Thrombotic events and mortality risk in patients with newly diagnosed polycythemia vera or essential thrombocythemia.

Patients with polycythemia vera (PV) and essential thrombocythemia (ET) have increased thrombotic risk. This retrospective, real-world analysis of Medicare patients (age ≥ 65 years) newly diagnosed with high-risk PV or intermediate-/high-risk ET compared mortality risk among those with versus without thrombotic events during the study period. Patients diagnosed with PV or ET with ≥ 1 inpatient or ≥ 2 outpatient claims (January 1, 2010-December 31, 2017; index was date of first qualifying claim) were included. The study included 50,405 Medicare beneficiaries with PV and 124,569 with ET. During follow-up (median [range]: PV, 34.5 [0-97.3] months; ET, 25.5 [0-97.4] months), 14,334 patients (28.4%) with PV and 30,478 (24.5%) with ET experienced thrombotic events (most commonly ischemic stroke [PV, 46.0%; ET, 42.5%]. Mortality risk was increased for patients with versus without post-index thrombosis for both PV (adjusted hazard ratio [aHR; 95% CI], 18.6 [16.1-21.6]; P < 0.001) and ET (aHR [95% CI], 25.2 [23.1-27.5]; P < 0.001). Median survival was shorter for patients who experienced a thrombotic event ≤ 1 year post-index versus those who did not (PV, 5.1 years vs not reached; ET, 3.7 vs 6.7 years; both P < 0.001). These findings highlight the importance of thrombosis risk mitigation in PV and ET management.

Burden of Aquagenic Pruritus in Polycythaemia Vera.

Aquagenic pruritus (AP) has a significant influence on quality of life (QoL) in patients with polycythaemia vera. This study analysed the impact of AP on patient well-being in 102 patients with polycythaemia vera. Intensity of pruritus was evaluated using a visual analogue scale (VAS), verbal rating scale (VRS) and a 4-item Itch Questionnaire. Psychosocial aspects of AP were assessed with the Hospital Anxiety and Depression Scale (HADS), EQ-5D and itch-specific QoL questionnaire (ItchyQoL). AP of mean duration 6.6 ± 8.6 years and intensity 4.8 ± 1.9 points (VAS) was present in 42/102 individuals. The prevalence of depression and anxiety among patients with AP was 23.8% and 9.5%, respectively. Depression was more frequent in the AP group (vs. non-AP). Moreover, patients with AP had higher HADS-anxiety scoring than those without pruritus (p = 0.005). A negative correlation was found between duration of AP and EQ-5D-VAS. The ItchyQol score of 37.3 ± 12.3 points was influenced by the extent (p =0.01) and duration of episodes of AP (p = 0.02). In conclusion, AP places an additional burden on patients with polycy-thaemia vera, negatively influencing their QoL.

Polycythemia vera disease burden: contributing factors, impact on quality of life, and emerging treatment options.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by clonal expansion of a hematopoietic progenitor, erythrocytosis, often leukocytosis and/or thrombocytosis, and nearly always an activating mutation in Janus kinase 2 (JAK2). The PV symptom burden can be considerable, in part driven by small or large vessel thrombotic tendency, splenomegaly, fatigue, pruritus, and a chronic risk of disease transformation to myelofibrosis or acute myeloid leukemia. In addition, patients with PV have an increased risk of mortality compared with the general population that often results from cardiovascular complications or disease transformation. Further, healthcare utilization and costs are higher in patients with PV than noncancer controls. First-line therapy options for high-risk patients may effectively manage PV in some instances; however, some patients do not receive adequate benefit from current treatment options and experience a more severe disease burden as a result. This may be especially true for those patients who are resistant to or intolerant of hydroxyurea or interferon-based therapies. New treatments currently being investigated in phase 3 clinical trials may alleviate disease burden in this patient population.

It is time to change thrombosis risk assessment for PV and ET?

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms to be diagnosed according to the WHO classification. Molecular profiling must include the analysis of JAK2 (looking for the V617F point-mutation in PV and ET, screening exon 12 for mutations only in V617F-negative PV), CALR and MPL mutations (both in V617F-negative ET). The current risk stratification to predict thrombosis requires two parameters: age over 60 years and prior history of thrombosis. On the basis of these two risk factors patients can be stratified in low-risk and high-risk and receive a proper treatment. However, a modern stratification of thrombotic risk might consider "new" low-risk patients: conventional low-risk plus absence of leukocytosis from diagnosis onwards and a hematocrit level below 45% during the course of disease for PV; conventional low-risk plus absence of leukocytosis from diagnosis onwards, JAK2 negativity, CALR positivity, and absence of cardiovascular risk factors for ET.

