Essential thrombocythemia: 2024 update on diagnosis, risk stratification, and management.

OVERVIEW: Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often indolent but might be interrupted by thrombotic or hemorrhagic complications, microcirculatory symptoms (e.g., headaches, lightheadedness, and acral paresthesias), and, less frequently, by disease transformation into myelofibrosis (MF) or acute myeloid leukemia. DIAGNOSIS: In addition to thrombocytosis (platelets ≥450 × 109 /L), formal diagnosis requires the exclusion of other myeloid neoplasms, including prefibrotic MF, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis. Bone marrow morphology typically shows increased number of mature-appearing megakaryocytes distributed in loose clusters. GENETICS: Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner; in addition, about 50% harbor other mutations, the most frequent being TET2 (9%-11%), ASXL1 (7%-20%), DNMT3A (7%), and SF3B1 (5%). Abnormal karyotype is seen in <10% of patients and includes +9/20q-/13q-. SURVIVAL AND PROGNOSIS: Life expectancy is less than that of the control population. Median survival is approximately 18 years but exceeds >35 years in younger patients. The triple A survival risk model, based on Age, Absolute neutrophil count, and Absolute lymphocyte count, effectively delineates high-, intermediate-1-, intermediate-2-, and low-risk disease with corresponding median survivals of 8, 14, 21, and 47 years. RISK FACTORS FOR THROMBOSIS: Four risk categories are considered: very low (age ≤60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (same as low but age >60 years), and high (thrombosis history or age >60 years with JAK2 mutation). MUTATIONS AND PROGNOSIS: MPL and CALR-1 mutations have been associated with increased risk of MF transformation; spliceosome with inferior overall and MF-free survival; TP53 with leukemic transformation, and JAK2V617F with thrombosis. Leukemic transformation rate at 10 years is <1% but might be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype. TREATMENT: The main goal of therapy is to prevent thrombosis. In this regard, once-daily low-dose aspirin is advised for all patients and twice daily for low-risk disease. Cytoreductive therapy is advised for high-risk and optional for intermediate-risk disease. First-line cytoreductive drugs of choice are hydroxyurea and pegylated interferon-α and second-line busulfan. ADDITIONAL CONTENT: The current review includes specific treatment strategies in the context of extreme thrombocytosis, pregnancy, splanchnic vein thrombosis, perioperative care, and post-essential thrombocythemia MF, as well as new investigational drugs.

How I treat myeloproliferative neoplasms in pregnancy.

ABSTRACT: Although myeloproliferative neoplasms (MPNs) are traditionally considered diseases of adults in their sixth or seventh decade, these conditions do occur in young patients; for example, for essential thrombocythemia, in particular, there is a second peak in women of reproductive age. Therefore, pregnancy is an uncommon but not rare occurrence and clinical challenge in some scenarios. Here, we discuss in detail our local approach to the management of pregnancy in patients with MPN while taking a case-based approach. We include relevant updates in the field and point to a future research strategy that should be internationally focused to obtain as much information in as short a time as possible.

Significant heterogeneity in management of calreticulin-mutated essential thrombocythemia and its progression to myelofibrosis: results of a national survey.

Despite the recent publication of calreticulin (CALR)-mutated essential thrombocythemia (ET) management guidelines by the European Leukemia Net (ELN), there remains a paucity of data regarding the optimal way to manage this condition. To determine practice around Australia, we constructed a survey asking investigation and treatment questions in a hypothetical case of a young woman with CALR-mutated ET and subsequent progression to myelofibrosis. 51 of 88 hematologists replied. The responses demonstrated significant heterogeneity in specific issues such as the use of aspirin, when to initiate cytoreduction, the preferred type of cytoreduction, and platelet targets. These observations support the ELN acknowledgment that a strong evidence base for many management recommendations is lacking in this disease, and that substantial further research is needed.

The effect of thrombocytapheresis on hemogram and biochemistry parameters in patients with essential thrombocytemia.

