Masked Polycythemia Vera Research Articles

Masked polycythemia vera manifested by splanchnic venous thrombosis during pregnancy: a clinical case

Ph-negative myeloproliferative disorders such as polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis are rare clonal hematopoietic diseases that typically occur at age over 50. Only 10–15% of PV cases are diagnosed during the reproductive years, most commonly manifested as splanchnic venous thrombosis (SVT). Here, we demonstrate a case of a 6-weeks pregnant woman with a history of stillbirth and miscarriage presented with SVT. A terminal ileal resection and right hemicolectomy were performed, as well as the appointment of low molecular weight heparin in the postoperative period was initiated that allowed the patient to continue the pregnancy and deliver a child. The JAK2 V617F mutation was detected and masked PV was diagnosed according to bone marrow findings. In this article, we discuss the etiology of SVT in adults and effect of JAK2 V617F mutation on pregnancy outcomes as well as summarize current knowledge about pregnancy outcomes in PV.

Cytogenetics in Essential Thrombocythemia: Phenotype and Molecular Correlates and Prognostic Relevance in 818 Informative Cases

▪BackgroundCytogenetic abnormalities at diagnosis are relatively uncommon in essential thrombocythemia (ET). In the current study of 818 consecutive patients with ET who were fully annotated for karyotype, we describe the spectrum and prevalence of cytogenetic abnormalities at diagnosis, followed by a comprehensive assessment of phenotypic and molecular correlates and prognostic relevance.MethodsThe study cohort consisted of 818 consecutive patients with ET that were diagnosed according to the World health Organization 2016 criteria and underwent evaluation between 1967-2021. In order to minimize the inadvertent inclusion of patients with masked polycythemia vera, JAK2 mutated cases with hemoglobin (Hb) level >16 g/dL in women and 16.5 g/dL in men were excluded; similarly, cases with anemia defined by sex adjusted Hb level of <11 g/dL in women and <12.5 g/dL in men were also excluded, in order to avoid inadvertent inclusion of patients with prefibrotic myelofibrosis. Cytogenetic studies were performed either at or within one year of diagnosis and reported according to the International System for Human Cytogenetic Nomenclature. Disease status and survival information was updated in May 2021. JMP Pro 16.0.0 software package, SAS Institute, Cary, NC was utilized for all analyses.Results •Prevalence and spectrum of cytogenetic abnormalitiesKaryotype was normal in 755 patients (92%), showed loss of Y chromosome (-Y) in 16 (2%), and showed abnormalities other than -Y in 47 (5.7%); most common abnormalities included del(20q) (n=10, 21%), trisomy 9 (n=8, 17%), trisomy 8 (n=2, 4%), del(5q) (n=2, 4%), and del(3p) (n=2, 4%). Other sole cytogenetic abnormalities were identified in 18 (38%) patients. •Phenotypic and molecular correlatesAbnormal karyotype, other than -Y, in comparison with normal karyotype was associated with older age (median age; 63 vs 58 years, p=0.02), lower hemoglobin level (p=0.003), and a higher incidence of arterial thrombosis prior to/at diagnosis (25% vs 13%; p=0.03). 603 patients were annotated for driver mutations; abnormal/normal/-Y frequencies were 78%/60%/71% for JAK2, 22%/26%/14% CALR, 0%/3%/0% MPL and 0%/10% /14% triple negative (p=0.31). NGS information was available in 226 patients and showed absence of ASXL1 mutation in all patients with abnormal karyotype vs 8/211 (4%) with normal karyotype vs 2/4 (50%) with -Y (p<0.0001). •Disease transformation and overall-survival.At a median follow-up of 9.6 years (range; 0.01-49.4 years), a total of 96 patients (12%) underwent fibrotic transformation: 6 (13%) with abnormal karyotype, 89 (12%) with normal karyotype and 1 (6%) with -Y (p=0.77). Leukemic transformation rates were also similar with respective frequencies of 4%, 3% and 0% (p=0.71). Abnormal karyotype and -Y were associated with inferior survival with median of 12 years (range; 0.1-34) and 9 years (range; 0.01- 19.9), respectively, compared to 21 years (range; 0.01-49.4) for normal karyotype (p<0.0001) (Figure). In univariate analysis, risk factors for overall survival included abnormal karyotype (p=0.001), - Y (p=0.004), age >60 years (p<0.0001), leukocytosis >11 x10 9/L (p<0.0001), male gender (p=0.0003), and history of thrombosis (p=0.001). During multivariable analysis, abnormal karyotype other than -Y (p=0.003), age >60 years (p<0.0001), leukocytosis >11 x10 9/L (p=0.001), and male gender (p=0.01) remained significant. Additional analysis suggested individual prognostic impact for del(20q) (p=0.04) and also for trisomy 9 (p=0.09) and other abnormalities (p=0.07), with borderline significance.ConclusionThe current study confirms the association of abnormal karyotype in ET with older age, lower hemoglobin level, and history of arterial thrombosis, and its mutual exclusivity with ASXL1 mutations. Our observation regarding the independent adverse impact of abnormal karyotype other than -Y, on overall survival, in the absence of association with fibrotic or leukemic transformation, requires clarification from additional studies, which should also investigate the effect of specific abnormalities. [Display omitted] DisclosuresSzuber: Novartis: Honoraria.

