Thrombocytosis in children and adolescents-classification, diagnostic approach, and clinical management.

Secondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations within the genes encoding key regulators of thrombopoiesis, i.e., thrombopoietin (THPO) and its receptor c-MPL (MPL) or the receptor's effector kinase Januskinase2 (JAK2). Furthermore, somatic mutations in JAK2, MPL, and in the gene-encoding calreticulin (CALR) have been described to act as driver mutations within the so-called Philadelphia-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Increasing knowledge on the molecular mechanisms and on the clinical complications of these diseases is reflected by the WHO diagnostic criteria and European LeukemiaNet (ELN) recommendations on the management of adult MPN. However, data on childhood thrombocytosis are rare, and no consensus guidelines for pediatric thrombocytosis exist. Current literature has highlighted differences in the epidemiology and molecular pathogenesis of childhood thrombocytosis as compared to adults. Furthermore, age-dependent complications and pharmacological specificities suggest that recommendations tailored to the pediatric population are necessary in clinical practice. Here we summarize literature on classification, diagnostics, and clinical management of childhood thrombocytosis.

The new WHO classification for essential thrombocythemia calls for revision of available evidences.

In the 2016 revised classification of myeloproliferative neoplasms pre-fibrotic primary myelofibrosis (pre-PMF) was recognized as a separate entity, distinct from essential thrombocythemia (ET). Owing that the majority of cases falling in the pre-PMF category were previously diagnosed as ET, one may question about the need to re-evaluate the results of epidemiologic, clinical, and molecular studies, and the results of clinical trials in the two entities. Based on a critical review of recently published studies, pre-PMF usually presents with a distinct clinical and hematological presentation and higher frequency of constitutional symptoms. JAK2V617F and CALR mutations in pre-PMF patients are superimposable to ET, whereas non-driver high-risk mutations are enriched in pre-PMF compared with ET. Thrombosis is not significantly different, whereas bleeding is more frequent in pre-PMF. Median survival is significantly shorter in pre-PMF and 10-year cumulative rates progression to overt myelofibrosis is 0-1% vs. 10-12%, and leukemic transformation is 1-2% vs. 2-6%, in ET and pre-fibrotic-PMF, respectively. Most patients fall in the lower prognostic IPSS group in which observation alone can be recommended. Patients at intermediate risk may require a symptom-driven treatment for anemia, splenomegaly or constitutional symptoms while cytoreductive drugs are indicated in the high-risk category.

Polycythemia vera and essential thrombocythemia: algorithmic approach.

PURPOSE OF REVIEW: To describe an algorithm-based approach, whenever available, to the diagnosis, the risk stratification criteria informing therapy and the current management of polycythemia vera and essential thrombocythemia. RECENT FINDINGS: Description of recurrent genetic abnormalities in driver genes, including Janus Kinase 2 (JAK2), myeloproliferative leukemia and calreticulin, a better appreciation of the key diagnostic role of bone marrow features, results of large epidemiologic studies and a few but landmark controlled clinical trials produced in the last decade, all resulted in a reappraisal of the approach to polycythemia vera and essential thrombocythemia. SUMMARY: The revised 2017 WHO classification of polycythemia vera and essential thrombocythemia allows early diagnosis and accurate distinction from other chronic myeloproliferative neoplasms, particulary prefibrotic myelofibrosis. The prognostic value of selected mutations is being appreciated and JAK2V617F mutation is currently incorporated as risk variable in prognostic system for essential thrombocythemia. Risk-adjusted stratification is used to select therapeutic approaches that include target agents. However, there is not yet a curative approach to these hematologic neoplasms, and although their management has much improved in the last decades, the associated morbidity and mortality remains significant and may be worsened by toxicities of therapeutic agents. Therefore, several clinically relevant endpoints remain unmet.

Thrombosis in essential thrombocytemia and early/prefibrotic primary myelofibrosis: the role of the WHO histological diagnosis.

