Diagnosis Of Essential Thrombocythemia Research Articles

A Nationwide Analysis of Outcomes of Stroke in Hospitalized Patients with Essential Thrombocythemia: 2006 to 2014

Background:Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm which is associated with an increased risk of thrombohemorrhagic complications as well as progression to myelofibrosis and frank leukemia. Patients with ET are at an elevated risk for stroke. However, studies of prevalence and outcomes of stroke in hospitalized patients with ET have been limited to case series. The median survival of patients with ET is comparable to normal population but the quality of life may be significantly altered due to the occurrence of thrombotic events in the cerebrovascular and cardiovascular systems. By conducting a retrospective analysis of nationwide data from hospitalized ET patients between the years of 2006 and 2014, we sought to identify if there are any statistically significant associations between stroke and/or in-hospital mortality with respect to patients' gender, age group, race, and comorbidities like hypertension, diabetes atrial fibrillation and chronic kidney disease.Methods:Data from the National Inpatient Sample was utilized to identify outcomes in hospitalized patient with ET who were admitted for stroke. The National Inpatient sample is a database maintained by the Agency for Healthcare Quality and Research. Utilizing the current procedural terminology code (CPT) for ET, outcomes of patients with ET who were hospitalized with stroke were studied for the year 2006 to 2014. Patient demographics of age, gender and race were collected and hospital characteristics of location and size were correlated to outcomes. The extent of common medical comorbidities such as hypertension, diabetes, chronic kidney disease and atrial fibrillation was studied in ET patients who died with and without stroke. Chi square test was used to determine odds ratios and multiple logistic regression was used to determine independent predictors of mortality.Results:Between 2006 to 2014, 552422 hospitalizations involved patients with a diagnosis of ET of which 20650 hospitalizations were due to stroke. Of these patients with stroke there was a preponderance of prevalence in females (13400 vs. 7251). The percentage of stroke in these hospitalizations varied between 3.64 to 4.29 over 15 years and mortality in these patients did not significantly change during this time period. The prevalence of stroke was highest amongst Asians and Caucasians (4.7% and 3.86%) with a statistically significant difference (p=0.0000). The age group of 80+ years and the difference in prevalence between different age groups (18-34 vs. 35-49 vs, 50-64 vs. 75-79) was statistically significant (p=0.0000) with Medicare being the insurance for most of these patients (p=0.000)). Notably, mortality was highest in the same group but was not significantly different from other age groups. Large sized hospitals were noted to have a higher proportion of ET patients with stroke compared to smaller and medium sized hospitals (p=0.0002). No difference in such proportions was noted in hospitals varying by region (Northeast vs. Midwest vs. South vs. West). Burden of medical comorbidities as measured by Charlson's comorbidity index was noted to be in the 4-6 range. Similarly, hypertension, hyperlipidemia, diabetes, atrial fibrillation, smoking status were also found to be more frequent in ET patients with stroke. A majority of ET patients with stroke were discharged to skilled nursing facilities. Multiple regression showed that female gender, atrial fibrillation, stroke, higher Charlsons comorbidity score and 80+ age were independent predictors of mortality (OR: 0.75, 1.35, 1.8, 2 to 5.7, 13.9 respectively).Conclusions:Patients with ET who are hospitalized with stroke have significantly worse outcomes. This study demonstrated that a statistically significant difference exists among different age groups of patients with ET and stoke who died during hospitalization when stratification is made using age groups and Charlson Score. This study may serve as an initial point to include new risk factors for further risk stratification. Early identification of patients at higher risk may reduce the incidence and decrease the morbidity of stroke in patients with ET. DisclosuresKota:BMS: Honoraria; Novartis: Honoraria; Xcenda: Honoraria; Incyte: Honoraria; Pfizer: Honoraria.

Mutations and Thrombosis in Essential Thrombocythemia and Polycythemia Vera: Mayo-Careggi Alliance Study