BACKGROUND: Essential thrombocythemia is one of the chronic myeloproliferative neoplasms characterized by clonal proliferation of myeloid cells with variable morphological maturation and hematopoietic activity.It is characterized by excessive clonal platelet production with a tendency to thrombosis and bleeding. Thrombocytapheresis is the removal of platelets by apheresis techniques. Thrombocytapheresis is generally recommended in patients with essential thrombocythemia with acute, severe thrombotic or hemorrhagic events. METHODS: The study included 39 patients who were diagnosed with essential thrombocythemia, started cytoreductive and aspirin therapy, and underwent thrombocytapheresis due to the development of acute severe thrombotic or hemorrhagic events, diagnosed in the adult hematology clinic of Inönü University Turgut Ozal Medical Center. Hemogram and biochemistry values of the patients were scanned retrospectively. RESULTS: After thrombocytapheresis, a statistically significant difference was found between the first and last measurements of hemoglobin, mean platelet volume, White blood cell, neutrophil, platelet, platelet distribution width, creatine, lactate dehydrogenase, fibronogen and calcium levels of the patients. CONCLUSION: The use of thrombocytapheresis in patients with essential thrombocytosis causes a rapid decrease in platelet values as well as an effect on hemogram and biochemistry parameters. Other hemogram and biochemistry parameters such as platelet value should be monitored in patients.

BCR::ABL1 negative myeloproliferative neoplasms: A review focused on essential thrombocythemia and polycythemia vera.

The classical myeloproliferative neoplasms are divided into chronic myeloid leukemia, and the Philadelphia negative polycythemia vera, essential thrombocythemia and primary myelofibrosis. These are heterogenous diseases, originating from the clonal proliferation of myeloid stem cells, resulting in increased mature cell numbers in one or more myeloid lineages. The most commonly seen mutations in the Philadelphia negative myeloproliferative neoplasms include those in Janus kinase, myeloproliferative leukemia protein and the calreticulin genes. Philadelphia negative myeloproliferative neoplasms occur infrequently, with a combined annual incidence of 2.58 per 100,000. There are many overlapping symptoms of Philadelphia negative MPNs, such as fatigue, night sweats, hepatosplenomegaly and circulatory symptoms due to increased cell numbers. Total Symptom Score of the MPN Symptom Assessment Form is used to assess symptom burden on patients. The most worrisome complications are thrombo-hemorrhagic events, and risk stratification is especially important as treatment of disease is based on their category. Phlebotomy and aspirin are the mainstay of treatment in low-risk polycythemia vera and essential thrombocythemia patients, whereas high-risk disease calls for additional cytoreduction, usually with hydroxyurea.

Essential Thrombocythemia in Adolescents and Young Adults: Clinical Aspects, Treatment Options and Unmet Medical Needs.

OPINION STATEMENT: Current treatment of essential thrombocythemia (ET) should primarily prevent thrombo-hemorrhagic events, without increasing the rate of fibrotic progression or leukemic evolution, and secondarily control microvascular symptoms. Unlike other classic BCR::ABL1-negative myeloproliferative neoplasms, ET is frequently diagnosed in adolescents and young adults (AYA), defined as individuals aged 15 to 39 years, in up to 20% of patients. However, since the current risk stratification of this disease is based on models, including that of ELN, IPSET-Thrombosis and its revised version, mainly applied to an older patients' population, international guidelines are needed that specifically consider how to evaluate the prognosis of AYAs with ET. Furthermore, although ET is the most frequent MPN among AYA subjects, there is a lack of specific recommendations on how to treat it in this subgroup of patients, as management decisions are typically extrapolated from those for the elderly. Accordingly, since AYAs with ET represent a unique disease subset defined by attenuated genetic risk, more indolent phenotype, and longer survival than their older counterparts, treatment selection requires special attention to specific issues such as the risk of fibrotic/leukemic transformation, carcinogenicity, and fertility. This review article will provide a comprehensive overview of the diagnosis, prognostic stratification, and possible therapeutic approaches for AYA patients with ET, including antiplatelets/anticoagulants and cytoreductive agents, with a focus on pregnancy management in real-life clinical practice.

A review of essential thrombocythemia and its complications.

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by an increased platelet count in the peripheral blood and excessive megakaryopoiesis in the bone marrow. In one-third of cases, the disease remains benign and does not lead to complications. In the remaining cases, however, ET may present with thromboembolic and hemorrhagic complications and transform into more aggressive myeloid neoplasms, with a negative effect on morbidity and mortality. Despite extensive research and a better understanding of the pathogenesis and etiology of the complications associated with ET, limited data are available on the management of complications and emergencies. This article highlights the complications and emergencies associated with ET and discusses treatment options and the controversies associated with management.

Two Cases of Gastric Varices with Left-sided Portal Hypertension Due to Essential Thrombocythemia Treated with Gastric Devascularization or Partial Splenic Embolization.