BACKGROUND: Vascular events represent the most frequent complications of thrombocytemias. We aimed to evaluate their risk in the WHO histologic categories of Essential Thrombocytemia (ET) and early Primary Myelofibrosis (PMF). METHODS: From our clinical database of 283 thrombocytemic patients, we selected those with available bone marrow histology performed before any treatment, at or within 1 year from diagnosis, and reclassified the 131 cases as true ET or early PMF, with or without fibrosis, according to the WHO histological criteria. Vaso-occlusive events at diagnosis and in the follow-up were compared in the WHO-groups. RESULTS: Histologic review reclassified 61 cases as ET and 72 cases as early PMF (26 prefibrotic and 42 with grade 1 or 2 fibrosis). Compared to ET, early PMF showed a significant higher rate of thrombosis both in the past history (22% vs 8%) and at diagnosis (15.2% vs 1.6%), and an increased leukocyte count (8389 vs 7500/mmc). Venous thromboses (mainly atypical) were relatively more common in PMF than in ET. Patients with prefibrotic PMF, although younger, showed a significant higher 15-year risk of developing thrombosis (48% vs 16% in fibrotic PMF and 17% in ET). At multivariate analysis, age and WHO histology were both independent risk-factors for thrombosis during follow-up; patients >60 yr-old or with prefibrotic PMF showed a significantly higher risk at 20 years than patients <60 yr-old with ET or fibrotic PMF (47% vs 4%, p = 0.005). CONCLUSIONS: Our study support the importance of WHO histologic categories in the thrombotic risk stratification of patients with thrombocytemias. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2020211863144412 .

WHO classification of myeloproliferative neoplasms (MPN): A critical update.

Although the revised World Health Organization (WHO) criteria for the diagnosis and classification of myeloproliferative neoplasms (MPN) were defined by a panel of expert hematopathologists and clinicians, controversy has been repeatedly expressed questioning the clinical usefulness and reproducibility of these diagnostic guidelines. In particular, the distinction between essential thrombocythemia (ET), early/prefibrotic primary myelofibrosis (PMF) and initial stages of polycythemia vera (PV) is still a matter of debate. In this context, it has been argued that clinical correlations with histological features were not firmly substantiated. On the other hand, recently published data from independently performed studies have repeatedly validated the reproducibility of the WHO criteria and provided persuasive evidence that discrimination of early/prefibrotic PMF has a significant impact on the risk of myelofibrotic and leukemic transformation. However, as has been explicitly required, the WHO concept is based on the recognition of characteristic bone marrow patterns and a consensus of clinical and molecular data.

Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis).

Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO)-defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis-derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events.

[Classification and diagnosis of essential thrombocythemia].

Although the fourth edition of the World Health Organization (WHO) classification of the diagnostic criteria for myeloproliferative neoplasms is widely accepted, the diagnosis of essential thrombocythemia has been debated. One of the controversies focuses on the provisional entity known as refractory anemia, which exhibits ringed sideroblasts associated with marked thrombocytosis (RARS-T). To date, it has not been made clear whether RARS-T is a form of ET or a separate and unique disease entity. Recent findings, which may shed light on this debate, have demonstrated that more than 60% of RARS-T patients exhibit somatic mutations of SF3B1, a gene encoding a core component of the RNA-splicing system. Another debate is focused on the role of bone marrow histopathology in the diagnosis of essential thrombocythemia. Bone marrow histopathology has been considered to be a major diagnostic criterion for essential thrombocythemia since the previous version of the WHO classification criteria was published. The histological features of bone marrow are important to distinguish essential thrombocythemia from early, prefibrotic stages of primary myelofibrosis, which frequently exhibit elevated platelet levels. The specific histological bone marrow patterns of the diseases were outlined in the fourth version of the WHO classification; however, several investigators have claimed that the criteria exhibit poor interobserver reproducibility and are not sufficiently robust to discriminate essential thrombocythemia and early-stage primary myelofibrosis. This review highlights the recent debates on the role of bone marrow histopathology in essential thrombocythemia.

Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification.

Controversy persists regarding the role of histopathology in the distinction between essential thrombocythemia (ET) and early-prefibrotic primary myelofi-brosis (PMF) presenting with thrombocythemia. To investigate the impact and reproducibility of bone marrow (BM) morphology according to the World Health Organization classification, 295 patients with the presumptive clinical diagnosis of either ET or early PMF were studied. Data of this cohort (Vienna group) were compared with 732 corresponding patients (Cologne group). Evaluating blindly (only age and gender known) BM specimens, the 2 groups of pathologists achieved an overall consensus of 78% regarding the total series and 88% concerning the discrimination between ET versus PMF. In 126 ET and 81 early PMF patients without pretreatment and complete documentation, a 90% concordance with the independently established clinical diagnosis was found. In 12 patients, overlapping of histopathology and some clinical findings between ET and polycythemia vera occurred. Contrasting ET, early PMF showed significant differences of presenting hematologic data and an unfavorable prognosis (estimated mean survival, 14 vs 21 years). Comparison of clinical and survival data of the Vienna cohort with the historical Cologne series revealed an overall congruence. This study highlights the impact of BM morphology for the differentiation between true vs false ET.