Background:Thrombosis is a characteristic feature in essential thrombocythemia (ET) and polycythemia vera (PV). Previous studies had focused on thrombotic events occurring after diagnosis and did not always distinguish between arterial and venous thrombosis. Arterial thrombosis in ET has been associated with age >60 years, JAK2 mutations, leukocyte count >11 x 109/l, history of thrombosis and cardiovascular risk factors, and venous thrombosis with male sex (Blood 2011;117:5857). In the current two-enter study, we looked for associations between both driver and other mutations, with first incidences of arterial and venous thrombosis in ET and PV, analyzed together and separately.Methods:Study patients were recruited from the Mayo Clinic, Rochester, MN, USA and the University of Florence, Florence, Italy, based on availability of next-generation sequencing-derived mutation information. Diagnoses were according to the 2016 World Health Organization criteria (Blood. 2016;127:2391). Conventional statistics was employed to examine significance of associations, with separate analysis of arterial vs venous thrombosis, occurring at any time before or after formal diagnosis of ET or PV. For the purposes of the current study, only first events were considered.Results:906 molecularly-annotated patients (416 from Mayo and 490 from Florence), including 502 ET and 404 PV cases, were included in the current study. The Mayo/Florence cohorts included 270/232 ET (median age 57/54 years, 60%/59% females) and 146/258 PV (median age 63/58 years, 52%/44% females) patients; median follow-up was 9.9/12.9 years for ET and 10.7/12.4 years for PV. Driver mutation distribution in ET was 55% JAK2, 27% CALR, 5% MPL and 13% triple-negative. Most frequent mutations, other than JAK2/CALR/MPL, were TET2 (14%; 11% in ET and 18% in PV) and ASXL1 (13%; 13% in ET and 13% in PV).301 (33%) patients experienced first time thrombosis, before or after diagnosis, including 152 (30%) in ET and 149 (37%) in PV (p=0.03); arterial events occurred in 174 (19%) patients, including 96 (19%) in ET and 78 (19%) in PV (p=0.9); venous events occurred in 177 (20%) patients, including 82 (16%) in ET and 95 (24%) in PV (p=0.007). The number of vascular events after diagnosis was 174 (19%) for arterial and 154 (17%) for venous thrombosis, with no significant difference between ET and PV.Associations with arterial thrombosis:In multivariable logistic regression analysis that included both ET and PV (n=906), age >60 years (23% vs 16%; OR, 1.6, 95% CI 1.1-2.2) and absence of ASXL1 and RUNX1 mutations (21% vs 9%; OR 2.6, 95% CI 1.4-4.8) were associated with arterial thrombosis; these associations remained significant (or near significant) when ET and PV were analyzed separately; in addition, JAK2 mutations in ET displayed borderline significance (p=0.05). Overall incidence of arterial events in ET was estimated at 27% in the presence of all three risk factors (i.e. older age, presence of JAK2 mutations and absence of ASXL1/RUNX1 mutations), 21% with two risk factors, 13% with one risk factor and 9% in the absence of all three risk factors (p=0.01).Associations with venous thrombosis:In multivariable analysis, including both ET and PV (n=906), JAK2 mutations (p<0.001), higher leukocyte count (p=0.03) and younger age (p=0.04) were identified as being significant. Analysis of ET patients only (n=502) identified JAK2 mutations (p<0.001; OR 2.4, 95% CI 1.4-4.1), absence of SRSF2 mutations (p=0.03) and younger age (p=0.04) as independent risk factors and in PV patients (n=404), higher leukocyte count (p=0.06).Prognostic interaction between JAK2 mutations and age:In ET, the overall frequency of venous events was 27% for young patients with JAK2 mutations vs 13% for older JAK2 mutated cases vs 10% for JAK2 unmutated young patients vs 13% for JAK2 unmutated older patients (p<0.001). The corresponding percentages for arterial events were 20%, 24%, 14% and 19%, respectively (p=0.1).Conclusions:JAK2 mutations contribute to the risk of both venous (younger patients) and arterial (young and older patients) thrombosis, in an age-dependent manner; the association with venous thrombosis might explain the higher incidence of venous thrombosis in PV, compared to ET. Additional studies are required to confirm the observed lower risk of thrombosis in patients with ASXL1, RUNX1 and SRSF2 mutations and provide insight into the underlying biological explanation. DisclosuresNo relevant conflicts of interest to declare.

Serum Erythropoietin Levels in Essential Thrombocythemia: Phenotypic and Prognostic Correlates

Background:Subnormal serum erythropoietin (EPO) level is widely accepted as a minor diagnostic criterion for polycythemia vera (PV) and has retained its value in the revised 2016 World Health Organization (WHO) classification scheme of myeloid neoplasms (Blood. 2016;127:2391). While over 80% of PV patients exhibit subnormal EPO values (Haematologica. 2004;89:1194), very little is known about the incidence, phenotypic connotation, or prognostic significance of serum EPO levels in essential thrombocythemia (ET).Methods:Study patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnosis of ET was in strict accordance with the 2016 WHO criteria (Blood. 2016;127:2391) and only patients with EPO measurements at diagnosis or during their chronic phase were considered under the following provisions: i) no evidence of myelofibrotic or leukemic transformation; ii) no treatment with cytoreductive agents at the time of sample collection (and for those with EPO sampling at diagnosis, no prior exposure to cytoreductive therapy); iii) no hemoglobin levels below sex-adjusted values for anemia; and iv) systematic exclusion of all cases of masked PV. Serum erythropoietin levels were measured using Mayo-verified standard immune-enzymatic assay consistent with CLIA requirements with reference range between 4-21 mIU/mL. Standard statistical methods and time-to-event curves prepared using the Kaplan-Meier method were used to compare EPO-stratified groups. The JMP® Pro 13.0.0 software package was used for all analyses (SAS Institute, Cary, NC, USA).Results:Among 177 informative ET patients (median age 51 years, range 18-88; 71% females), median serum EPO concentrations were 5.2 mIU/mL (range <1-25) overall and 2.6 mIU/mL (range <1-3.9) and 7.2 mIU/mL (range 4-25) in those with subnormal versus normal/above normal EPO levels, respectively (p<0.0001). The majority of EPO measurements were at the time or within one year of diagnosis (67%), with the remainder obtained at referral or during the chronic clinical course. Risk stratification disclosed low, intermediate, and high risk status in 45%, 33% and 23% of patients, respectively, with no appreciable differences between EPO-stratified subsets.Subnormal serum EPO levels clustered clinically with JAK2 mutations (95% vs 60%; p<0.0001), higher hemoglobin (median 14.7 vs 13.8 g/dl, range: 12.1-17.8 vs 12-17.1; p<0.0001) and leukocyte counts (median 9.7 vs 8.2 x 109/l, range: 4-28.1 vs 3.9-22; p=0.0001), and arterial thrombosis after diagnosis (13% vs 5%; p=0.04). In addition, all three documented conversions to PV (p=0.01) and none of the six fibrotic progressions (p=0.02) occurred in patients with subnormal serum EPO levels (Table 1).While serum EPO level had no bearing on overall survival data (p=0.41) (Figure 1A), subnormal circulating EPO concentrations were significantly associated with superior myelofibrosis-free survival (p=0.02) (Figure 1B) but conversely, inferior polycythemia-free survival (p=0.03) (Figure 1C).Conclusions:We conclude that subnormal serum EPO levels are relatively frequent in ET, cluster with disease features that are reminiscent of polycythemia vera, and might be associated with a lower risk of fibrotic progression. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Early/prefibrotic primary myelofibrosis in patients who were initially diagnosed with essential thrombocythemia.

