INTRODUCTION — Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by excessive, clonal platelet production. While at least half of patients with ET are asymptomatic at the time of diagnosis, the majority will develop vasomotor, thrombotic, or hemorrhagic manifestations at some point during the course of their disease.
The prognosis and management of ET will be reviewed here. An overview of the MPNs, as well as discussions of the pathologic mechanisms, clinical manifestations, and diagnosis of ET, are presented separately. (See "Overview of the myeloproliferative neoplasms" and "Diagnosis and clinical manifestations of essential thrombocythemia".)
The general approach to the patient with an elevated platelet count is also discussed separately. (See "Approach to the patient with thrombocytosis".)
GOALS OF CARE — The goal of treatment of ET is to prevent thrombotic and hemorrhagic complications and to alleviate symptoms (eg, headaches, dizziness, visual disturbances, burning dysesthesia). Available treatment options are not curative and have not been shown to prolong survival nor prevent disease transformation to acute myeloid leukemia (AML) or post-ET myelofibrosis. (See "Diagnosis and clinical manifestations of essential thrombocythemia", section on 'Clinical features'.)
PRETREATMENT EVALUATION — All patients with ET should have a complete history and physical examination that documents symptoms, signs, and laboratory studies that may alter management strategy. It is our practice to include an evaluation of the following:
●A history of venous thrombosis (eg, deep venous thrombosis, pelvic, mesenteric, hepatic, portal), arterial thrombosis (eg, cerebral, coronary, ophthalmic, or distal/extremities), or first trimester spontaneous abortion, and a history of hemorrhagic complications (eg, gastrointestinal, mucosal bleeding, epistaxis, urogenital, deep hematoma, hemarthrosis). (See "Diagnosis and clinical manifestations of essential thrombocythemia", section on 'Thrombosis and hemorrhage'.)
●The presence and severity of vasomotor symptoms, which may include headaches, dizziness, visual disturbances, burning dysesthesia of the palms and soles (erythromelalgia), paresthesias, acrocyanosis, cutaneous ulcers, cognitive or psychiatric deficits, and seizures. (See "Diagnosis and clinical manifestations of essential thrombocythemia", section on 'Vasomotor symptoms'.)
●An assessment of cardiovascular risk factors, including hypertension, diabetes mellitus, active tobacco use, and hyperlipidemia.
●Spleen and liver size by physical examination, and findings of clinical bleeding/bruising.
●Laboratory studies, including a complete blood count with differential and review of the peripheral smear, and chemistries with liver and renal function and electrolytes. Peripheral blood should be tested for JAK2 V617F mutation and, if negative, for mutations of CALR exon 9, and MPL exon 10.
For patients with clinical evidence of bleeding or platelet counts >1 million/microL (1000 x 103/microL), we suggest testing for acquired von Willebrand syndrome. (See 'Extreme thrombocytosis or bleeding' below.)
●We calculate a modified International Prognostic Score of thrombosis in World Health Organization essential thrombocythemia (IPSET-thrombosis score) for estimating the risk of thrombosis with therapy [1,2]. (See 'Risk stratification' below.)
RISK STRATIFICATION — The initial management of patients with ET is largely dictated by the risk of thrombotic complications, as calculated by prognostic scores. Important factors in assessing risk of thrombotic complications include a prior history of venous or arterial thrombosis, age over 60 years, JAK2 V617F mutation, and cardiovascular risk factors (eg, hypertension, diabetes mellitus, and current smoking) [1,2].
Our management strategy takes into account these risk factors and stratifies patients based on the International Prognostic Score of thrombosis in World Health Organization essential thrombocythemia (IPSET-thrombosis) score, as follows [2]:
●High-risk disease – History of thrombosis at any age and/or age >60 with a JAK2 V617F mutation
●Intermediate-risk disease – Age >60, no JAK2 mutation detected, and no history of thrombosis
●Low-risk disease – Age ≤60 with JAK2 mutation and no history of thrombosis
●Very low-risk disease – Age ≤60, no JAK2 mutation detected, and no history of thrombosis
While the presence of cardiovascular risk factors (ie, diabetes mellitus, hypertension, and current smoking) is not incorporated into the IPSET-thrombosis score, we consider these factors when deciding on the overall treatment strategy, including recommendations regarding the use of aspirin. (See 'Low-dose aspirin' below.)