Management of Polycythemia Vera: a Survey of Canadian Physician Practice Plans

Introduction:The 2016 World Health Organization (WHO) revised classification criteria for the diagnosis of polycythemia vera (PV) allow for an earlier detection of masked PV. Changes in diagnosis include a lower hemoglobin threshold to a hemoglobin of >165 g/L (160 g/L in women) from >185 g/L (165 g/L in women), and inclusion of a bone marrow biopsy (Arber et al., 2016).The literature is scarce about the clinical uptake of new diagnostic algorithms for PV. Our objectives were, in a cohort of Canadian Hematologists, to identify how the newly revised 2016 WHO diagnostic criteria of PV are being incorporated into hematology practice, and if the treatment of PV is comparable to the approaches outlined by the Canadian Myeloproliferative Neoplasm (MPN) Group (Sirhan et al., 2015). These national guidelines differ from the WHO criteria in that they suggest a diagnosis of PV can be made without a bone marrow biopsy if there is presence of elevated red blood cell volume as per the 2008 WHO criteria.Methods:An institution research ethics board approved cross-sectional survey of practicing Canadian hematologists/oncologists was conducted. Potential participants were drawn from 299 currently active members of the Canadian Hematology Society (CHS) over a 10 week period. The survey was offered in English and French and was collected anonymously using an online survey-distributing website, SurveyMonkey.com™. Paper copies of the survey were also distributed at the Leukemia Day conference in Toronto, April 6th, 2017. We assessed whether age, sex, practice type, practice setting, average number of PV patients seen per year, and awareness of the WHO 2016 criteria and/or the Canadian MPN Group guidelines influences management decisions. Univariate analysis was conducted with Fisher's exact test. For univariable analysis, Fisher's exact test was used if the explanatory variable was categorical and the Wald chi-square test from a multiple logistic regression was used if the explanatory variable was continuous. For multivariable analysis, logistic regression using the penalized maximum likelihood method was used to test the joint significance of explanatory variables on outcome. Penalized likelihood is a general approach to reducing small-sample bias in maximum likelihood estimation. All analyses were conducted using SAS version 9.4.Results:86 respondents completed the survey in total, (69 online surveys and 17 with paper copies). Table 1 describes the respondents' characteristics, diagnosis and treatment approach. The mean number of patients seen by respondents was 22.6 (SD 23.6) with a median of 15 (range of 0-120). Respondents who saw more PV patients yearly were more likely to use a formal symptom assessment score, such as the MPN10 score or the Edmonton Symptom Assessment System, on univariate analysis (P=0.015). Type of practice was associated with respondents offering aspirin to all PV patients without contra-indications to anti-platelet therapy (P=0.0009) on univariate analysis while practice setting or number of PV patients seen per year did not. Respondents who were aware of the Canadian MPN Group guidelines were more likely to phlebotomize patients to a target hematocrit of <45% irrespective of gender (P=0.042). Younger practitioners were more likely to use age over 60 as an indication for initiating cytoreductive therapy which was independent of other confounders in the multivariable analysis (P=0.0006). Most (85.3%) respondents would recommend indefinite anticoagulation in patients with PV who developed unprovoked venous thromboembolism (in whom there were not contraindications to anticoagulation).Discussion:The survey confirmed that heterogeneity of practice in diagnosis and management of PV among Canadian hematologists remains despite the revised 2016 WHO classification criteria and the guidelines set forth by the Canadian MPN Group. It has also shown that awareness of the guidelines and the updated diagnostic criteria translated into adopting approaches advocated in these documents. The survey suggests that targeted education in specific segments of the PV treatment providers may result in wider adoption of the guidelines and diagnostic criteria. [Display omitted] DisclosuresKuo:Alexion: Consultancy, Honoraria, Other: Site-PI for ALXN1210-PNH-301, ALXN1210-PNH-302, ALXN1210-aHUS-311, PKD natural history study, aHUS natural history study (M11); Celgene: Consultancy, Other: Site-PI on ACE-536-B-THAL-001; Agios: Consultancy, Other: Site-PI for AG-348-003 and PKD natural history study; Novartis: Consultancy, Honoraria; Pfizer: Other: Site-Pi for GMI1070 study; Phoenicia Biosciences: Other: Scientific collaboration; Abfero: Other: Scientific collaboration. Panzarella:Celgene Canada: Consultancy. Gupta:Incyte: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Trinkaus:Janssen and Amgen: Honoraria.

Classical Philadelphia-negative myeloproliferative neoplasms (MPNs): A continuum of different disease entities.