A new entity, namely early/prefibrotic primary myelofibrosis (PMF), was introduced as a subtype of PMF in the 2016 revised World Health Organization (WHO) criteria for myeloproliferative neoplasms (MPN). It was diagnosed based on histopathological features of bone marrow (BM) biopsy specimens together with clinical parameters [leukocytosis, anemia, elevated lactate dehydrogenase (LDH) values, and splenomegaly]. The aim of this study was to evaluate the prevalence of early/prefibrotic PMF in patients who were previously diagnosed with ET, and to compare clinical features at diagnosis and outcomes between early/prefibrotic PMF and essential thrombocythemia (ET) patients. BM biopsy samples obtained at the time of ET diagnosis were available in 42 patients. Sample reevaluation according to the 2016 revised WHO criteria revealed that early/prefibrotic PMF accounted for 14% of patients who were previously diagnosed with ET, which was comparable to the rates in previous reports. Compared to patients with ET, patients with early/prefibrotic PMF had higher LDH values and higher frequencies of splenomegaly. Overall, myelofibrosis-free and acute myeloid leukemia-free survivals were comparable between the 2 groups. Accurate diagnosis is required to clarify the clinical features of Japanese ET patients.

Impact of Myeloproliferative neoplasms on patients\u2019 employment status and work productivity in the United States: results from the living with MPNs survey

BackgroundPatients with the myeloproliferative neoplasms (MPNs) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are at increased risk for thrombotic and cardiovascular events and experience a variety of burdensome symptoms. However, there is a paucity of data in the biomedical literature about how MPNs impact productivity in the workplace. This analysis of the Living with MPNs survey was conducted to evaluate the impact of MPNs on employment, career potential, and work productivity.MethodsThis cross-sectional online survey included respondents aged 18–70 years living in the United States with a diagnosis of MF, PV, or ET. The survey consisted of ~ 100 questions related to MPN diagnosis, disease-related medical history, MPN-related symptoms and functional status, changes in employment and work productivity, and impact on daily activities since diagnosis. The MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) was used to assess symptom burden. The Work Productivity and Activity Impairment Specific Health Problem questionnaire (WPAI-SHP) was used to assess the effects of MPNs on work productivity and activity (7-day recall) among currently employed respondents. Correlations between MPN-SAF TSS and WPAI-SHP scores were calculated using Spearman’s coefficients.ResultsOf 904 respondents, 592 were employed (MF, n = 174; PV, n = 248; ET, n = 170) at the time of their MPN diagnosis. Approximately half (50.5%) of the 592 employed survey respondents reported ≥1 change in employment status because of their diagnosis, most commonly “left a job” (30.2%) “went on medical disability leave” (24.8%), and “had reductions in work hours for at least 3 months” (21.8%). Among respondents who remained employed at the time of survey participation (n = 398), mean WPAI-SHP scores were as follows: absenteeism, 6.9%; presenteeism, 27.4%; overall work impairment, 31.1%; and activity impairment, 32.8%. WPAI-SHP scores positively correlated with MPN-SAF TSS (correlation coefficients, 0.37–0.70; P < 0.001).ConclusionsHalf of the employed respondents had an employment status change (eg, leaving a job, medical disability leave, early retirement) because of their disease since the diagnosis. Currently employed respondents reported meaningful impairments in work productivity and activities of daily living that were attributable to their MPNs, and the degree of impairments highlighted the severity of symptom burden.

Genetic Alterations in Essential Thrombocythemia Progression to Acute Myeloid Leukemia: A Case Series and Review of the Literature.

The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.

Thrombosis in myeloproliferative neoplasms

Among all types of myeloproliferative neoplasms (MPNs), polycythemia vera (PV) and essential thrombocythemia (ET) require careful management of both thrombosis and hemostasis. One recent concern associated with MPNs is the JAK2 mutation (V617F). This mutation is essential for MPN pathology, but it has also garnered attention for its association with thrombosis. Several studies have reported the mechanisms underlying the onset of thrombosis in both PV and ET and have also discussed the association between JAK2 mutations and thrombotic tendencies. Arterial thrombosis is a common clinical symptom that is associated with the diagnosis and course of both PV and ET. Particularly, cerebral infarction has been identified as the leading cause of death in patients with untreated PV. Notably, PV and ET are also associated with a high incidence of venous thromboembolism (VTE). The occurrence of this type of thrombosis at atypical sites, such as cerebral venous sinus thrombosis and splanchnic vein thrombosis (SVT), is not uncommon. Generally, patients with PV and ET have good life expectancy; their treatment essentially focuses on dealing with thrombosis and bleeding. Phlebotomy may be used for treating patients with PV; however, low-dose aspirin is used to prevent the onset of arterial thrombosis. For patients with a history of VTE, oral anticoagulants are commonly prescribed to prevent recurrence.

Management of essential thrombocythemia in a resource-limited country: A Nigerian case study

Essential thrombocythemia (ET) is one of the classical clonal myeloproliferative neoplasms (MPNs) that constitute a clinical entity distinct from the other MPNs such as polycythemia vera and primary myelofibrosis despite the similarities in their molecular basis. The genetic basis of ET has been associated with the detection of the mutation of three mutually exclusive driver mutations, namely, Janus kinase 2 (JAK2), calreticulin, and myeloproliferative leukemia genes, making them important biomarkers in the diagnosis of ET. This condition is clinically characterized by thrombohemorrhagic complications and progression to myelofibrosis and acute myeloid leukemia. The reduction of the thrombotic complication and/or the associated hemorrhage constitutes the primary goal of the therapeutic practice for the management of ET. We report here seven cases of ET referred to the University College Hospital within a 3-year period (2014–2016). This case series describes the management practices and the therapeutic outcomes in the patients (using the resolution of the clinical presentations and decrease in platelet count). The report also highlights some of the challenges encountered in the management of ET in a resource-limited country like Nigeria.