Survival data and risks for thrombosis, hemorrhage, leukemic transformation, and post-ET myelofibrosis are discussed below. (See 'Outcomes and prognosis' below.)
MANAGEMENT
Treatment overview — The goals of ET management are to alleviate symptoms and minimize complications of the disease (eg, thrombotic events, bleeding) [3]. Most patients have a normal life expectancy. Available treatment options are not curative and have not been shown to prevent disease transformation nor prolong survival. However, treatment can help to control symptoms and minimize complications.
When initiating therapy, the following general therapeutic principles should be kept in mind:
●The most frequent symptoms are vasomotor, and they are generally manageable with low-dose aspirin (40 to 100 mg/day orally, once or twice daily) [4,5]. Low-dose aspirin also reduces the risk of recurrent arterial thrombotic events and may benefit those with cardiovascular risk factors (hypertension, diabetes, active smoking). (See "Diagnosis and clinical manifestations of essential thrombocythemia", section on 'Vasomotor symptoms'.)
●Doses of aspirin lower than 100 mg/day and avoidance of nonsteroidal anti-inflammatory drugs may lessen bleeding complications in patients with ET [6,7]. Aspirin should not be given to patients with ET and acquired von Willebrand syndrome (aVWS); control of thrombocytosis may alleviate aVWS and reduce spontaneous bleeding in this setting [8]. (See "Acquired von Willebrand syndrome", section on 'Laboratory testing' and 'Low-dose aspirin' below.)
●Approximately 20 percent of patients with ET present with major thrombotic events and another 15 percent may experience recurrent thromboses [9,10]. This complication is most common in patients (of any age) with a prior history of thrombosis, and/or those >60 years old with JAK2 V617F mutation. Cytoreductive therapy plus systemic anticoagulation and/or low-dose aspirin is recommended in these high-risk patients. (See 'High- and intermediate-risk disease' below and 'Low-dose aspirin' below.)
●Cytoreductive therapy is more controversial in intermediate-risk patients (ie, >60 years old without JAK2 V617F mutation and no thrombotic history). It is generally not offered to younger patients without a history of thrombosis (low- and very low-risk categories). (See 'High- and intermediate-risk disease' below and 'Low- and very low-risk disease' below.)
●aVWS may be seen in patients with platelet counts >1 million/microL. Cytoreductive therapy given to control thrombocytosis may ameliorate this complication. The use of cytoreductive agents for treatment of such elevated platelet counts in the absence of other indications (eg, thrombosis, aVWS) is not indicated. (See 'Extreme thrombocytosis or bleeding' below.)
●When cytoreductive therapy is used, the dose is adjusted to target a platelet count of 100,000 to 400,000/microL [9,11]. (See 'Cytoreductive therapies' below.)
●All patients with ET should stop smoking and aim to control cardiovascular risk factors.
High- and intermediate-risk disease — Cytoreductive treatment with hydroxyurea (HU) is recommended for patients with ET of any age with a prior history of venous or arterial thrombosis. It is also suggested for all patients over age 60, especially in those with a JAK2 V617F mutation.
In addition to HU, these patients should be treated with systemic anticoagulation and/or an antiplatelet agent, as follows (see 'Pretreatment evaluation' above):
●Venous thrombosis – All patients with a history of venous thrombosis are at high risk for additional thrombotic events; for most such patients, we recommend long-term therapy with HU plus systemic anticoagulation. Neither anticoagulation alone nor the combination of HU plus aspirin is sufficient for this population. (See 'Hydroxyurea' below.)
●Arterial thrombosis – Patients with a history of arterial thrombosis are at high risk for further arterial events; for most such patients, we recommend HU plus low-dose aspirin, rather than aspirin alone. We administer aspirin once daily for most patients with a history of arterial thrombosis, and offer twice daily aspirin to those who also have cardiovascular risk factors and/or vasomotor symptoms. (See 'Low-dose aspirin' below and 'Hydroxyurea' below.)