Classical Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell-derived disorders characterized by uncontrolled proliferation of differentiated myeloid cells and close pathobiologic and clinical features. According to the 2016 World Health Organization (WHO) classification, MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision aimed in particular at strengthening the distinction between masked PV and JAK2-mutated ET, and between prefibrotic/early (pre-PMF) and overt PMF. Clinical manifestations in MPNs include constitutional symptoms, microvascular disorders, thrombosis and bleeding, splenomegaly secondary to extramedullary hematopoiesis, cytopenia-related symptoms, and progression to overt MF and acute leukemia. A dysregulation of the JAK/STAT pathway is the unifying mechanistic hallmark of MPNs, and is guided by somatic mutations in driver genes including JAK2, CALR and MPL. Additional mutations in myeloid neoplasm-associated genes have been also identified, with established prognostic relevance, particularly in PMF. Prognostication of MPN patients relies on disease-specific clinical models. The increasing knowledge of MPN biology led to the development of integrated clinical and molecular prognostic scores that allow a more refined stratification. Recently, the therapeutic landscape of MPNs has been revolutionized by the introduction of potent, selective JAK inhibitors (ruxolitinib, fedratinib), that proved effective in controlling disease-related symptoms and splenomegaly, yet leaving unmet critical needs, owing the lack of disease-modifying activity. In this review, we will deal with molecular, clinical, and therapeutic aspects of the three classical MPNs aiming at highlighting either shared characteristics, that overall define a continuum within a single disease family, and uniqueness, at the same time.

New Perspectives on Polycythemia Vera: From Diagnosis to Therapy

Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. Major changes to its diagnostic criteria were made in the 2016 revision of the World Health Organization (WHO) classification, with both hemoglobin and hematocrit diagnostic thresholds lowered to 16.5 g/dL and 49% for men, and 16 g/dL and 48% for women, respectively. The main reason leading to these changes was represented by the recognition of a new entity, namely the so-called “masked PV”, as individuals suffering from this condition have a worse outcome, possibly owing to missed or delayed diagnoses and lower intensity of treatment. Thrombotic risk stratification is of crucial importance to evaluate patients’ prognosis at diagnosis. Currently, patients are stratified into a low-risk group, in the case of younger age (<60 years) and no previous thromboses, and a high-risk group, in the case of patients older than 60 years and/or with a previous thrombotic complication. Furthermore, even though they have not yet been formally included in a scoring system, generic cardiovascular risk factors, particularly hypertension, smoking, and leukocytosis, contribute to the thrombotic overall risk. In the absence of agents proven to modify its natural history and prevent progression, PV management has primarily been focused on minimizing the thrombotic risk, representing the main cause of morbidity and mortality. When cytoreduction is necessary, conventional therapies include hydroxyurea as a first-line treatment and ruxolitinib and interferon in resistant/intolerant cases. Each therapy, however, is burdened by specific drawbacks, underlying the need for improved strategies. Currently, the therapeutic landscape for PV is still expanding, and includes several molecules that are under investigation, like long-acting pegylated interferon alpha-2b, histone deacetylase inhibitors, and murine double minute 2 (MDM2) inhibitors.

Overt and Masked Polycythemia Vera Within the Scope of Ph-Negative Myeloproliferative Diseases

Aim. To study the structure of Ph-negative myeloproliferative diseases (Ph- MPD) and to identify morphological markers for diagnosing masked polycythemia vera (PV). Materials &amp; Methods. Bone marrow core biopsy samples from the database of pathology department of National Research Center for Hematology within the period from January 2014 to June 2017 provided the basis for analyzing the diagnosed Ph- MPD cases. The trial included the bone marrow core biopsy samples of the patients treated and fol-lowed-up not only at the National Research Center for Hematology but also at other medical centers in the Russian Federation in the context of clinical, laboratory and molecular data. Results. In 1611 Ph- MPD patients PV prevailed corresponding to 40.6 % of all cases. In the PV group the masked form was diagnosed in 29 % of patients. Primary myelofibrosis (PMF) was diagnosed in 26.6 % of all patients including 10 % of cases with pre-fibrosis/early stage. The 3d most frequent disorder was essential thrombocythemia (ET) which corresponded to 16 %. JAK2 driver mutation was identified in all 654 PV patients. In 4 cases out of them exon 12 mutation was detected. A similar mutation was found out in PMF (53 %) and ET (60 %). In 36 % of PMF patients and 27 % of ET patients CALR mutation was detected. MPL mutation was identified in 4 % of PMF cases and was not discovered in ET. Triple negative patients were identified in 7 % of PMF and 13 % of ET cases. The designation of “myeloproliferative disease unclassifiable” can be applied to 16.8 % of cases. The trial deals with morphological criteria for diagnosing masked PV during examination of bone marrow core biopsy samples. In 30 % of patients with masked PV (according to the 2017 WHO classification) and splenomegaly (&gt; 14 cm) portal vein thrombosis was identified. Conclusion. In the Ph- MPD group PV diagnosis prevailed (40.6 %). The histological analysis of bone marrow core biopsy samples of the patients with the masked PV accounting for 29 % of all PV cases, revealed morphological features typical of overt PV. Histological analysis of bone marrow is a reliable method for diagnosing overt and masked PV. Among morphological characteristics of the bone marrow of patients with masked PV and portal vein thrombosis special attention should be paid to the MF-1 grade of reticulin fibrosis (29 % of cases) and loose clusters of megakaryocytes (71.4 %).