How I treat myelofibrosis.

It is currently assumed that myelofibrosis (MF) originates from acquired mutations that target the hematopoietic stem cell and induce dysregulation of kinase signaling, clonal myeloproliferation, and abnormal cytokine expression. These pathogenetic processes are interdependent and also individually contributory to disease phenotype-bone marrow stromal changes, extramedullary hematopoiesis, ineffective erythropoiesis, and constitutional symptoms. Molecular pathogenesis of MF is poorly understood despite a growing list of resident somatic mutations that are either functionally linked to Janus kinase (JAK)-signal transducer and activator of transcription hyperactivation (eg JAK2, MPL, and LNK mutations) or possibly involved in epigenetic dysregulation of transcription (TET2, ASXL1, or EZH2 mutations). Current prognostication in primary MF is based on the Dynamic International Prognostic Scoring System-plus model, which uses 8 independent predictors of inferior survival to classify patients into low, intermediate 1, intermediate 2, and high-risk disease groups; corresponding median survivals are estimated at 15.4, 6.5, 2.9, and 1.3 years. Such information is used to plan a risk-adapted treatment strategy for the individual patient, which might include observation alone, conventional or investigational (eg, JAK inhibitors, pomalidomide) drug therapy, allogenic stem cell transplantation with reduced- or conventional-intensity conditioning, splenectomy, or radiotherapy. I discuss these treatment approaches in the context of who should get what and when.

Rethinking disease definitions and therapeutic strategies in essential thrombocythemia and polycythemia vera.

The seminal discovery of the JAK2V617F mutation, which is highly prevalent in Philadelphia-negative myeloproliferative disorders, now renamed neoplasms, triggered an almost unprecedented explosion of interest and data in the field. Descriptions of additional mutations in exon 12 of JAK2, at position 515 in MPL, and a number of other mutations at low frequency followed these discoveries. These advances in our understanding of molecular pathogenesis of these conditions coincided with the publication of results from two major clinical studies, ECLAP and PT-1, which contributed important clinical insights and facilitated significant correlative data collection. This article, focusing mainly upon essential thrombocythemia and polycythemia vera, reviews four major themes: the impact upon classification of these disorders considering a radical review of current terminology, and then three areas pertinent to clinical management: the indications for cytoreductive therapy in which the key targets are to reduce thrombohemorrhagic complications, relieve disease-related symptoms, and minimize the risk of transformation to secondary myeloid malignancy such as myelodysplasia, leukemia, and secondary myelofibrosis; and second reviewing current and, last, future therapeutic options, in particular interferon and JAK2 inhibitors.

Decisional flow with a scoring system to start platelet-lowering treatment in patients with essential thrombocythemia: long-term results.

We prospectively tested, at diagnosis in essential thrombocythemia (ET) patients with no clear indication to platelet (PLT)-lowering treatment, a scoring system based on age, PLT level, cardiovascular diseases, previous thrombotic events, smoking and dysmetabolic diseases. From 04/92 to 03/98, 168 consecutive patients were enrolled. Hydroxyurea (HU) was started at diagnosis in 32 "symptomatic" patients and in 33 patients aged >70 years. The remaining 103 patients ("asymptomatic" and aged <70 years) were classified according to our scoring system. Thirty-two patients with score > or = 4 started HU early after diagnosis. The remaining 71 patients with score <4 at diagnosis received anti-aggregating agents only; of them, 24 (33.8%) started HU during follow-up after a median time from diagnosis of 28 months, while 47 (66.2%) did not start any PLT-lowering treatment. Thrombotic complications occurred in 9/103 patients (8.7%); in particular, they occurred in 4/32 patients (12.5%) with score > or = 4 receiving HU since diagnosis and in 5/71 (7%) with score <4 under anti-aggregating agents only. This scoring system appears effective to discriminate a different risk of thrombotic events, and could be useful to decide when a PLT-lowering therapy needs to be started.

JAK2(V617F) allele burden discriminates essential thrombocythemia from a subset of prefibrotic-stage primary myelofibrosis.