●Age >60 years and no history of venous or arterial thrombosis – The risk of thrombosis is increased by the presence of a JAK2 V617F mutation. For older adults with JAK2 V617F mutation, we recommend long-term therapy with HU plus aspirin, rather than aspirin alone. For those without a JAK2 V617F mutation, we suggest long-term therapy with HU plus aspirin, although the benefit is less clear. We administer the aspirin once daily for most patients, and offer twice daily aspirin to those who also have cardiovascular risk factors and/or vasomotor symptoms. (See 'Hydroxyurea' below and 'Low-dose aspirin' below.)
The use of HU in older patients with ET is supported by the only randomized trial that evaluated the benefit of cytoreductive therapy in high-risk patients [12]. At a median follow-up of 27 months, the incorporation of HU resulted in a lower incidence of recurrent thrombosis (4 versus 24 percent), and this benefit was maintained after a median follow-up of 73 months [13]. Other uncontrolled studies have also shown a reduced risk of thrombosis associated with adequate platelet control in ET [9,11,14]. (See 'Hydroxyurea' below.)
Low- and very low-risk disease — Cytoreductive therapy is not recommended for most patients with ET under age 60 with no history of thrombosis or aVWS. These patients with low- and very low-risk ET can be managed with aspirin alone or observation. A potential exception is for patients with platelet counts >1 million/microL complicated by aVWS. This is discussed separately. (See 'Extreme thrombocytosis or bleeding' below.)
We suggest that a choice among these options be guided by the following clinical and molecular features:
●Presence of vasomotor symptoms – Daily low-dose aspirin. Although the benefit has not been proven clinically, we increase the frequency of aspirin to twice daily if symptoms persist or if cardiovascular risk factors are present.
●Both JAK2 V617F mutation and cardiovascular risk factors – Twice daily low-dose aspirin alone. Although a benefit for this approach hasn't been evaluated in clinical trials, laboratory observations suggest this may be beneficial [15,16]. (See 'Twice daily low-dose aspirin' below.)
●Either JAK2 V617F mutation or cardiovascular risk factors – Daily low-dose aspirin alone.
●Neither JAK2 V617F mutation nor cardiovascular risk factors, and no vasomotor symptoms – Observation without treatment.
There are no randomized trials that have evaluated different treatment options for low- and very low-risk ET. Support for this approach comes from observational studies that have demonstrated a lower rate of thrombotic complications in these patients. As an example, in one observational study, the incidence of thrombotic and hemorrhagic events in young patients with low-risk ET (age <60 years, no history of thrombosis or hemorrhage, and a platelet count <1.5 million/microL) did not differ from that of an age- and sex-matched control population [17].
Support for differences in the suggested aspirin frequency is not guided by clinical trials. Laboratory studies suggest that twice daily aspirin may provide more sustained cyclooxygenase 1 (COX-1) inhibition to account for increased platelet turnover in ET [15,16]. This may be particularly applicable to patients with a higher risk of thrombosis such as those with JAK2 V617F mutation and/or cardiovascular risk factors (ie, diabetes mellitus, hypertension, and current smoking) [2]. This is discussed in more detail separately. (See 'Twice daily low-dose aspirin' below.)
Specific therapies — The following sections describe the evidence supporting the use of specific therapies in patients with ET.
Low-dose aspirin — Aspirin is given to the majority of patients with ET to reduce the incidence of vascular events and vasomotor symptoms. Lower doses (eg, 40 to 100 mg, once or twice daily) are preferred to higher doses. Aspirin should not be used in ET patients with aVWS. This is discussed in more detail separately. (See 'Extreme thrombocytosis or bleeding' below.)
Data supporting the use of aspirin in ET come from retrospective studies in patients with ET and polycythemia vera (PV) and extrapolation from a randomized trial in PV [18-21]. In this randomized placebo-controlled trial, aspirin did not reduce overall mortality or cardiovascular mortality but was associated with a reduced risk of a combined endpoint of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk 0.40) [21]. Retrospective studies have also noted that low-dose aspirin is especially effective in treating the vasomotor symptoms of acral paresthesias and erythromelalgia [4,22]. (See "Diagnosis and clinical manifestations of essential thrombocythemia", section on 'Vasomotor symptoms'.)
The use of higher dose aspirin (eg, 900 mg/day) in ET is discouraged, because of an increased incidence of gastrointestinal hemorrhage when high-dose aspirin was used in combination with dipyridamole in patients with PV [23,24].