Aquagenic pruritus in essential thrombocythemia is associated with a higher risk of thrombosis

BackgroundThromboses and phenotypic evolutions (leukemia, myelofibrosis) are the most frequent complications in polycythemia vera (PV) and essential thrombocythemia (ET). Aquagenic pruritus (AP) is not only PV symptom, but is also present in ET. The presence of pruritus in PV is associated with a lower risk of arterial thrombosis. AimsTo date, no equivalent study has been done to analyse the impact of AP for ET patients. Materials & MethodsWe used the data from our cohort of patients with myeloproliferative neoplasms seen in our institution (OBENE database, NCT02897297). We collect information at diagnosis, presence or not of AP and all types of complications during their follow‐up. To avoid masked PV, all JAK2 positive cases were tested isotopic red mass cell if appropriate. ResultsAmong 396 ET patients, presence of AP was found in 42 (10.6%). ET patients with AP were more proliferative, more symptomatic at diagnosis and more difficult to treat. Furthermore, they presented increased risk of thromboses (30.9 versus 17%, P = .03; OR = 2.2 [1.01;4.66]) and phenotypic evolutions (33.3 versus 13.3%, P = .0007; OR = 3.2 [1.44;6.77]), during follow‐up. DiscussionAquagenic pruritus is classically associated to PV. But we confirmed here that AP is also present in ET and characterizes patients with higher risk of morbidity (thrombotic events and phenotypic evolutions). ConclusionsThe systematic determination of the presence of AP in ET patients should permit us to better identify these high‐risk patients for better management and follow‐up.

Impact of World Health Organization (WHO) Revised Criteria-2016 on the Diagnosis of Polycythemia Vera.

The diagnosis of polycythemia vera (PV) requires the integration of clinical and laboratory findings, bone marrow morphologic features, and JAK2 analysis. JAK2V617F (exon 14) mutation is found in 95% of PV cases. In PV, addition of characteristic bone marrow morphology as one of three major diagnostic criteria allowed reduced hemoglobin/hematocrit threshold for diagnosis to 16.5g/dL/49% in men and 16g/dL/48% in women. JAK2 mutation is still the third major diagnostic criterion in PV. Low serum erythropoietin level is now considered as minor criterion in PV and is used to detect cases, which are negative for JAK2 mutation. In this retrospective study, cases diagnosed as PV from January 2013 to December 2015 were reclassified using WHO 2016 criteria. Their clinical and laboratory parameters along with treatment and outcome were studied. Out of 26 patients of previously diagnosed PV, either definitively or provisionally, twenty-one were found to comply with the new 2016 revision of the WHO Criteria. Median age was 55.5years, with a male preponderance. The median values of hemoglobin, hematocrit and platelets were 17.5gm/dL, 56.7% and 493 × 109/L, respectively. JAK2V617F was mutated in 17 cases. Bone marrow showed hypercellularity, panmyelosis and marked megakaryocyte dyspoiesis in all patients. All patients had normal oxygen saturation, confirming the primary nature of the disease. Our study, first of its kind in India, underscores the importance of the 2016 revision of the WHO document in detecting cases of masked PV.

Masked polycythemia vera: analysis of a single center cohort of 2480 red cell masses

Masked polycythemia vera: analysis of a single center cohort of 2480 red cell masses

S1610 MASKED POLYCYTHEMIA VERA: ANALYSIS OF A SINGLE CENTER SERIES OF 2480 RED CELL MASSES.