Quantification of IGF-1 Receptor May be Useful in the Differential Diagnosis of Essential Thrombocytosis from Reactive Thrombocytosis- Suggested to Add IGF-1Receptor Quantification As the Minor Criteria for the Diagnosis of ET

Introduction. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia lists the criteria for the diagnosis of essential thrombocythemia (ET ) as 1) Platelet count more than 450 x 109/L 2) BM biopsy 3) Not meeting WHO criteria for BCR-ABL CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms, 4) Presence of JAK2, CALR, or MPL mutation The minor criteria included Presence of a clonal marker or absence of evidence for reactive thrombocytosis .Among these criteria , the most reliable criteria for diagnosis of ET is the presence of JAK2, CALR, or MPL mutation, these mutually exclusive mutations with respective incidences of 55%, 25%, and 3% , so approximately 17% are so called ET . These 17 % cases will depend on other criterias to make a definite diagnosis as ET. Bone marrow criteria is helpful in some cases but in many cases, the differential from re-active thrombocytosis (RT) could be misleading , So a substantial portion of triple-negative patients with ET have evidence of polyclonal: the use of cytoreductive drugs in these patients is questionable We have recently published using IGF-1R quantification by flow cytometry could be helpful in differentiating polycythemia from secondary polycythemia Now we also found quantification of IGF-1R by flow cytometry to be helpful in the diagnosis of ET from reactive thrombocytosis. Materials and Methods: Nineteen patients with ET (treatment naive), 20 with reactive thrombocytosis (RT) (5 sickle cell disease, 5 arthritis, 5 iron deficiency, 3 metastatic Cancer, 2 with infection, one with bleeding) and 23 normal volunteer controls were studied. Flow cytometry: MNC were isolated from peripheral blood then incubated with fluorophore-conjugated primary antibody or isotype controls for 30 min at room temperature and analyzed by FACS Calibur System (BD Biosciences, San Jose, CA). PE-conjugated antibody against human IGF-1R was purchased from R&D Systems. Results: Untreated ET patients had significantly higher IGF-1R (290.8, 86.83-475.2) than RT patients (127.0, 47.75-177.2),(P =220 means that a patient belongs to ET group, with sensitivity of 47.4% and specificity equal to 94.7%. Conclusion: Quantification of IGF-1 receptor may be useful in the differential diagnosis of Essential thrombocythemia from reactive thrombocytosis, especially in those cases where no driver mutations were detected (triple negative). Disclosures Wang: Celgen: Research Funding.

Predictors of Vascular Events and Disease Transformation in Chinese Patients with Myeloproliferative Neoplasms during Long-Term Follow-up

Abstract Introduction and objectives: Myeloproliferative neoplasms (MPN) are a group of heterogeneous clonal hematopoietic disorders that comprise polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). There is an increased risk of hemorrhage, thrombosis, cardiovascular (CV) event and transformation to myelofibrosis or acute leukemia. This study aims to review the clinicopathological characteristics and outcome, and prognostic indicators in a large Chinese population of patients with MPN. Methods: Patients with the diagnosis of PV, ET, PMF and MPN-unclassifiable were recruited from 2012 to 2016 in a tertiary referral center in Hong Kong. Retrospective data from the date of diagnosis were retrieved from the clinical records and reviewed by independent investigators. Progression-free survival (PFS) was defined as the duration from diagnosis to transformation to myelofibrosis, acute leukemia or death. Overall survival (OS) was defined from the duration from diagnosis to death or last follow-up. Categorical variables were compared using Pearson's chi-square or Fisher's exact test. PFS and OS were evaluated by Kaplan-Meier analysis and were compared by log-rank test. Univariate and multivariate analyses were performed with the Cox proportional hazard model. Results: 285 patients (142 men, 143 women) were included. PV, ET, PMF and MPN-U accounted for 22%, 60.0%, 10% and 8% of cases respectively (Table 1). Cytogenetic information at diagnosis was available in 47.7% (n=136) of the patients, of which 83% (N=113) had normal karyotypes. No other recurrent chromosomal abnormalities were observed apart from loss of chromosome Y. Among 230 molecularly annotated patients, 70% (N=162) harbored JAK2 V617F mutation. In 28 JAK2 V617F negative patients, 50% (N=14) and 4% (N=1) had CALR and JAK2 exon 12 mutations respectively. 13 patients were triple negative for JAK2, CALR and MPL mutations. Of all patients, treatment included aspirin prophylaxis (92%, N=263), hydroxyurea (92%, N=261), pegylated interferon (10.5%, N=30) and ruxolitinib (6.3%, N=18). CV events were observed in 45 (16%) patients, including 21 transient ischemic attacks, 14 ischemic strokes, 7 acute myocardial infarctions and 2 acute limb ischemia. 34 (76%) events occurred at diagnosis and 11 (24%) occurred while patients were on treatment. Significant risks associated with CV events were age > 50 years (p=0.002) and hypertension (p=0.038). Diabetes mellitus (p=0.163), hyperlipidemia (p=0.699), smoking (p=0.085) and concurrent ischemic heart disease (p=0.470) were not shown to be significant. Progression to MF was observed in 17% (n=11) of PV patients (median follow-up: 14.7, 9.5-27.6 years) and 12% (n=21) of ET patients (median follow-up:10.7, 1.5 - 22.6 years). Leukemic transformation occurred in 9 patients (3%) (ET, N=3, primary MF, N=1, secondary MF, N=5) at a median follow-up of 10.4 (1.0 - 22.6) years. Age >60 years and presence of splenomegaly at diagnosis were associated with inferior PFS; and age >60 years was associated with infereior OS in PV/ET patients (Figure 1). Based on these clinical criteria, PV/ET patients were divided into 3 groups, viz., age > 60 years with splenomegaly (n=8), age 60 years and splenomegaly remained significant risks for inferior PFS in univariate analysis, whereas on multivariate analysis, splenomegaly was only the significant risk for inferior PFS(Figure 2). Conclusion: This study showed that age >50 years and hypertension were associated with increased risk of cardiovascular events in MPN patients. Age > 60 years and splenomegaly on presentation were significant risks for disease transformation in PV/ET. Download : Download high-res image (171KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.

NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018.

Myeloproliferative neoplasms (MPNs) are a group of heterogeneous disorders of the hematopoietic system that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). PV and ET are characterized by significant thrombohemorrhagic complications and a high risk of transformation to MF and acute myeloid leukemia. The diagnosis and management of PV and ET has evolved since the identification of mutations implicated in their pathogenesis. These NCCN Guideline Insights discuss the recommendations outlined in the NCCN Guidelines for the risk stratification, treatment, and special considerations for the management of PV and ET.