Twice daily low-dose aspirin — The optimal dosing of aspirin in ET is not known. We offer twice daily aspirin to the following groups of patients with ET:
●Patients who remain symptomatic with microvascular symptoms despite once daily low-dose aspirin treatment [19,25].
●Patients with both JAK2 V617F and cardiovascular risk factors for thrombosis [26].
Support for this approach comes from the following observations. Whereas low-dose aspirin taken once daily is known to inhibit platelet thromboxane A2 (TXA2) synthesis by at least 97 percent in healthy subjects through the irreversible inhibition of platelet COX-1 [27], the same aspirin regimen did not fully inhibit TXA2 production in approximately 80 percent of patients with ET [15,16]. This may be due to increased platelet turnover in ET, with the emergence of young platelets with intact COX-1 activity in the 24 hours between aspirin doses.
In one trial that evaluated functional platelet response in patients with ET, the same total daily dose of aspirin was more effective when administered in two divided doses (100 mg twice daily) than in a single dose (200 mg once daily) [15]. More clinically relevant outcomes were not reported.
Cytoreductive therapies — Patients at high risk for venous or arterial thrombosis should be treated with cytoreductive therapy to reduce the risk of thrombosis. Hydroxyurea is the preferred cytoreductive agent for most patients. The selection of patients for cytoreductive therapy and additional details regarding the management of these patients (eg, the use of systemic anticoagulation and/or aspirin) are presented separately. (See 'High- and intermediate-risk disease' above.)
While no studies have directly compared different target platelet counts, most experts aim for a platelet count of 100,000 to 400,000/microL, which was the target used in the most contemporary large scale clinical trials evaluating these agents. These studies are described in the following sections.
Hydroxyurea — Hydroxyurea (HU) is the preferred cytoreductive agent for most patients. HU is effective at reducing platelet counts and thrombotic risk in ET, and it is generally well tolerated, widely available, and relatively inexpensive.
The recommended initial dose of HU is 15 mg/kg per day by mouth. Doses are adjusted to achieve a platelet count in the range of 100,000 to 400,000/microL and to limit neutropenia and anemia [9,11].
Hydroxyurea efficacy — HU effectively reduces platelet counts in ET, but reported response rates have varied widely because target platelet levels differ between studies [12,13,28-31].
Examples of studies that have reported response rates to HU using uniform criteria (see 'Assessing response to therapy' below) include:
●In a randomized study involving 114 patients with ET, compared with no myelosuppressive therapy, treatment with HU reduced the risk of recurrent thrombosis in high-risk patients (<4 versus 24 percent) at a median follow-up of 27 months [12]. This benefit was maintained after a median follow-up of 73 months [13].
●A retrospective study of 166 patients treated with HU reported a complete response in 81 percent and partial response in 15 percent using the ELN/IWG-NRT criteria (including a target platelet count <400,000/microL) [32].
Hydroxyurea versus anagrelide — Two randomized trials have compared the efficacy, safety, and tolerability of HU versus anagrelide for the treatment of ET, and found that HU is at least as effective for preventing recurrent thrombosis, yet has a more favorable toxicity profile:
●In one trial, 809 patients with ET (diagnosed according to the Polycythemia Vera Study Group criteria) and considered to be at high risk for vascular events were randomly assigned to receive treatment with either HU or anagrelide; treatment was adjusted to maintain the platelet count at <400,000/microL [28]. Both groups also received low-dose aspirin (75 to 100 mg/day orally). The following were observed:
•Equivalent long-term control of the platelet count was achieved in both groups.
•After a median follow-up of 39 months, the composite risk of arterial thrombosis, venous thrombosis, serious hemorrhage, or death from vascular causes was increased in patients treated with anagrelide (odds ratio 1.6, 95% CI 1.0-2.4).
•Anagrelide was associated with an increase in bone marrow reticulin [33], and a higher rate of transformation to myelofibrosis at five years (7 versus 2 percent; odds ratio 2.9, 95% CI 1.2-6.9).
•There was no difference in the rates of transformation to myelodysplastic syndrome and/or acute myeloid leukemia (AML).