Left-sided portal hypertension (LSPH) is a condition of extrahepatic portal hypertension that often results in bleeding from isolated gastric varices (GVs). LSPH is sometimes caused by myeloproliferative diseases, such as essential thrombocythemia (ET). We herein report two cases of GVs with LSPH due to ET that were successfully controlled by gastric devascularization (GDS) or partial splenic embolization (PSE). Since each patient with LSPH due to ET has a different pathology, optimal treatment should be performed depending on the patient's condition, such as platelet counts, hemodynamics, or the prognosis. We believe that these cases will serve as a reference for future cases.

Essential thrombocythemia: challenges in clinical practice and future prospects.

Essential thrombocythemia (ET) was first described in 1934, and subsequently, progress has been made in better understanding the molecular pathogenesis and which patients may have greatest risk of progression or vascular events. However, it has been more than a decade since a new therapy has been approved for ET. We are beginning to understand more comprehensively both the heterogeneity of this disease, which is largely driven by driver mutation status, as well as the effect of disease-related symptoms, such as fatigue, on patients. In this review we provide a practical overview of diagnosis and management of ET with focus on challenging patient scenarios and some consideration of what comprehensive care might entail. Finally, we also discuss newer therapies and how these might be assessed.

Essential Thrombocythemia and Post-Essential Thrombocythemia Myelofibrosis: Updates on Diagnosis, Clinical Aspects, and Management.

Although several decades have passed since the description of myeloproliferative neoplasms (MPN), many aspects of their pathophysiology have not been elucidated. In this review, we discuss the mutational landscape of patients with essential thrombocythemia (ET), prognostic scores and salient pathology, and clinical points. We discuss also the diagnostic challenges of differentiating ET from prefibrotic MF. We then focus on post-essential thrombocythemia myelofibrosis (post-ET MF), a rare subset of MPN that is usually studied in conjunction with post-polycythemia vera MF. The transition of ET to post-ET MF is not well studied on a molecular level, and we present available data. Patients with secondary MF could benefit from allogenic hematopoietic stem cell transplantation, and we present available data focusing on post-ET MF.

In-Hospital Outcomes of Acute Myocardial Infarction With Essential Thrombocythemia and Polycythemia Vera: Insights From the National Inpatient Sample.

Background Acute myocardial infarction (AMI) with essential thrombocythemia (ET) or polycythemia vera is rare, and there are scarce real-world data on its management and impact on in-hospital outcomes. Methods and Results Dates of current retrospective cohort study were obtained from the US National Inpatient Sample from October 2015 to 2019 for hospitalizations with AMI. The primary outcome was in-hospital mortality, and the secondary outcome was major adverse cardiac or cerebrovascular events, stroke, and bleeding; major adverse cardiac or cerebrovascular event was defined by a composite of all-cause mortality, stroke, and cardiac complications. Of the 2 871 934 weighted AMI hospitalizations, 0.27% were with ET and 0.1% were with polycythemia vera. Before propensity matching, AMI hospitalization with ET was associated with increased risk of in-hospital mortality (7.1% versus 5.7%; odds ratio [OR], 1.14 [95% CI, 1.04-1.24]), major adverse cardiac or cerebrovascular events (12.6% versus 9%; OR, 1.36 [95% CI, 1.26-1.45]), bleeding (12.7% versus 5.8%; OR, 2.28 [95% CI, 2.13-2.44]), and stroke (3.1% versus 1.8%; OR, 1.66 [95% CI, 1.46-1.89]). Polycythemia vera was associated with an increased risk of in-hospital mortality (7.8% versus 5.7%; OR, 1.21 [95% CI, 1.04-1.39]) and major adverse cardiac or cerebrovascular events (12.0% versus 9%; OR, 1.18 [95% CI, 1.05-1.33]). After propensity matching, ET was associated with increased risk of bleeding (12.6% versus 6.1%; OR, 2.22 [95% CI, 1.70-2.90]), and AMI with polycythemia vera was not associated with worse in-hospital outcomes. Conclusions AMI hospitalization with ET is associated with high bleeding risk before and after propensity score matching, particularly for hospitalizations treated with percutaneous coronary intervention. The management of AMI requires a multidisciplinary and patient-centered approach to ensure safety and improve outcomes.

Challenges of diagnosing and managing pre-fibrotic myelofibrosis: A case-based and practical approach.

Pre-Fibrotic Myelofibrosis is a frequently under-recognised entity that has distinct features separate to those of both Essential Thrombocythaemia and overt Primary Myelofibrosis. Misdiagnosis is relatively common due to subtle differences in bone marrow trephine morphology and multidisciplinary approaches are required. The clinical phenotype and disease course is heterogeneous and hence management approaches tend to vary widely. Although patients may initially be asymptomatic, disease-related complications can include troublesome symptom burdens, increased incidence of both arterial and venous thromboses, haemorrhage, anaemia and an inherent risk of disease evolution to either overt myelofibrosis or blastic phase disease. Specific prognostic tools with high discriminatory power are lacking. Within this review we use case-based approaches to review the current literature, highlight challenges in both diagnostics and disease management and suggest contemporary approaches to improve patient outcomes.