Observational retrospective study of vascular modulator changes during treatment in essential thrombocythemia

Essential thrombocythemia (ET) patients are at risk of developing thrombotic events. Qualitative platelet (PLT) abnormalities and activation of endothelial cells (ECs) and PLTs are thought to be involved. Microparticles (MPs) can originate from PLTs (PMPs), ECs (EMPs), or red cells (RMPs). Previous studies have indicated that MPs contribute to ET pathophysiology. Endothelial modulators (eg, nitric oxide [NO], adrenomedullin [ADM], and endothelin-1 [ET-1]) are also involved in the pathophysiology of this condition. We hypothesized that treatments for reducing PLT count might also indirectly affect MP generation and endothelial activity by altering endothelial modulator production. The rationale of this study was that hydroxyurea (HU), a cytostatic drug largely used in ET, induces the production of a potent vasoactive agent NO in ECs. An observational retrospective study was designed to investigate the relationship between MPs, NO, ADM, and ET-1 in ET patients on treatment with HU, anagrelide (ANA), aspirin (ASA), and a group of patients before treatment. A total of 63 patients with ET diagnosis: 18 on HU+ASA, 15 on ANA+ASA, 19 on ASA only, and 11 untreated patients, and 18 healthy controls were included in this study. Blood samples were analyzed for MP (absolute total values) and functional markers (percentage values) by flow cytometry. PLT-derived MPs were studied using CD61, CD62P, CD36, and CD63, whereas endothelial-derived MPs were studied using CD105, CD62E, and CD144. Endothelial modulator markers (NO, ADM, and ET-1) were measured by ELISA. Total MP count was higher in the group treated with ANA+ASA (P<0.01). MP markers modified in ET patients returned to levels of healthy controls following treatment, in particular, in patients on ANA treatment. NO and ADM values were higher in the HU group (P<0.001). HU and ANA treatment also affected MP production in a cell origin-specific manner. HU and ANA, although acting via different pathways, have similar final effects. For instance, HU causes vasodilatation by increasing NO and ADM levels, whereas ANA impairs vasoconstriction by reducing ET-1. In conclusion, therapy with HU cytostatic drugs and ANA can reduce PLT count in ET, and also affect endothelial modulatory agents, with HU sustaining vasodilation and prothrombotic MP concentration, whereas ANA decreases vasoconstriction.

Clinical evaluation of the revised International Prognostic Score of Thrombosis for essential thrombocythemia (IPSET-thrombosis) in a cohort of 746 Chinese adult patients

目的评估修订版国际血栓预测模型（IPSET）在中国原发性血小板增多症（ET）患者中的应用价值，探索适用于中国ET患者的血栓预测模型。方法对1982年3月1日至2012年4月30日期间诊治的746例成人ET患者的病历资料进行回顾性分析。结果全部746例患者中，男305例，女441例，诊断时中位年龄52（18~87）岁。采用修订版IPSET将患者分组，其中极低危组271例（36.3%）、低危组223例（29.9%）、中危组63例（8.4%）、高危组189例（25.3%），四组的无血栓生存差异有统计学意义（χ2=72.301，P<0.001）。修订版IPSET在原版IPSET低危组中区分出36例中危患者，在原版IPSET中危组中区分出19例高危患者，在原版IPSET高危组中区分出51例低危患者，避免了部分患者的治疗不足或过度。修订版IPSET低危组中有心血管危险因素（CVF）者的血栓发生率显著高于无CVF者[16.3%（8/49）对5.2%（9/174），χ2=5.264，P=0.022]，而与中危组相当[16.3%（8/49）对14.3%（9/63），χ2=0.089，P=0.765]。因此，在修订版IPSET的基础上，低危组中伴CVF者被划分至中危组，即为适于中国ET患者的修订版IPSET，此模型能区分出更多的血栓患者。结论修订版IPSET在血栓预测方面优于原版IPSET，将修订版IPSET优化后得到了更适于中国ET患者的修订版IPSET，为中国ET患者的分层治疗提供了依据。

Significance of combined detection of JAK2V617F, MPL and CALR gene mutations in patients with essential thrombocythemia.

The aim of this study was to analyze the mutation rate of JAK2V617F, MPLW515L/K and CALR genes in adult patients with essential thrombocythemia (ET) and the accuracy of the combined detection by the receiver operating curve. Three hundred and forty-two cases with high-platelets (≥300×109/l) were consecutively selected. The patients were analyzed for routine blood examination, bone marrow biopsy and genetic testing. One hundred and fifty-four cases (45.03%) were diagnosed with ET and 188 cases of secondary thrombocythemia according to the hematopoietic and lymphoid tissue tumor classification standards of 2008. It was found that the mutant type of three genes showed three bands, whereas only one band for wild-type. The JAK2V617F and MPL mutations did not cause a change in the open reading frame and the CALR mutation resulted in its change. The mutation rate of JAK2V617F and CALR in ET group was significantly higher than that in the secondary thrombocythemia group (p<0.05). The positive mutation rate of MPL was only 4.55%. JAK2V617F-positive mutation alone was used to diagnose with ET. The area under the curve (AUC) was 0.721. The sensitivity was 72.4%, the specificity was 79.5% and the cut-off value was 0.25. When CALR-positive mutation alone was used to diagnose ET, the AUC, sensitivity, specificity and cut-off value were 0.664, 68.4, 82.4 and 0.09%, respectively. JAK2V617F combined with CALR mutation were used for diagnosis of ET. The AUC was 0.862, the sensitivity was 85.9%, the specificity was 87.8%, and the cut-off values were 0.21 and 0.07. In conclusion, the positive mutation rate of JAK2V617F and CALR in ET was higher, and the sensitivity, specificity and accuracy of the diagnosis of ET were significantly improved using the detection of JAK2V617F and CALR.