●In the noninferiority ANAHYDRET study, 259 patients with previously untreated World Health Organization-defined ET at high risk for thrombohemorrhagic events were randomly assigned to receive either HU or anagrelide, with the following results after a follow-up of 730 patient-years [34]:
•Anagrelide was not inferior to HU in preventing thrombohemorrhagic complications.
•Infectious events, leukopenia, and anemia were more common in those taking HU, while cardiac events (eg, hypertension, palpitations, tachycardia) were more common in those taking anagrelide.
Important limitations to the ANAHYDRET study were that only approximately one-third of patients in either treatment arm received aspirin, there was a high rate of discontinuation of both drugs, and no results were given regarding the rate of transformation to post-ET myelofibrosis and leukemia.
Toxicity — HU is generally well tolerated and side effects are usually mild, including oral ulcers, hyperpigmentation, skin rash, and nail changes (table 1) [35]. In a study of 993 consecutive patients with myeloproliferative neoplasms treated with HU (50 percent with ET), mucocutaneous toxicity (including perimalleolar or oral aphthous ulcers, erythema and skin infiltration) was reported in 8 percent; one-half of these affected patients required permanent drug discontinuation because of these side effects [36]. A small percentage of patients will develop fever, nausea, diarrhea, abnormal liver function tests, or alopecia; rare cases of severe (including fatal) pulmonary toxicity have been reported [32,35,37].
Since HU is a potential teratogen, it is relatively contraindicated in pregnancy, in women with childbearing potential, and in women who are breastfeeding. Interferon may be considered as cytoreductive therapy in such patients with ET who require a reduction in platelet count. (See 'Pegylated interferon' below and 'Pregnant women or those who desire to become pregnant' below.)
Monitoring — The onset of action of HU is rapid, and it usually begins to reduce blood counts within three to five days of initiation of treatment. Similarly, its effect is short-lived once the medication is stopped. Accordingly, dose adjustments should not be made more frequently than once per week in order to prevent wide fluctuations in the platelet count. It is also important to counsel patients taking HU to avoid missing drug doses.
Initially, complete blood counts are obtained weekly and the frequency may be reduced as blood counts stabilize. Liver function tests should be obtained periodically to monitor for HU-induced alterations in liver function.
The platelet-lowering effect of HU is accompanied by varying degrees of neutropenia and anemia with megaloblastic features, including an increased mean cell volume (MCV). HU inhibits DNA synthesis by acting on ribonucleotide reductase (RR) and its effects may resemble those of vitamin B12 and/or folic acid deficiency. Although supplementation of these vitamins will not reverse HU-induced megaloblastic features and cytopenias, the product label suggests folic acid supplementation to avoid a masked folate deficiency. (See "Macrocytosis/Macrocytic anemia", section on 'Drug-induced macrocytosis'.)
Leukemogenicity — The impact of HU on the risk of leukemic transformation in patients with ET is difficult to assess because of the increased incidence of AML in ET. There is an inherent tendency for ET to evolve into AML [38-40], and long-term studies generally report a risk of leukemic transformation of 2 to 5 percent [41-43]. The risk of AML increases in association with longer disease duration and evolution into myelofibrosis [44].
Nonrandomized studies have drawn differing conclusions regarding the risk of AML following long-term treatment with HU. Reported rates of AML incidence when HU is used alone to treat ET range from 0 to 5 percent [12,13,28,32,41,45-49]. As examples:
●In one series of 357 patients followed for a median of eight years, the incidence of myelodysplastic syndrome (MDS) or AML in the entire population was 4.5 percent [45]. This risk was 3.5 percent in patients treated with HU alone and 14 percent in patients receiving HU in combination with 32P, busulfan, or pipobroman. This study revealed a high frequency of 17p chromosomal deletions (41 percent), but these changes may represent nonspecific clonal events that are unrelated to HU or other antecedent chemotherapy.
●In a retrospective study of 435 patients with ET, the 15-year cumulative risk of AML (2 percent) or myelofibrosis (4 percent) was not significantly influenced by treatment with single-agent chemotherapy, including HU [50].
HU is often used in nonhematologic conditions (eg, sickle cell disease and cyanotic congenital heart disease) that do not report an association with AML. (See "Hydroxyurea use in sickle cell disease", section on 'Adverse effects'.)
