg) and Δ Hmga2+/-JAK2 V617F+/- (double-Tg) mice were born at expected Mendelian ratios and we could analyze 5 - 6 of each. At 3 months old, leukocytosis, thrombocytosis, anemia and splenomegaly were most severe in double-Tg compared with JAK2 V617F-Tg or Δ Hmga2 -Tg mice. Relative to WT, peripheral leukocyte and platelet counts were nearly 16- and 4-fold higher in double-Tg, while 3- and 2-fold higher in JAK2 V617F-Tg mice, respectively. Mean spleen weights were 0.067, 0.10, 0.83 and 2.8 g in WT, Δ Hmga2 -Tg, JAK2 V617F-Tg and double-Tg mice, while BM cell counts were 2.4, 2.8, 0.4 and 1.2 x 107/femur, respectively. However, JAK2 V617F-Tg and double-Tg equally showed MF whereas no MF was detected in WT and DHmga2-Tg, suggesting that HMGA2 partly recovers cellularity in fibrotic BM. In the absence and presence of JAK2 V617F, HMGA2 augments lineage- Sca1+ Kit+ cells (WT: Δ Hmga2-Tg: JAK2 V617F-Tg: double-Tg= 0.17%: 0.19%: 0.17%: 0.27% in BM cells), endogenous erythroid colonies (1: 11: 13: 21 CFU-E/104 BM cells) and CD71+ Ter119+ erythroblasts (23%: 29%: 5.7%: 10% in BM and 2.0%: 4.4%: 7.9%: 16% in spleen cells), indicating HMGA2 contributes to expansion of hematopoietic stem/progenitor cells (HSPC) and erythroid commitment in JAK2 V617F+ hematopoiesis. Most Δ Hmga2-Tg and JAK2 V617F-Tg survived for over one year, but all double-Tg mice died within 4 months after birth due to severe splenomegaly and MF with no acute leukemia. To study the effect of HMGA2 on JAK2 V617F+ HSPC activity, we performed BMT with 0.25 x 106 Ly5.2+Δ Hmga2-Tg, JAK2 V617F-Tg or double-Tg cells with 0.75 x 106 Ly5.1+ competitor WT cells to lethally irradiated Ly5.1+ WT mice. Proportions of Ly5.2+ cells were higher in recipients of Δ Hmga2 -Tg than double-Tg cells, while JAK2 V617F-Tg cells were almost rejected at 8 weeks after BMT. To confirm role of HMGA2 without let-7 repression in JAK2 V617F+ hematopoiesis, we performed another BMT with 1 x 104 KIT+ cells of JAK2 V617F-Tg mice transduced with retroviral vector of Hmga2 with each let-7 -site-mutated full-length 3'UTR (Hmga2-m7) to sublethally irradiated WT mice. Recipients of JAK2 V617F-Tg cells with Hmga2-m7 developed MPN-like disease, whereas donor cells were rejected in recipients of JAK2 V617F cells with empty vector. In conclusion, HMGA2 may play a crucial role in hematopoiesis harboring JAK2 V617F by expanding HSPC, leading to disease progression. Disclosures No relevant conflicts of interest to declare.

Long-Term Evaluation of 205 Patients with Essential Thrombocythemia: Clinical Outcome, Efficacy and Safety with Respect to Different Therapies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4941-4941
Author(s):  
Nicola Vianelli ◽  
Antonio deVivo ◽  
Mauro Fiacchini ◽  
Alessandro Lucchesi ◽  
Benedetta Giannini ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Normal Population ◽  
Alkylating Agents ◽  
Thrombotic Event ◽  
Age At Diagnosis ◽  
Thrombotic Risk ◽  
Blastic Transformation ◽  
Solid Malignancy ◽  
Hemorrhagic Events

Abstract Essential Thrombocythemia (ET) is a myeloproliferative disorder associated with persistent thrombocytosis. The main clinical features are recurrent thrombotic and/or hemorrhagic events, involving both the arterial and venous systems. Data concerning the role of platelet-lowering agents to prevent thrombotic and hemorrhagic events are not conclusive, despite the risk associated to the use of some of them as hydroxyurea (HU) or alkylating agents like busulfan (BU), to induce a leukemic transformation or solid malignancy. We report here our experience, on 205 (M 78, F 127) consecutive ET patients (pts) referred to our Institute between January 1977 and December 2003, with a median follow-up of 76 months (4–318). Median age at diagnosis was 66 (15–91) years; median platelet (PLT) number was 780 (465–3700) x109/L. One hundred and ninety-five pts (95%) were considered at high risk for thrombosis. One hundred and eighty of them (92.3%) were treated with platelet-lowering agents: HU (82 pts), BU (39 pts), HU+BU (37 pts), IFNa (6 pts), HU+IFNa (10 pts), BU+IFNa (2 pts) or HU+BU+IFNa (4 pts). In 30/180 (16.7%) and 124/180 (68.9%) pts the treatments were able to maintain the PLT number <400x109/L (Complete remission) and 400–600x109/L (Partial remission), respectively, for at least 2/3 of their follow-up. Only three pts withdrawn HU or BU for toxicity. A total of 192 (93.6%) pts received antiplatelet agents (121 Aspirin, 34 Ticlopidine, 37 others) for a median period of 53(1–318) months; in 42 pts this therapy was withdrawn, in most cases after gaining control of the platelet count (PLT <600x109/L). During follow-up we registered 33 thrombotic events in 21 (10.2%) pts, and 22 hemorrhagic events in 20 (9.8%) pts, while dizziness, headache and other symptoms due to microvascular disturbance were present in 88 pts. Patients who received both HU and BU consecutively developed a significantly higher number of thrombotic events, compared to pts who received a single drug (p=0.004); this could be explained by the difficult control of the disease in this subgroup of pts. Previous thrombotic event, age and platelet number at diagnosis, thrombocytosis control during follow-up and presence of one or more common cardiovascular risk factors were evaluated in order to establish any correlation with thrombotic risk. Only the first two factors resulted significant. Blastic tranformations, myelofibrosis evolution and solid malignancy occurred in 2(1.0%), 4(1.9%) and 8(3.9%) pts, respectively. The two pts who showed blastic transformation were treated with a particularly high total dose of HU (3039500mg) if compared to the median dose administered (462000mg) or with the sequential association of HU and BU. No strict correlation was observed between the 8 pts who developed a solid malignancy and the therapy administered. The overall survival expressed by the Kaplan-Meier curve was approximately 85% at 12 years after diagnosis, that is similar to the life expectancy of normal population. In conclusion, in our experience HU and BU resulted effective with neglegible toxicity in controlling thrombocytosis in ET pts. Only previous thrombosis and older age at diagnosis significantly increase the risk of thrombotic event during follow-up. The ET blastic transformation seems to be related to the HU+BU association or to a higher total HU dose administered.

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