Thrombin generation - a potentially useful biomarker of thrombotic risk in Philadelphia-negative myeloproliferative neoplasms.

The diagnosis of essential thrombocythemia and polycythemia vera is often made during a thrombotic event which can be serious. Philadelphia-negative chronic myeloproliferative neoplasia patients have an increased thrombotic risk. This is assessed using various scoring systems but these are far from ideal and individual risk. The currend trend to personalised medicine requires finding the most useful thrombotic risk biomarker in these patients. Routine tests for coagulation do not take account of both pro- and anti-coagulant factors which is why these tests are not useful in patients with Philadelphia-negative myeloproliferative neoplasms. Thrombin generation reflects more accurately the balance between pro- and anti-coagulant factors. Some parameters of thrombin generation such as the endogenous thrombin potential are higher in Philadelphia-negative myeloproliferative neoplasm patients, especially in JAK2 V617F carriers than in healthy controls. They are even higher in those with reactive thrombocytosis. The JAK2 V617F allele burden correlates more with a higher thrombin generation potential in patients who are not treated with hydroxycarbamidum. Instead, JAK2 V617F-positive patients with Philadelphia-negative myeloproliferative neoplasms were the most sensitive to hydroxycarbamidum, as was reflected in lower values of platelet thrombin generation potential. The use of thrombin generation examination in these patients would enable detection of imminent thrombosis and personalised prophylactic management.

An underestimated blood parameter before myeloproliferative neoplasm diagnosis: the case of thrombocytosis and the delayed essential thrombocytemia diagnosis

Background: Thrombocytosis, i.e. platelet count >400.000/μL in peripheral blood, is also due to Essential Thrombocythemia (ET), and delaying the diagnosis of thrombocytosis might coincide with a delayed ET diagnosis. The purpose of our study was to investigate the factors virtually leading to a delay in ET diagnosis. Methods: We analyzed the interval between the first evidence of thrombocytosis and ET diagnosis, and defined it as ETunderestimation- period (ET-uP). We analyzed 280 ET patients followed at our Institution. To verify possible correlations with ET-uP, we investigated patients’ ages, gender, history of vascular complications, thrombocytosis, splenomegaly, and marrow fibrosis degree. We also considered their General Practitioners (GP) characteristics: age, personal computer use, number of patient visits in the two years before diagnosis. Univariate logistic analysis for each parameter was performed using the Spearman’s rank correlation coefficient to assess correlation with ET-uP. Multivariate logistic regression analysis was performed on the parameters that resulted significant at the previous analyses. The logistic regression analysis was performed dichotomizing the ET-uP variable using its median value. Results: Median ET-uP was 16 months (range 1-240). The analysis showed that a shorter ET-uP correlated with thrombocytosis (p<0.001) and previous cardiovascular events (p=0.04). At multivariate analysis, the Area. Under the Curve (AUC) of the (Receiver Operating Characteristic) ROC curve was 0.72. No correlation was found analyzing GP data. Conclusion: Our results underline a deficient medical practice, and prompt for corrective actions (use of more restrictive normal range for platelet count–with lower upper limit and warning flags for pathological findings) to timely commence the diagnostic workup of this condition.

Molecular Genetic Markers and Clinical Characteristics of Essential Thrombocythemia

Background &amp; Aims. The presence of different molecular genetic markers of clonality (mutations in JAK2, MPL, CALR) or their absence (triple negative status, TN) in essential thrombocythemia (ET) indicates a biological heterogeneity of the disease and can determine its clinical forms. The aim was to evaluate the association of molecular genetic markers with the clinical form and the prognosis of ET. Materials &amp; Methods. We analyzed the data of 240 patients with ET at the age of 20-91 years (median age 58.7 years), who were observed in the Russian Research Institute of Hematology and Transfusiology from 1999 to 2016 (median observation period 37.2 months). Results. The JAK2V617F (JAK2+) mutation was found in 182 (75.9 %) of 240 patients. CALR (CALR+) mutations were found in 30 (12.5 %): type 1 (CALP7+) mutations in 13/30 (43.3 %) and type 2 (CALR2+) in 17/30 (56.7 %). MPL (MPL+) mutations were found in only 2 (0.8 %) of 240 patients. None of the mutations were detected in 26 (10.8 %) of 240 patients (TN status). Significantly higher platelet counts were observed in CALP7+ and CALR2+ subgroups during the primary diagnosis of ET compared with JAK2+ and TN groups. The mean platelet counts were 1252 * 10&lt;sup&gt;9&lt;/sup&gt;/L for CALR2+ and 1079 * 10&lt;sup&gt;9&lt;/sup&gt;/L for CALP7+ vs 841 * 10&lt;sup&gt;9&lt;/sup&gt;/L (p &lt; 0.001; p = 0.06) and 775 * 10&lt;sup&gt;9&lt;/sup&gt;/L (p &lt; 0.001; p = 0.04) for JAK2+ and TN, respectively. Thrombosis was diagnosed in 50 (27.4 %) of 182 patients of the JAK2+ subgroup, in 8 (30.7 %) of the 26 patients of the TN subgroup, and in 2 (18.2 %) of 11 patients of the CALP7+ subgroup. No thrombosis was found in the CALR2+ and MPL+ subgroups (p &lt; 0.001). In general, the CALP7+ status was characterized as the most favorable in terms of prognosis (5-year overall survival rate of 100 %), compared to the least favorable TN status (5-year overall survival rate of 85 %). Conclusion. Mutations in the CALR gene were characterized by a more favorable prognosis in comparison with JAK2+and TN, as well as a decrease in the risk and frequency of thrombosis, despite higher platelet counts. TN-status of ET was associated with unfavorable prognosis.