In contrast, treatment with 32P or alkylating agents is associated with increased rates of AML in myeloproliferative neoplasms [41]; use of these agents should be discouraged, except in special circumstances. (See 'Limited lifespan' below.)
Anagrelide — While anagrelide is an effective cytoreductive agent, its use in ET has been limited by concerns about the potential for cardiac toxicity and post-ET myelofibrosis. Anagrelide is an oral imidazoquinazoline derivative that lowers platelet counts and inhibits platelet aggregation via platelet anti-cyclic AMP phosphodiesterase activity [51-53]. Its effect on platelet function should not be a concern in patients with ET since this effect is only seen at doses higher than those used for controlling thrombocytosis [54].
The initial dose is 0.5 mg orally, taken two to four times daily and titrated to optimize the platelet count; the usual oral maintenance dose is in the range of 1 to 4 mg/day. The most common toxicities are thought to be related to its vasodilatory properties and include headache, palpitations/tachycardia, and fluid retention.
Uncontrolled trials evaluating anagrelide in ET are described here. Trials that directly compared anagrelide with HU in ET demonstrated similar efficacy but unfavorable toxicity with anagrelide. These are described in more detail above. (See 'Hydroxyurea versus anagrelide' above.)
●In a study of 79 patients with ET, treatment with anagrelide resulted in a significant reduction in the platelet count, as well as a reduction in both major and minor arterial and venous thromboembolic complications [55].
●In a series of 577 patients treated with anagrelide for thrombocythemic states including ET, 24 percent had fluid retention and 2 percent were diagnosed with heart failure [56]. Anagrelide use in patients with ET and PV has been associated with acquired idiopathic cardiomyopathy [57] and must be given with caution in patients with known or suspected heart disease, which may limit its utility in older patients [58]. Anagrelide therapy has also been reported as a potential cause of high output heart failure. (See "Causes and pathophysiology of high-output heart failure".)
Pegylated interferon — Interferon (IFN) can control the platelet count in ET and reduce the risk of thrombotic complications [59-64]. IFN reduces the abnormal clone in some patients with ET [65], but there is no evidence that it can improve overall survival nor reduce the risk of AML or post-ET myelofibrosis [66]. Unlike HU and anagrelide, IFN is not contraindicated in pregnancy.
IFN alpha is a naturally occurring biologic response modifier that has anti-angiogenic, anti-proliferative, pro-apoptotic, immunomodulatory, and differentiating properties [64,67]. IFN alfa is a pharmaceutical product obtained from human leukocytes that contains several naturally occurring subtypes of IFN alpha; in some countries IFN alfa is referred to as IFN alpha. Pegylated interferon alfa-2a provides a more favorable toxicity profile than conventional IFN alfa, and its prolonged activity is compatible with once weekly dosing [68-70].
There are no studies in ET that directly compare treatment with IFN versus HU; a prospective, randomized evaluation of pegylated IFN alfa versus HU in ET and polycythemia vera is ongoing (NCT01259856) [71]. Considering the increased toxicity, parenteral route of administration, and higher cost, we restrict use of IFN as initial cytoreductive therapy to younger patients (eg, <40 years) and those who desire to become pregnant [41,72]. IFN is our preferred cytoreductive agent for patients who are resistant or intolerant to HU.
We suggest the use of pegylated IFN alfa-2a rather than IFN alfa because of its comparable efficacy, ease of administration, and more favorable toxicity profile [64,68,69,73-75]. Pegylated IFN alfa-2a is generally administered with an initial dose of 45 mcg/week subcutaneously for the first two weeks, and increased as tolerated to a maximal dose of 180 mcg/week. If pegylated IFN alfa-2a is not available, the usual starting dose of IFN alfa for PV is 3 million units subcutaneously three times per week.
IFN is more expensive and is generally less well tolerated than HU. Up to 35 percent of patients have discontinued IFN alfa therapy because of side effects such as fever, malaise, nausea, and vomiting [63,64,76,77].
Other approaches — Less commonly used approaches for the management of ET include other pharmacologic agents and plateletpheresis.