Distinct clustering of symptomatic burden among myeloproliferative neoplasm patients: retrospective assessment in 1470 patients.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

Comparison of JAK2V617F mutation assessment employing different molecular diagnostic techniques.

BACKGROUND: The JAK2(V617F) mutation is present in the majority of patients with polycythaemia vera and in approximately half of patients with essential thrombocythaemia and primary myelofibrosis. In this study we compare the results of JAK2(V617F) mutation detection using three different molecular techniques in the same group of patients affected by essential thrombocythaemia. PATIENTS AND METHODS: The JAK2 mutation was investigated with a qualitative method in 115 consecutive outpatients with a diagnosis of essential thrombocythaemia made according to WHO 2001 criteria. In 48/115 (41.7%) the allele burden was also evaluated with two different qualitative methods, of which one was a method developed in-house and the other was a commercially available method. RESULTS: The JAK2(V617F) mutation was detected by the qualitative method in 81/115 (69.6%) of the patients. Among the 48/115 patients in whom all three methods were applied, the qualitative method detected the mutation in 38 (79%). According to the quantitative method developed in-house, the mutation was present in 35/48 (73%) of the patients: of these, 2/35 (5.7%) patients were homozygous for the JAK2(V617F) mutation. The commercial quantitative method showed the mutation in 37/48 (77%) patients: of these, 9/37 (18%) patients were homozygous. Three of the 13 patients in whom no mutation was detected by the in-house method were positive for the JAK2(V617F) according to the commercial method. In one patient the search for the JAK2(V617F) mutation was positive with the in-house method but negative with the commercial kit. CONCLUSION: Detection of the JAK2(V617F) mutation may depend on the molecular technique used. Considering that detection of this mutation will not only have a diagnostic value, but also a role in treatment given the development of JAK2(V617F) pathway inhibiting drugs, indications on a reference molecular diagnostic technique for JAK2(V617F) assessment and quantification of its allele burden from a panel of experts are warranted.

Application of PRV-1 mRNA expression level and JAK2V617F mutation for the differentiating between polycytemia vera and secondary erythrocytosis and assessment of treatment by interferon or hydroxyurea.

Increased PRV-1 mRNA expression and the presence of Jak2(V617F) mutation in peripheral blood granulocytes are specific markers for chronic myeloproliferative disorders (MPD), which facilitate the differential diagnosis between polycythemia vera (PV) and secondary erythrocytosis (SE) and may be helpful for monitoring treatment efficacy in MPD patients. We evaluated the presence of the Jak2V617F mutation and increased PRV-1 mRNA expression along with previously established markers - erythropoietin (EPO) independent colony formation (EEC) and erythropoietin level for diagnosis of PV and assessment of treatment efficiency. Increased PRV-1 expression was found in 37 out of 46 patients diagnosed with PV (80%), in 4 out of 15 patients diagnosed with essential thrombocythemia (ET) (27%) and in 4 out of 8 patients with chronic idiopathic myelofibrosis (CIMF) (50%), and increased PRV-1 expression plus EEC formation was observed in 19 of 36 examined MPD patients indicating the superiority of PVSG and WHO bone marrow criteria for the diagnosis of ET, PV and CIMF. We could confirm a very high sensitivity, specificity and utility of the Jak2(V617F) mutation for differential diagnosis between PV and SE. Spontaneous EEC, serum EPO levels, PRV-1 expression was evaluated in 22 PV patients who carried the Jak2(V617F) mutation. A concordance of increased PRV-1 expression and presence of Jak2(V617F) mutation in 19/22 (85%); of increased PRV-1/Jak2/EEC in 14/22 (63%); and of Jak2/PRV-1/EEC/low Epo level in 10/22 (45%) patients was found indicating the superiority of the presence of Jak2(V617F) mutation for the diagnosis of PV. IFN-alpha therapy in patients with PV was more effective then hydroxyurea treatment and significantly reduced increased PRV-1 expression together with higher levels of Jak2(V617F) mutation (50-100%) in PV patients treated with hydroxy urea (HU) and lower levels of Jak2(V617F) mutation (35-90%) in PV patients treated with IFN-alpha. Normal PRV-1 expression level was observed in 44% of PV patients who achieved clinical remission and only in 3% of patient who did not. These preliminary observations indicate that the Jak2(V617F) mutation in particular and PRV-1 overexpression appear to be suitable markers for monitoring treatment efficiency in prospective randomised clinical studies comparing pegylated interferon and hydroxyurea in well defined PV patients with a clear indication for cytoreductive therapy.