Clinical Exome Sequencing Unravels New Disease Causing Mutations in Myeloproliferative Neoplasms (MPNs): A Pilot Study in Patients from the State of Qatar

In Qatar, a cluster of ET familial cases (25 families from 5 major tribes) has been documented. This observation represents a unique interest for the scientific community worldwide, as the cultural traditions of tribal marriages between 1stcousins is expected to lead to the preservation of a limited genetic pool (giving rise to founder effects). CES was employed to analyze a 3 probands from three unrelated families (S1, S2, S3). All 6 patients were Qatari belonging to consanguineous families with a positive family history of MPNs. CES confirmed the diagnosis in the 3 probands: two patients (S1 and S2) were classified as Essential Thrombocythemia (ET), one patient (S3) as unclassified MPNs. In the other 3 subjects (S4, S4, S6), several shared deleterious mutations and polymorphisms were uncovered. CES identified 10 novel mutations in known genes as well as 7 novel candidate genes and 2 (6%) previously reported mutations in the three probands (S1, S2, S3) who's diagnosis was confirmed . S1: a confirmed diagnosis and phenotype of ET (JAK2 and THPO), S2: a confirmed diagnosis and phenotype of ET (JAK2 and MPL) and S3: a confirmed diagnosis of U-MPNs (TERT, ATM, NUMA1 and ASXL) The mutations/variants were classified according to ACMG recommendations into 5 classes. The number of mutations/variants detected in each class is as follows: Class 1 - Previously reported as disease-causing: 6 Class 2 - Previously unreported, but of the type which can cause the disorder: 3 Class 3 - Previously unreported, may or may not be the cause of the disorder (Variant of uncertain clinical significance): 48 Class 4 - Previously unreported but likely neutral: 1 Class 5 - Previously reported as neutral: 3 CES identified a total of 61 interesting variants which occurred in 50 genes, 13 were recurrently. The vast majority of the prioritized variants were missense 50(82%); the remaining were frameshift (small insertions and deletions) 10(16%) or affecting splicing sites 1(2%). The most interesting finding is the presence of 10 novel mutations in known genes related to MPNs as well as 7 variants in novel candidate genes in the three probands who's diagnosis was confirmed via CES. This study presents novel data that contributes to understanding the high level of genetic complexity in MPNs Qatari patients. It has identified new variants in cancer-related genes potentially involved in the pathogenesis of the disease Our study of familial MPNs led to the identification of new disease-causing mutations and variants, some previously described as either germline or somatic. A clinical cohort of 3 Qatari probands suspected to have MPNs as well as three family members with a positive family history of MPNs presented at National Center for Cancer Care (NCCCR) S1) is a female who presented with high hemoglobin (Hb) level, red blood cells (RBCs) count, leukocytosis with neutrophilia, very high platelets and normal erythropoietin (EPO); subject 2 (S2) is a female who presented with normal Hb, RBCs count, slightly high WBCs and high platelets; subject 3 (S3) is a male who presented with high Hb, normal WBCs and EPO 3 family members, subject 4 -a mother presented with normal Hb level, sustained high RBCs count and slightly high WBCs count, subject 5 a daughter presented with unexplained sustained erythrocytosis, leukocytosis (absolute neutrophilia, for more than 2 years Chronic headache, normal MRI brain and no progression to cancer no Ischemic events, subject 6- healthy daughter with normal CBC indicesThe pattern of mutations identified was unique. In this study 10 novel mutations in known genes already implicated in the pathogenesis of MPNs were detected including THPO, CBL, ASXL1, MPL (2x), BCL2, MYO18B, MTOR, PDGFRB, TERT. Mutations/variants were detected in 9 genes not previously associated with MPNs suggesting potential novel gene associations. Pathogenic/likely pathogenic mutations, uncertain variants and neutral/likely neutral variants were identified using the CES approach. A complex combination of mutations was observed in our cohort of subjects. For example in subject 1 (S1), an ET patient, the following mutations were observed: THPO S184R, ITGA2 R76Q, JAK2 V617F, CBL E196G, CBFB G180S, FANCA S858R, ASXL1 T600P fs103. The following detailed analysis of each mutation reveals that all these mutations could potentially play a role in the pathogenesis of MPNs Disclosures No relevant conflicts of interest to declare.

Safety and Efficacy of Combined Ruxolitinib and Decitabine in Patients with Blast-Phase MPN and Post-MPN AML: Results of a Phase I Study (Myeloproliferative Disorders Research Consortium 109 trial)

Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) includePolycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). These stem cell disorders carry a propensity to evolve into acute myeloid leukemia (MPN-blast phase [BP] or post-MPN AML) with a dismal prognosis not meaningfully improved by conventional anti-leukemia therapy. Thus, MPN-BP is an urgent unmet clinical need. Responses in patients with MPN-BP to hypomethylating agents and single agent ruxolitinib have been reported. More recently, combination of ruxolitnib and decitabine has demonstrated synergistic activity in vitro in cells derived from patients with MPN-BP and from a murine model of MPN-BP (Rampal et al PNAS 2014). These observations led us to explore the safety of combined decitabine and dose escalation of ruxolitinib in MPN-BP.Objective: To establish the maximum tolerated dose (MTD) of ruxolitinib in combination with a fixed dose of decitabine (DEC-RUX).Methods: We conducted an open label Phase I trial in patients with MPN acceleration phase (AP) as defined by 10%-19% blasts in the peripheral blood or bone marrow or a diagnosis of MPN-BP as defined by ≥ 20% blasts in the blood or bone marrow, following a previous diagnosis of ET, PV or PMF. Patients were enrolled in a standard 3+3 phase I design with an MTD defined as a dose <33% DLT. Ruxolitinib was administered at doses of 10mg, 15mg, 25mg, or 50mg every 12 hours in combination with concurrent decitabine at a dose of 20mg/m2 daily intravenously over 5 days and repeated every 28 days. Adverse events were assessed using the NCI CTCAE v. 4.0. DLTs were defined as Grade 3 or higher non-hematologic toxicity events not clearly related to disease and grade 4 hematologic events with a bone marrow cellularity of ≤5% and no evidence of leukemia. Response assessment was carried out every cycle using modified Cheson criteria: CR required 0% peripheral blood blasts, WBC ≥4x109/L, hemoglobin ≥10g/L, and platelets ≥100x109/L; CRi required 0% peripheral blood blasts with incomplete count recovery; and PR required ≥50% decrease in peripheral blood blasts regardless of blood counts.Results: A total of 21 patients were accrued to study (Table 1). The median age was 63 years (range 48-88). 52% carried a diagnosis of MPN-AP, and 48% carried a diagnosis of MPN-BP. 29% of patients and 24% of patients had prior exposure to ruxolitinb and decitabine, respectively. The median number of cycles received varied from 10.5 cycles in the 10mg BID cohort to 2 and 2.5 cycles in the 25mg BID and 50mg BID cohorts, respectively (Table 2). The most common Grade 3/4 non-hematologic AEs observed were due to infection in all dosing cohorts. In terms of hematologic toxicity, treatment emergent Grade 3/4 anemia was observed in 1 patient in each of the 10mg BID, 15mg BID, and 50mg BID cohorts. Grade 3/4 leukopenia was observed in only 1 patient at the 50mg BID cohort, and Grade 3/4 thrombocytopenia was observed in 2 patients in the 10mg BID cohort and 1 patient in the 15mg BID cohort. DLT rate was below 33% for all dose levels so the MTD was not reached. The most common reason for ending study treatment was toxicity/adverse events (33%) followed by disease progression (22%). 9 patients died during study or follow-up. Of those, 5 (56%, 2 in 10mg BID cohort, 1 in 15mg BID cohort, 2 in 50mg BID cohort) died of infection, 3 (33%, 1 in each of 10mg, 25mg, and 50mg BID cohorts) of progressive disease, and 1 (11%, 25mg BID cohort) of hemorrhage.The median overall survival for patients on study was 10.4 months (95% CI 3.3 mo - not reached). CR/CRi as best response was observed in 7/21 patients (33%, 95% CI 15-57%; 2 CR, 5 CRi; Table 2).Conclusions: DEC-RUX combination therapy was safely administered to patients with MPN-AP/BP and an MTD was not reached. Based on pre-clinical data, observed safety profile, duration of treatment, and clinical responses in this phase I trial, the Recommended Phase II Dose of RUX was selected as 25mg BID for an induction cycle followed by 10mg BID in all ensuing cycles. Molecular and bone marrow pathology responses will be presented at the meeting. [Display omitted] [Display omitted] DisclosuresMascarenhas:Promedior: Research Funding; CTI Biopharma: Research Funding; Novartis: Other: DSMB , Research Funding; Janssen: Research Funding; Roche: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding. Hexner:Blueprint medicines: Consultancy; Novartis: Research Funding. Abboud:Alexion: Honoraria; Takeda: Honoraria; Novartis: Research Funding; Teva: Research Funding, Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria; Baxalta: Honoraria; Seattle Genetics: Research Funding; Gerson and Lehman Group: Consultancy; Cardinal: Honoraria. Levine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Mesa:Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding; Celgene: Research Funding; Galena: Consultancy; Ariad: Consultancy; Gilead: Research Funding; CTI: Research Funding.

Essential Thrombocythemia: A Comparison of Overall and Thrombosis Free Survival in Two Discrete Periods of the First Decade of 2000. a Retrospective Analysis

To evaluate the prognosis of patients with Essential Thrombocythemia (ET) in the first decade of the century we assessed retrospectively the thrombosis free survival (TFS) and the overall survival (OS) of the patients diagnosed from 01/01/2000 to 31/12/2009 and collected in the database of our group. The diagnosis of ET was performed with PVSG, WHO 2001 or WHO 2008 criteria, according to the period of the first observation. The whole population of 757 patients was then divided in two groups: the first (group I) with the diagnosis performed between 01/01/2000 to 31/12/2005 (334 patients) with a median follow-up of 111,9 months, the second (group II) diagnosed between 01/01/2006 to 31/12/2009 (385 patients) with a median follow-up of 58,2 months. The main clinical features of the two groups of patients are reported in the Table 1. No difference was observed between the two groups as to age, gender, platelet and WBC count, Hb level, Cardio-Vascular Risk Factors (CVRF), spleen enlargement and occurrence of previous thrombotic events. The frequency of the JAK-2 V617F mutation resulted significantly different (49.1% vs 68.4%) but in the group I the search of the mutation was never performed at the diagnosis. The TFS and OS were calculated from the date of diagnosis to the date of any appropriate event or to the date of last follow-up with Kaplan-Meier product limit method; the comparison of proportions and median values was computed with the Chi-squared and the Mann-Withney tests, as indicated. No significant difference emerged neither for TFS (p= 0,09, HR 1,42, 95% C.I. 0.89-2.30) nor for OS (p= 0,15, HR 1,34, 95% C.I. 0,87-2,06). We also considered the type of treatment used in the two groups to assess the potential link between the therapy and TFS or OS. No difference emerged between the two groups as to anti-aggregating treatment (mainly ASA), equally utilized in both groups [287/369, 77,8%, and 330/383, 78,3%, respectively (p = 0,95)]. As for the cyto-reductive therapy, Hydroxyurea was used in 74.8% vs 67.9% (p= 0.60) and alkylating agents in 1.9% vs 2.1% (p= 0.85), whereas Anagrelide was used in 10,6% vs 3,9% (p= 0,001) and Interferon in 9,5% vs 5,2% (p= 0,037), respectively. This more frequent use of Anagrelide and Interferon in the first group (2000-2005) did not modify TFS and OS of the patients. In conclusion, no improvement was observed in the prognosis of ET patients in the recent years: thus, new efforts to identify patients at risk and the introduction of new drugs as JAK-2 inhibitors are warranted to improve the prognosis of these patients. [Display omitted] DisclosuresBreccia:Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria; Ariad: Honoraria. Cimino:Celgene: Honoraria; Bristol-Mayer: Honoraria. Lo Coco:Pfizer: Consultancy; Baxalta: Consultancy; Novartis: Consultancy; Lundbeck: Honoraria, Speakers Bureau; Teva: Consultancy, Honoraria, Speakers Bureau. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.