Background:Recently, masked polycythemia vera (mPV) was defined in the WHO 2016 Myeloproliferative Neoplasms (NMP) classification as a new entity: harboring JAK2V617F mutation, combining features of both Essential Thrombocythemia (ET) (isolated thrombocytosis) and Polycythemia vera (PV). It is impossible to distinguish ET from mPV based on hemoglobin or hematocrit values and bone marrow biopsy is required to discriminate between the two.Aims:We retrospectively analyzed the red cell masses (RCM) made in our institution to determine whether this test could help differentiating these entities.Methods:We analyzed 2480 consecutive patients in whom a RCM was performed in our center for suspected polycythemia during the last 7 years. Among the JAK2V617F positive patients, the characteristics of the following groups of patients were studied: ”PV“ (JAK2V617F mutation, RCM &gt; 125%, hemoglobin greater than 18.5/16.5 g/dL (male/female)); ”mPV“ (JAK2V617F mutation, RCM &gt; 125% and hemoglobin 16.5–18.5/15–16.5 g/dL); ”JAK2V617F‐positive ET with hemoglobin level similar to mPV“ (JAK2V617F mutation, VG &lt;125%, hemoglobin 16.5–18.5/15–16.5 g/dL).Results:In this cohort, 37.3% of the 2480 patients had a RCM &gt; 125% confirming polycythemia. Patients with lower hemoglobin levels (between 15–16.5 g/dL in 56 women and 16.5–18.5 g/dL in 112 men) could be classified according to the RCM level between mPV (n = 113) when RCM was &gt; 125% or JAK2V617F‐positive ET (n = 55) when RCM was &lt;125% of predicted value. Mean platelet counts were significantly lower in PV patients than in mPV and ET patients, while no difference was observed between mPV and ET patients. Mean platelet counts were 460 G/L (+/‐ 222 G/L) in PV, 560 G/L (+/‐ 245 G/L) in mPV and 563 G/L (+/‐ 252 G/L) in ET (p PV vs mPV = 0.0014, p PV vs ET = 0.0075 and p mPV vs ET = NS). Mean serum Erythropoietin levels were comparable in the mPV and PV groups and lower than in the ET group (PV: 3.41 +/−2.3 mIU/mL, mPV: 3.42 +/−2.2 mIU/mL and ET: 6.22 +/−4.09 mIU/mL, p PV vs mPV = NS, p mPV vs ET = 0.0003 and p PV vs ET = 0.0002). JAK2V617F allelic burden was significantly different between the three groups. Mean mutant allelic ratios were 46% +/‐ 22%, 31% +/‐ 23% and 19.9% +/‐ 20% in PV, mPV and ET, respectively (p PV vs mPV &lt;0.0001, p mPV vs ET = 0.0094 and p PV vs ET &lt; 0.0001). Finally, the proportion of patients with hemodilution was significantly higher in the mPV group with plasma volume &gt; 110% in 35% of mPV, 14% of PV, and 2% of ET patients respectively (p mPV vs. PV &lt; 0.001, p mPV vs ET &lt; 0.001 and p PV vs. ET = NS). This difference between PV and mPV patients could not be attributed to an increased spleen volume as the proportion of patients with splenomegaly was 19% in PV, 19% in mPV and 5.7% in ET patients (p PV vs mPV = NS, p mPV vs ET = 0.02 and p PV vs ET = 0.02).Summary/Conclusion:This study demonstrates that mPV can be distinguished from PV and ET based on RCM measurement even when bone marrow biopsy is not performed. Our findings may explain why masked PV presents some characteristics of ET (thrombocytosis) and PV (low EPO, increased RCM, relative microcytosis), but is a distinct entity (hemodilution even in the absence of splenomegaly, intermediate JAK2 mutant allelic burden between ET and PV). These results also suggest that mPV probably needs to be managed like PV, since these patients present a true erythrocytosis.

A CBC algorithm combined with immature platelet fraction is able to identify JAK2 V617F mutation-positive polycythaemia vera patients.

The recent lowering of the World Health Organisation (WHO) haemoglobin (Hb) and haematocrit (HCT) thresholds for diagnosis of polycythaemia vera (PV) has markedly increased the proportion of complete blood counts (CBC) that could be referred for haematologist review for comment, including advice on JAK2 V617F mutation analysis. The utility of an algorithm based on CBC indices and immature platelet fraction (IPF) to select cases for haematologist review was investigated. IPF analysis was performed on 22 patients with known JAK2 V617F mutation and 41 patients who were negative for this mutation previously tested because of suspicion of PV. A reference range study for IPF was performed on 102 normal patients. The algorithm was applied to data from 163358 CBC analyses to identify those most likely to have PV for review by a haematologist. The CBC algorithm and IPF requirement were satisfied by 47 patients (0.03%), eight of whom were known to have myeloproliferative disorders; the remaining 39 were referred for haematologist review. Utilising the algorithm enables identification of patients with a high likelihood of PV for haematological review. Large numbers are able to be screened efficiently and cost-effectively. Some patients with masked PV are able to be detected before clinical presentation.

A Nationwide Epidemiologic Study for Disease Transformation and Secondary Cancers in Korean Patients with Myeloproliferative Neoplasms