Other pharmacologic agents
●Pipobroman – Pipobroman is an oral piperazine derivative, structurally classified as an alkylating agent [78]. The drug is not available in the United States, but it is used in Europe for the treatment of ET. The initial dose is 0.8 to 1.0 mg/kg per day by mouth; anticipated side effects include nausea, abdominal cramps, diarrhea, stomatitis, and dry skin. In studies with short-term follow-up, pipobroman has not been associated with an increased risk of AML in ET, but a small risk may exist with long-term therapy [45,79-81]. The risk of developing AML increases significantly when pipobroman is used with other agents, such as HU [45]. (See 'Leukemogenicity' above.)
●Pacritinib – Pacritinib is a kinase inhibitor that is approved by the US Food and Drug Administration (FDA) for treatment of post-essential thrombocythemia myelofibrosis with a platelet count <50,000/microL [82].
●Others – Historically, other agents, including 32P and busulfan, were used to control platelet counts and reduce the risk of thrombosis in ET. However, both are associated with increased rates of AML, and they are not recommended except in special settings. As an example, 32P may be appropriate in a patient with ET who has serious, life-shortening comorbidities that make medication administration unusually difficult. This is discussed in more detail separately. (See 'Limited lifespan' below.)
Plateletpheresis — Removal of platelets by apheresis techniques has been employed in patients with ET who have extreme degrees of thrombocytosis. Because plateletpheresis lowers the platelet count only transiently, this intervention should be followed by the use of a myelosuppressive agent in order to maintain a platelet count within the recommended range (ie, <400,000/microL).
Randomized trials of plateletpheresis have not been conducted and this technique is usually reserved for those with acute, serious thrombotic or hemorrhagic events [83,84]. As examples:
●Severe or life-threatening organ dysfunction (eg, stroke, pulmonary embolism, ischemic digital necrosis) [85-88]
●Acute bleeding due to acquired von Willebrand syndrome [89,90]
Patients with ET are less likely to benefit from plateletpheresis in the following settings:
●Asymptomatic patients
●To reduce the incidence of first trimester spontaneous abortions [83,91]
●Perioperative management [92,93]
●Patients who refuse myelosuppressive agents (because of its transient effect)
Technical aspects of plateletpheresis and its complications are discussed separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology" and "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)
Special populations — Decisions regarding treatment must take into account the nature and severity of symptoms, the risks of thrombohemorrhagic complications, and concerns regarding transformation to AML or post-ET myelofibrosis. In choosing a particular platelet-lowering agent, one should consider the patient's age, other comorbid conditions, childbearing potential, and anticipated life expectancy.
Resistance/intolerance to hydroxyurea — Up to one-quarter of patients with ET who are treated with hydroxyurea (HU) demonstrate resistance or intolerance. The preferred second-line agent in this setting is not well defined, but both efficacy and adverse effects should be considered. Because patients with ET who receive more than one cytotoxic agent are at higher risk of developing MDS/AML [13,94], a non-leukemogenic drug (eg, IFN, anagrelide) should be used in patients with resistance or intolerance to HU.
Pegylated interferon alfa-2a is our preferred agent for HU resistance/intolerance. Other acceptable options include anagrelide or a repeat trial of HU (for patients whose intolerance may be lessened by a lower dose). This recommendation is consistent with guidelines from European LeukemiaNet (ELN) [95].
A study of HU treatment in 166 patients reported resistance in 15 and intolerance in 21 [32]. Compared with patients who achieved a complete response, patients with HU resistance had a sixfold higher risk of death from any cause, eightfold higher rate of development of myelofibrosis, and median survival of 2.4 years from onset of resistance-defining anemia.
Studies that reported outcomes of treatment of HU-refractory ET include:
●A multicenter study that included 65 patients with ET that was refractory to HU reported a 69 percent overall response rate (26 percent complete response) at 12 months to pegylated IFN alfa-2a [96]. Grade ≥3 toxicity included cytopenias, myalgia/arthralgia, depression, dyspnea, and headache (all of which were reported in <10 percent of patients); adverse events led to discontinuation of therapy in 14 percent.