Patient-reported outcomes of patients with myelofibrosis or essential thrombocythemia enrolled in the MOST study.

The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) is an ongoing, noninterventional study assessing clinical characteristics and patient-reported outcomes (PROs) of patients with myelofibrosis (MF) or essential thrombocythemia (ET). This analysis assessed PROs at enrollment; symptom burden and quality of life (QoL), work productivity, and activity were assessed using validated questionnaires in patients with low- or intermediate-1-risk (age-alone) MF, or high- or low-risk ET (receiving ET-directed therapy) at enrollment. In MF and ET cohorts, fatigue had highest mean symptom score. Women had higher mean total symptom scores (TSS), mean symptom scores, and reduced QoL versus men. In patients with MF, mean TSS and symptom scores were similar between risk groups. Patients with low-risk ET had higher mean TSS and symptom scores than patients with high-risk ET. In conclusion, patients with lower risk MF and low- or high-risk ET experience significant symptom burden affecting QoL and ability to work.

Towards a Personalized Definition of Prognosis in Philadelphia-Negative Myeloproliferative Neoplasms.

PURPOSE OF REVIEW: Philadelphia-negative myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic (pre-), and overt-primary myelofibrosis (primary MF, PMF). PV and ET could evolve into secondary MF (SMF), whose early diagnosis relies on monitoring signs of possible progression. All MPNs have a risk of blast phase (BP), that is associated with a very dismal outcome. Overall survival (OS) is different among MPNs, and disease-specific prognostic scores should be applied for a correct clinical management. In this review, an overview of current prognostic scores in MPNs will be provided. RECENT FINDINGS: The biological complexity of MPNs and its role on the trajectory of disease outcome have led to the design of integrated prognostic models that are nowadays of common use in PMF patients. As for PV and ET, splicing gene mutations could have a detrimental role, but with the limit of the not routinary recommended application of extensive molecular analysis in these diseases. SMF is recognized as a distinct entity compared to PMF, and OS estimates should be calculated by the MYSEC-PM (Myelofibrosis SECondary-prognostic model). Both in PMF and SMF, decisions as selection of patients potentially candidates to allogenic stem cell transplant or that could benefit from an early shift from standard treatment are based not only on conventional prognostic scores, but also on multivariable algorithms. The expanding landscape of risk prediction for OS, evolution to BP, and SMF progression from PV/ET informs personalized approach to the management of patients affected by MPNs.

Low-risk polycythemia vera and essential thrombocythemia: management considerations and future directions.

Thrombotic events are a distinctive feature of the myeloproliferative neoplasms (MPNs) polycythemia vera (PV) and essential thrombocythemia (ET). Patients with these MPNs may also experience a poor quality of life secondary to symptom burden, as well as progression of disease to acute leukemia or myelofibrosis. Over the years, various risk stratification methods have evolved in order to attempt to predict thrombotic risk, which is the largest contributor of morbidity and mortality in these patients. More than half of PV and ET patients are low- or intermediate-risk disease status at the time of diagnosis. While therapeutic development is presently focused on high-risk patients, there is a paucity of therapies, outside of aspirin and therapeutic phlebotomy, which can reduce the thrombotic risk or delay disease progression in low-risk patients. In this review, we first describe the various complications that patients with PV and ET experience, and then detail our evolving understanding of risk stratification in these diseases. We then highlight the available evidence on the management of low-risk PV and ET and include a description of novel therapies currently under investigation in this space. We conclude with recommendations for future directions to advance our understanding and improve the treatment of low-risk PV and ET.

Validation and reliability of current guidelines for the treatment of essential thrombocythemia under real-world clinical settings in Japan.