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (pMF) are three major components of myeloproliferative neoplasms (MPNs). They may be transformed to either secondary MF (sMF) or secondary acute myeloid leukemia (sAML). In addition, they can have second cancers during follow up (FU). It is important to understand the incidence rates and patterns of the transformation and second cancers because by the information we can understand clinical courses of MPNs holistically and figure out the actual socio-economic impact of MPNs on patients and communities.South Korea has a compulsory National Health Insurance System (NHIS), covering ~97% of the population. Claims data from health care providers to NHIS are submitted to the Health Insurance Review and Assessment Service (HIRA) for reimbursement for a service provided to patients. Because claims data for the remaining ~3% of the population belonging to the National Medical Aid Program are also reviewed by HIRA, nationwide epidemiologic studies are feasible. We conducted an epidemiologic study to elucidate clinical course of MPNs patients focusing on disease transformation and second cancers by analyzing the HIRA database. Cumulative incidence (CI) of transformation or second cancer were calculated considering death as a competing risk.A total of 7,471 patients (median age 60 years, range 11-106) who were diagnosed as one of the three kinds of MPNs from Jan. 2008 to Dec. 2016 and with appropriate F/U data for the analysis were included (4,405 for ET, 2,470 for PV, and 596 patients for pMF). Among ET patients (median F/U duration 46.7 months), 223 patients (5.06%) underwent any transformation during study period; ET→PV (i.e., initially diagnosed ET but changed to PV later; N = 80), ET→PV→sMF (N = 2), ET→PV→sAML (N = 1), ET→sMF (N = 68), ET→sMF→sAML (N = 6), and ET→sAML (N = 66), respectively. Among PV patients (median F/U duration 47.4 months), 33 patients (1.36%) underwent transformation to either sMF (N = 13) or sAML (N = 20), respectively. Among pMF patients (median F/U duration 31.9 months), 81 patients (13.59%) underwent transformation to sAML. Patients whose diagnosis was changed from ET to PV during F/U showed higher transformation rate to sMF (2.41% vs. 0.53%; p = 0.0273) and a tendency of higher sAML (1.20% vs. 0.81% to sAML; p = 0.6950) compared to primary PV patients.Five-year CI of transformation to sMF and sAML were 1.4% and 1.91% in ET patients, 0.69% and 0.97% in PV patients, and N/A and 16.54% in pMF patients, respectively (Table 1). Five-year CI of second lymphoid malignancies and solid cancers were 0.66% and 10.68% in ET, 0.17% and 6.67% in PV, and 1.30% and 12.09% in pMF patients, respectively (Table 1).Although this study has relatively short F/U duration and lacks information regarding mutational status, it clearly shows that 1) transformations are common in MPNs patients in the order of pMF, ET, followed by PV. 2) Patients whose diagnosis had changed from ET to PV during F/U had a tendency of higher transformation rate: They may be true transformed PV patients who had different biologic feature to primary PV patients, or some of them might be so-called ‘masked PV’ patients harboring JAK2 mutation and marrow findings of PV (Barbui et al. Am J Hematol 2014). 3) Patients with ET had a significantly high risk for second solid cancers almost as those with pMF did. Longer F/U of those population and future studies by subgroup analyses of PV (primary PV vs. transformed or masked PV) and ET (ET vs. pre-fibrotic MF according to 2016 WHO criteria) would further clarify the characteristics of transformation and second cancer in MPNs patients. [Display omitted] 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.

Management of Polycythemia Vera: A Survey of Canadian Physician Practice Patterns

BackgroundThe 2016 World Health Organization (WHO) revised classification criteria for the diagnosis of polycythemia vera (PV) allows for an earlier detection of masked PV. The literature is scarce about the clinical uptake of new diagnostic algorithms for PV. In a cohort of Canadian hematologists, we aimed to identify how the revised 2016 WHO diagnostic criteria of PV are being incorporated into hematology practice, and if the treatment of PV is comparable to the approaches outlined by the Canadian Myeloproliferative Neoplasm Group. Materials and MethodsA cross-sectional survey of practicing Canadian hematologists/oncologists was distributed to active members of the Canadian Hematology Society using an online survey-distributing website. Univariate and multivariate analysis was performed. ResultsThe survey was completed by 86 respondents in total. Only type of practice was associated with respondents offering aspirin to all patients with PV (P = .0009). Respondents who were aware of the Canadian Myeloproliferative Neoplasm Group guidelines were more likely to phlebotomize patients to a target hematocrit of < 45% irrespective of gender (P = .042). Younger practitioners were more likely to use age over 60 years as an indication for initiating cytoreductive therapy (P = .0006). Most (85.3%) respondents would recommend indefinite anticoagulation in patients with PV who developed unprovoked venous thromboembolism. ConclusionThe survey confirmed that heterogeneity of practice in diagnosis and management of PV among Canadian hematologists exists, suggesting that targeted education in specific segments of the PV treatment providers may result in wider adoption of the guidelines and diagnostic criteria.

The WHO diagnostic criteria for polycythemia vera—role of red cell mass versus hemoglobin/hematocrit level and morphology

Regarding diagnosis of polycythemia vera (PV), discussion persists about hemoglobin (Hb) and/or hematocrit (Hct) threshold values as surrogate markers for red cell mass (RCM) and the diagnostic impact of bone marrow (BM) morphology. We performed a retrospective study on 290 patients with PV (151 males, 139 females; median age 65years) presenting with characteristic BM features (initial biopsies, centralized evaluation) and endogenous erythroid colony (EEC) formations. This cohort included (1) a group of 229 patients when following the 2008 versus 256 patients diagnosed according to the 2016 World Health Organization (WHO) guidelines, all presented with increased RCM; (2) masked PV patients with low Hb (n = 143)/Hct (n = 45) recruited from the 2008 WHO cohort; (3) a cohort of 17 PV patients with elevated diagnostic Hb/Hct levels but low RCM; and (4) nine PV patients with increased RCM, opposing low Hb/Hct values. All patients were treated according to current PV guidelines (phlebotomies 87%, hydroxyurea 79%, and acetylsalicylic acid 87%). Applying the 2016 WHO criteria significantly increased concordance between RCM and Hb values compared with the 2008 WHO criteria (90 vs. 43% in males and 83 vs. 64% in females). Further analysis of the WHO 2016 PV cohort revealed that increased RCM is associated with increased Hb/Hct (93.8/94.6%). Our study supports and extends the diagnostic impact of the 2016 revised WHO classification for PV by highlighting the importance of characteristic BM findings and implies that Hb/Hct threshold values may be used as surrogate markers for RCM measurements.