Objective, planimetry-based assessment of megakaryocyte histological pictures in Philadelphia-chromosome-negative chronic myeloproliferative disorders: a perspective for a valuable adjunct diagnostic tool.

Philadelphia-chromosome-negative chronic myeloproliferative disorders (Ph- CMPDs)--essential thrombocythemia (ET), chronic idiopathic myelofibrosis (CIMF), and polycythemia vera (PV)--may show clinical and morphological similarities, particularly at the early stages. The differential diagnosis of Ph- CMPDs is important due to their different treatment and prognosis. Cytological features of megakaryocytes are considered valuable in this differentiation. To establish an objective measure of megakaryocyte dysplasia in Ph- CMPDs, we performed computer-assisted morphometry of more than 4,000 cells from 20 cases of ET, 10 of CIMF, 10 of PV, and 10 controls. Megakaryocyte sets from three Ph- CMPDs differed significantly in respect to many planimetric parameters, but not a single shape or size parameter could have been used as a discriminative tool between the entities. However, the discriminant function analysis with the simultaneous assessment of 12 planimetric variables allowed for a proper classification of 20 of 20 ET, 10 of 10 PV, and 9 of 10 CIMF cases based solely on the morphometric features of megakaryocytes. Additionally, we identified certain new patterns of megakaryocytes specific for ET, PV, and CIMF, which, although not dominating in one Ph- CMPD, are unlikely to occur in two others. Objective measurements of megakaryocyte sizes and shapes may assist the diagnosis of Ph- CMPDs.

Budd-Chiari syndrome as the first manifestation of polycythemia vera in young women with inherited thrombophilic state: an aggressive form of myeloproliferative disorder requiring multidisciplinary management.

The Budd-Chiari syndrome (BCS), characterized by the obstruction and occlusion of the suprahepatic veins, is a rare but typical complication occurring in patients with polycythemia vera (PV). We describe three young women who developed BCS as first manifestation of PV, in association with an inherited thrombophilic state and in the absence of concomitant use of oral contraceptives. Our report illustrates the existence of an aggressive form of myeloproliferative disorder, which requires prompt recognition and immediate therapeutic intervention including cytostatic drugs and anticoagulant treatment. Furthermore, we suggest the need of routine screening for thrombophilic state in young women affected by PV.

A mail survey of United States hematologists and oncologists: a comparison of business reply versus stamped return envelopes.

Mailed surveys are a popular means of obtaining data on large populations. In July 1999 a mail survey was conducted among 3000 randomly selected members of the American Society of Hematology to assess their approach to diagnosis and treatment of polycythemia vera. Because the researchers and the study population are members of the same professional organization with a vested interest in the results, we anticipated that the advantages of return stamped postage seen in previous studies would be less significant. The response rate for stamped return envelopes was 38% versus 32% for business reply envelopes. This statistically significant difference (P =.0005) of six percentage points is comparable to previous research. Excluding labor, the total cost per returned survey was $2.62 for business reply envelopes versus $1.82 for stamped return envelopes. We conclude that stamped return envelopes are a more effective and cost-efficient means of procuring data from physician specialists.

Are current methods of measurement of erythropoietin (EPO) in human plasma or serum adequate for the diagnosis of polycythaemia vera and the assessment of EPO deficiency?

Current methodology for the immunoassay of erythropoietin (EPO) in human plasma or serum is reviewed, with an emphasis on measurement of EPO concentrations in the low and normal ranges, analytical interference and blood sampling requirements. In only 2 out of 8 research or in-house immunoassays reported since 1987 was there evidence that patients with polycythaemia vera (PV) could be identified, PV being an EPO-independent form of polycythaemia in which EPO concentrations are low in untreated cases. The same was true for only 1 out of 13 currently available kit methods. Remarkable differences in sample stability have been observed with different methods. Measurement of EPO in serum is recommended in most published articles. However, only EDTA plasma seems to be acceptable for the one generally available method with proven high diagnostic sensitivity for PV. It is concluded that most EPO assay methods have not been shown to be adequate for the measurement of the low EPO concentrations, and thus have poor diagnostic sensitivity for PV. It is inferred that they might not be appropriate to assess states of EPO deficiency. Only when a sufficiently sensitive diagnostic method becomes generally available will it be possible to define the various causes of low EPO concentrations. As in other fields of polypeptide hormone measurement, further developments in the field of EPO assay may be expected to be important in diagnostic medicine.