OBJECTIVE: Current guidelines for essential thrombocythemia (ET) patients recommend different treatment approaches based on thrombosis risk stratification models. However, these recommendations may not be applicable to some patients under real clinical settings. Therefore, we carried out a retrospective real-world validation study. METHODS: Thrombosis-free survival (TFS) was compared between treatment naïve ET patients receiving different treatment approaches. ET patients were stratified by three representative risk models, the conventional, the International Prognostic Score for thrombosis in ET (IPSET-thrombosis), and revised IPSET-thrombosis. Treatment decisions were largely made by individual physicians, taking into account patient preferences and backgrounds. RESULTS: A total of 179 ET patients were included, and thrombotic events were observed in 26 patients. TFS was significantly longer in high-risk patients of all risk models receiving a combination of cytoreductive therapy (CRT) and antiplatelet therapy (APT) compared to CRT alone. Similar results were seen in intermediate-risk patients stratified by IPSET-thrombosis. In contrast, in very low- and low-risk patients of all risk models, TFS was not affected by addition of CRT, indicating that observation or APT alone is an appropriate treatment approach for these patients. CONCLUSION: We demonstrate that current guidelines provide optimal treatment approaches for Japanese ET patients under real-world clinical settings.

Relevance of early diagnosis in polycythemia vera and essential thrombocythemia: A single center's experience.

OBJECTIVES: This work aims to describe the proportion of patients with polycythemia vera (PV) or essential thrombocythemia (ET) and thrombosis prior to the diagnosis who had erythrocytosis or thrombocytosis prior to the thrombosis. PATIENTS AND METHODS: This is a retrospective review of 63 patients with PV and 130 with ET. RESULTS: In regard to PV, we found prior erythrocytosis in 7 (11.1%) of the 17 cases (27%) with thrombosis prior to diagnosis. In ET, we found prior thrombocytosis in 10 (7.7%) of the 25 cases (19.2%) with thrombosis prior to diagnosis. The median time between the laboratory finding and thrombosis was 8.2 months and 11.8 months for PV and TE, respectively. In both entities, patients with thrombosis prior to diagnosis had significantly lower survival. CONCLUSION: A significant proportion of patients with thrombosis prior to the diagnosis of PV and ET present with erythrocytosis or thrombocytosis prior to the episode of thrombosis. This could allow for anticipating diagnosis and treatment.

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives.

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression. Clinically evident progression includes evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre-PMF to overt PMF, and transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Thrombosis, major hemorrhage, severe infections, or increasing symptom burden (e.g., pruritus, night sweats) may herald progression. Subclinical types of progression may include increases in the extent of bone marrow fibrosis, increases of driver gene mutational allele burden, and clonal evolution. The underlying causes of MPN progression are diverse and can be attributed to genetic alterations and chronic inflammation. Particularly, bystander mutations in genes encoding epigenetic regulators or splicing factors were associated with progression. Finally, comorbidities such as systemic inflammation, cardiovascular diseases, and organ fibrosis may augment the risk of progression. The aim of this review was to discuss types and mechanisms of MPN progression and how their knowledge might improve risk stratification and therapeutic intervention. In view of these aspects, we discuss the potential benefits of early diagnosis using molecular and functional imaging and exploitable therapeutic strategies that may prevent progression, but also highlight current challenges and methodological pitfalls.

Thrombocytapheresis for acquired von Willebrand syndrome in a patient with essential thrombocythemia and recent multivisceral transplantation.

BACKGROUND: Essential thrombocythemia (ET) is associated with increased risk of bleeding secondary to acquired von Willebrand syndrome (AVWS). Bleeding in ET requires urgent platelet reduction by cytoreductive therapy such as hydroxyurea or thrombocytapheresis. We report on the efficacy and safety of thrombocytapheresis in managing AVWS in a patient with ET and multivisceral transplantation. CASE REPORT: The patient was a 51-year-old female who underwent multivisceral transplantation. Her postoperative course was complicated by bleeding from oral cavity, IV lines, gastrointestinal and upper respiratory tracts as well as vaginal bleeding, which coincided with ET flare with a platelet count of 1512 × 109 /L. Coagulation studies including von Willebrand factor (vWF) antigen and activity, vWF propeptide antigen, and vWF multimer analysis were consistent with AVWS. Hydroxyurea was initiated. However, due to major bleeding, rapidly increasing platelet count, and uncertainty of response to hydroxyurea being given through the enteral tube, thrombocytapheresis was initiated for rapid platelet reduction. The patient tolerated the procedure well. Platelet count was reduced from 1636 × 109 /L to 275 × 109 /L with rapid cessation of bleeding. The patient's condition stabilized over the next few days; however, bleeding recurred with increasing platelet count, which required a second thrombocytapheresis 8 days after the first one. The patient was maintained on hydroxyurea 500 mg twice/day. At 11-month follow-up, she had a normal platelet count and no recurrence of bleeding. DISCUSSION: Thrombocytapheresis is safe and efficient in managing postoperative bleeding due to ET/AVWS in solid organ transplant patients. The procedure can be an adjunct to bridging therapy before response to hydroxyurea is achieved.