OBJECTIVE: Among Philadelphia chromosome-negative myeloproliferative neoplasms (Ph(-) MPN), essential thrombocythemia (ET) and the prefibrotic phase of primary myelofibrosis (PMF) represent two subtypes with considerable overlap. MATERIALS AND METHODS: In this study, histopathological classification of 490 MPN cases was correlated with the allelic burden of JAK2(V617F) and MPL(W515L). RESULTS: Ph(-) MPN entities largely overlap with regard to JAK2(V617F) and MPL(W515L) allele burden, but ET displayed mutant allele burden <50%. PMF with different stages of myelofibrosis all yielded similar JAK2(V617F) allele burden. At initial presentation one-quarter of prefibrotic PMF cases exhibited an allele burden exceeding 50% (38% median JAK2(V617F) alleles, n=102). In ET, its main differential diagnosis, not a single case was found with >40% JAK2(V617F) alleles (median, 24% JAK2(V617F) alleles; n=90; p<0.001). Increase in JAK2(V617F) alleles during follow-up could not be linked to fibrosis or blastic progression but was related to polycythemic transformation in ET. MPL(W515L) was found in 3% of ET and 8% of PMF, with a significantly higher percentage of mutated alleles in fibrotic than prefibrotic PMF (median, 78% MPL(W515L) alleles; p<0.05). CONCLUSION: Histopathological categories ET and prefibrotic PMF correlate with significant differences in mutant allelic burden of JAK2(V617F), but not of MPL(W515L) which, by contrast to JAK2(V617F), shows a higher percentage of mutated alleles in fibrotic than in prefibrotic cases. Thus, for Ph(-) MPN in which ET and prefibrotic PMF represent the most probable diagnoses, a JAK2(V617F) allele burden >50% favors a diagnosis of prefibrotic PMF.

The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos.

The first formal classification of chronic myeloid neoplasms is credited to William Dameshek, who in 1951 described the concept of "myeloproliferative disorders (MPD)" by grouping together chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2001 World Health Organization (WHO) classification of myeloid malignancies included these MPDs under the broader category of chronic myeloproliferative diseases (CMPD), which also included chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), and "CMPD, unclassifiable." The revised 2008 WHO classification system featured the following changes: 1) the term "CMPD" was replaced by "myeloproliferative neoplasm (MPN)," 2) mast cell disease was formally included under the category of MPN, and 3) the subcategory of CEL/HES was reorganized into "CEL not otherwise specified (CEL-NOS)" and "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1"; CEL-NOS remained a subcategory of "MPN," whereas the latter neoplasms were now assigned a new category of their own. Furthermore, diagnostic criteria for PV, ET, and PMF were revised by incorporating recently described molecular markers (eg, JAK2 and MPL mutations) as well as underscoring the role of histology in differentiating reactive from clonal myeloproliferations. As a result, red cell mass measurement is no longer necessary for the diagnosis of PV, and ET can now be diagnosed at a lower platelet count threshold. The revised WHO document continues to promote the recognition of histologic categories as a necessary first step toward the genetic characterization of myeloid malignancies.

Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy.

The recent discovery of JAK2 and/or MPL mutations in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) has had a major impact on how we diagnose and treat these disorders. For instance, the presence of a JAK2 mutation is now considered conditio sine qua non for the diagnosis of PV and the World Health Organization classification system has recently revised its diagnostic criteria for PV, ET, and PMF to include JAK2 and MPL mutations as clonal markers. From the standpoint of treatment, JAK-STAT is now identified as a legitimate target pathway for drug development in myeloproliferative neoplasms. Herein, I will first outline my views regarding current management in ET, PV, and PMF and then discuss emerging data on preclinical and clinical activity of anti-JAK2 small molecule drugs. Am. J. Hematol., 2008. (c) 2008 Wiley-Liss, Inc.

Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT).

The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) is comprised of hematologists, hematopathologists, and laboratory scientists and its main goal is to provide a forum for scientific exchange and collaboration. During its first general meeting in April 2006, the IWG-MRT established uniform treatment response criteria for chronic idiopathic myelofibrosis (CIMF); also known as agnogenic myeloid metaplasia (AMM), myelofibrosis with myeloid metaplasia (MMM), and many other names in the hematologic literature. This document summarizes the proceedings from the second meeting of the IWG-MRT, in November 2006, where the group discussed and agreed to standardize the nomenclature referring to CIMF: (i) the term primary myelofibrosis (PMF) was chosen over several other designations including CIMF, AMM, and MMM, (ii) myelofibrosis that develops in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET) will be referred to as post-PV MF and post-ET MF, respectively, and (iii) "leukemic" transformation will be recognized as blast phase disease (PMF-BP, post-PV/ET MF in blast phase).