European LeukemiaNet study on the reproducibility of bone marrow features in masked polycythemia vera and differentiation from essential thrombocythemia.

The purpose of the study was to assess consensus and interobserver agreement among an international panel of six hematopathologists regarding characterization and reproducibility of bone marrow (BM) histologic features used to diagnose early stage myeloproliferative neoplasms, in particular differentiation of so-called masked/prodromal polycythemia vera (mPV) from JAK2-mutated essential thrombocythemia (ET). The six members of the hematopathology panel evaluated 98 BM specimens independently and in a blinded fashion without knowledge of clinical data. The specimens included 48 cases of mPV according to the originally published hemoglobin threshold values for this entity (male: 16.0-18.4 g/dL, female: 15.0-16.4 g/dL), 31 cases with overt PV according to the updated 2016 WHO criteria, and 19 control cases. The latter group included cases of JAK2-mutated ET, primary myelofibrosis, myelodysplastic syndrome, and various reactive conditions. Inter-rater agreement between the panelists was very high (overall agreement 92.6%, kappa 0.812), particularly with respect to separating mPV from ET. Virtually all cases of mPV were correctly classified as PV according to their BM morphology. In conclusion, a central blinded review of histology slides by six hematopathologists demonstrated that highly reproducible specific histological pattern characterize PV and confirmed the notion that there are no significant differences between mPV and overt PV in relation to BM morphology.

Extension of 2016 World Health Organization (WHO) Classification into a New Set of Clinical, Laboratory, Molecular, and Pathological Criteria for the Diagnosis of Myeloproliferative Neoplasms: From Dameshek to Vainchenker, Green, and Kralovics

Improved Clinical, Laboratory, Molecular, and Pathological (CLMP) 2017 criteria for myeloproliferative neoplasms (MPN) define the JAK2V617F trilinear MPNs as a broad continuum of essential thrombocythaemia (ET), polycythaemia vera (PV), masked PV, and post-ET or post-PV myelofibrosis (MF). Normal versus increased erythrocyte counts (5.8×1012/L) on top of bone marrow histology separate JAK2V617F ET and prodromal PV from early and classical PV. Bone marrow histology of the JAK2V617F trilinear MPNs show variable degrees of normocellular megakaryocytic, erythrocytic megakaryocytic and erythrocytic megakaryocytic granulocytic (EMG) myeloproliferation, peripheral cytoses, and splenomegaly related to JAK2V617F allele burden. MPL515 thrombocythaemia displays predominantly normocellular megakaryocytic proliferation. CALR thrombocythaemia intially presents with megakaryocytic followed by dual granulocytic and megakaryocytic myeloproliferation without features of PV. The megakaryocytes are large, mature, and pleomorphic with hyperlobulated nuclei in JAK2V617F ET and prodromal, classical, and masked PV. The megakaryocytes are large to giant with hyperlobulated staghorn-like nuclei in MPL515 thrombocythaemia. The megakaryocytes are densely clustered, large, and immature dysmorphic with bulky (bulbous) hyperchromatic nuclei in CALR thrombocythaemia and MF.

Polycythemia Vera: New Diagnostic Concept and Its Types

Polycythemia vera (PV) is a clonal Ph-negative myeloproliferative disorder characterized by excessive myeloid proliferation of three hematopoietic cell lineages leading to ineffective myelopoiesis. According to WHO classification (2008), hemoglobin and hematocrit values are listed among the major diagnostic criteria. However, in many PV patients the levels may be below the diagnostic level, thus leading to underdiagnosis of PV. At present, three clinical types of the disease are recognized: 1) masked (latent/prodromal), 2) classic (overt), and 3) PV with progression/transformation into myelofibrosis. The masked form is most difficult for diagnosis, being highly heterogeneous with regard to clinical manifestations, laboratory data, medical history, and the course of the disease. It includes early stages, some of them with very high platelet count, imitating essential thrombocythemia, cases with abdominal thrombosis, and latent PV. Bone marrow trephine biopsy appears to be the most reliable method for diagnosis of masked PV. Findings typical for PV are readily visible, including hypercellular bone marrow with three-lineage myeloid proliferation, excess of megakaryocytes with mild to moderate cellular atypia and polymorphism. Grading of reticulin fibrosis has impact on prognosis and reflects the risk of progression into myelofibrosis. In revised edition of WHO classification (2016), the typical bone marrow histopathology will be included among the major criteria for the diagnosis of PV, meaning that bone marrow trephine biopsy is a mandatory diagnostic procedure in patients with borderline levels of hemoglobin and hematocrit.

Clinical Impact of Bone Marrow Morphology for the Diagnosis of Essential Thrombocythemia: Comparison Between the British Standards (BCSH) and the WHO Criteria

Background Accurate diagnosis of essential thrombocythemia (ET) continues to be a challenging issue for both hematopathologists and clinicians. Diagnosis is usually performed by applying either the 2014 British Committee for Standards in Haematology (BCSH) guidelines or the 2008 World Health Organization (WHO) criteria. While the WHO classification requires bone marrow morphology (BM) as a major criterion, the BCSH guidelines allow diagnosis also based solely on clinical symptoms and is more focused on exclusion of the other subtypes of myeloproliferative neoplasia (MPN). However, prefibrotic/early stages of primary myelofibrosis (prePMF) may also present with thrombocytosis, while failing to meet the diagnostic signs and symptoms characterizing overt PMF. Moreover, a small fraction of polycythemia vera (PV) patients may present with low hemoglobin and hematocrit levels, but a platelet count in keeping with BCSH- and WHO-defined ET, thus mimicking phenotypically ET at onset (masked PV). Clinical outcome in prePMF patients is considerably worse than in ET patients, while treatment strategies are likely to change for prePMF patients with the use of interferon-alpha or JAK1/2-inhibitors.Aims The aim of this study was to investigate the prognostic relevance of BM morphology for ET diagnosis as underscored by the WHO classification versus the first set of the BCSH criteria that do not include BM evaluation.Methods A clinic-pathological database including 450 MPN patients was created by clinicians and hematopathologists from a major Austrian center. Treatment-naive BM biopsies were centrally re-reviewed by three of the authors, who were completely blinded to initial data (except for age and gender). Follow-up data, including clinical course and mutation status, were analyzed after the completion of the histopathology review. For purpose of this study we selected two cohorts of ET patients presenting with a sustained platelet count > 450x10^9/L: (1) 209 ET patients in accordance with the diagnostic requirements of the BCSH (A1-A3) that included no BM biopsy examination. (2) 152 patients in strict agreement with the diagnostic guidelines of the WHO including BM biopsy evaluation as major criterion. Both cohorts were compared and analyzed to regarding their presenting clinico-pathological data, driver mutation status, and follow-up. Diagnosis of post-ET myelofibrosis or progression into overt myelofibrosis with myeloid metaplasia was made according to previously published criteria.Results Following the BCSH criteria, 209 patients were diagnosed as ET. When reclassifying those cases according to the WHO criteria including BM morphology examination, 80 (38.3%) patients were diagnosed as prePMF and 14 (6.7%) as PV and two were diagnosed as PMF (0.9%). Comparison of clinical features of BCSH-ET and WHO-ET revealed significant differences in LDH levels and palpable splenomegaly at diagnosis. Fibrosis-free survival was significantly shorter in BCSH-ETs (Fig. 1A) as was overall survival (Fig. 1B). When reclassifying the BCSH cohort according to WHO criteria, progression-free and overall survival were significantly shorter in WHO-confirmed prePMF (Fig. 1C and 1D).Summary/Conclusion The striking differences in outcome are certainly linked with the entry of many prePMF cases in the BCSH-confirmed cohort. The inclusion of these cases, as well as cases with masked PV demonstrates, that BCSH criteria A1-3 may lead clinicians to refrain from performing BM biopsy in patients with elevated thrombocyte counts, which impairs accurate diagnosis with subsequent inadequate management and inferior prognosis. Our results highlight the central role of BM biopsy to achieve accurate diagnosis and differentiation of ET and prePMF. [Display omitted] DisclosuresGisslinger:Geron: Consultancy; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Consultancy; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau.

The Incidence of Thrombosis of Masked PV Compared with PV and ET in A Single Institute

Objective: Polycythemia Vera (PV) and Essential Thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPN) characterized by frequent thrombotic complication. Thus, the important goal of therapy is to prevent thrombosis. However, there are some JAK2V617F mutation-positive patients who show bone marrow features characteristic for PV but do not meet the World Health Organization (WHO) diagnostic criteria of PV. Recently, a new definition of masked PV is proposed; which is hypothesized as the initial manifestation of MPN. Masked PV is believed to have thrombosis more frequently than PV and ET. Here, we evaluated the outcome of patients who corresponded to masked PV. Design: We reviewed our patients retrospectively who were diagnosed as PV or ET in our institute. From medical records, we evaluated the incidence of thrombosis of patients who corresponded to masked PV. Patients: Eligible patients were JAK2V617F mutated PV or ET patients who were diagnosed in our hospital according to WHO criteria. They were classified as overt PV if hemoglobin level was >18.5g/dl in males and >16.5g/dl in females. When hemoglobin level of 16.018.4g/dl in males and 15.0-16.4 g/dl in females, they were classified as masked PV. The remaining patients with>45 10/mL of platelets were diagnosed as ET. Main Outcomes Measure: The incidence of thrombosis was 17% in masked PV and this was less frequently than in overt PV or ET. Results: Among 56 JAK2V617F-mutated patients, 6 patients (11%) were classified as masked PV and all of them were males. Their leucocyte counts was lower (11300 vs 10950/mL) and platelets counts was higher (51.6 vs 61.4 10/mL) than overt PV. Median age was 60 in overt PV, 68 in ET and 47.5 in masked PV. The incidence of thrombosis was 36%, 28% and 17%, respectively. In masked PV patients of our hospital, the incidence of thrombosis was less frequently. A possible reason for that is the treatment which maintained the Hematocrit (Hct) level below 50% in masked PV patients. Conclusion: In our patients the masked PV did not show high incidence of thrombosis, possibly because of the treatment that maintained the Hct level below 50%.