●A phase II trial randomly assigned 110 patients with HU resistance/intolerance to ruxolitinib versus physician's choice of best available therapy (BAT; primarily anagrelide, interferon, or resumption of HU) [97]. There were no differences between treatment arms with regard to complete response rate at one year, or rates of thrombosis, hemorrhage, and transformation at two years; ruxolitinib was superior by some measures of symptom relief but was also associated with higher rates of adverse events (anemia, thrombocytopenia, infection). Conclusions from this trial are limited because of its nonstandardized diagnostic processes, substantial switching between BAT agents, and frequent use of HU in patients who were previously found to be intolerant or resistant.
Resistance or intolerance to HU as defined by the ELN requires one or more of the following [98]:
●Platelet count >600,000/microL after three months of ≥2 g/day of HU (≥2.5 g/day in patients with a body weight >80 kg)
●Platelet count >400,000/microL combined with white blood cell (WBC) count <2500/microL or hemoglobin <10 g/dL at any dose of HU
●Leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HU
●HU-related fever
Pregnant women or those who desire to become pregnant — The management of ET in pregnant women or those who desire to become pregnant requires a thoughtful balance between the goals of minimizing symptoms and reducing complications of ET versus potential harm to the developing fetus.
The decision to initiate therapy in these patients is guided by the risk stratification described above. (See 'Management' above.)
Outcomes of pregnancy in women with ET — Women with ET have a higher rate of fetal loss when compared with the general population. Studies evaluating the risk of spontaneous abortion in women with ET have reported mixed results, but aspirin and interferon may be associated with a higher probability of live birth.
Use of aspirin and interferon are associated with higher odds ratios (OR) of live birth without significant maternal or fetal adverse effects, according to a meta-analysis and review of the literature that included 767 women and 1210 pregnancies from 22 studies of women with myeloproliferative neoplasms (most of whom had ET) [99]. Overall, the live birth rate was 71 percent, which is lower than the expected rate of 80 percent in the general population. Aspirin treatment in 227 patients (from 11 studies) was associated with an unadjusted OR of 8.6 (95% CI 4.0-18.1) and was not associated with increased bleeding events, when used alone or with heparin. Interferon treatment of 90 patients (from six studies) was associated with unadjusted OR of 9.7 (95% CI 2.3-41.0). Addition of heparin to aspirin was not associated with higher OR of live birth. The most common adverse maternal event was preeclampsia, with an incidence of 3.1 percent.
Choice of treatment — The management of pregnant women with ET should be informed by IPSET-thrombosis risk stratification, as described above. Those with high- or intermediate-risk disease are candidates for cytoreductive therapy, whereas those with low- or very low-risk disease can usually be managed with aspirin or observation alone. The choice of cytoreductive therapy differs from that of the general population due to concerns about potential teratogenicity of HU and anagrelide [59,95,100-105]. We suggest interferon rather than HU or anagrelide for most pregnant women (or those who desire to become pregnant) who require a cytoreductive agent. We suggest use of aspirin to reduce pregnancy loss.
The use of HU in the first trimester is often discouraged because antimetabolites are implicated in fetal malformations associated with chemotherapy [106]. However, there are numerous reports of successful pregnancies in patients with ET who were treated with HU, and in a review of the literature on the use of HU in ET, AML, chronic myeloid leukemia, and sickle cell disease, there were no reports of fetal malformations in nine patients exposed to HU in the first trimester [107]. Similarly, no ill effects to the fetus were observed following second and third trimester exposures [59,95,100,101,103].
We do not consider the inadvertent exposure to either anagrelide or HU as a reason to terminate pregnancy. Instead, such patients should be reassured that inadvertent exposures to either of these agents have not resulted in adverse pregnancy outcome [107]. The use of anagrelide or HU should not be withheld from the high-risk pregnant woman who does not tolerate interferon alfa therapy, provided she is well-informed of the risks and benefits.
While pregnancy may compound the thrombotic risk of ET, we do not routinely offer prophylaxis in this setting unless there are other indications for thromboprophylaxis. This is principally due to a lack of prospective trials evaluating the efficacy of thromboprophylaxis with heparin in women with ET during pregnancy or postpartum. Some experts offer prophylaxis to patients with additional risk factors for thrombosis (eg, prior history of venous thrombosis, cesarean delivery). (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".)
Some clinicians offer low-dose aspirin or interferon to women with ET who have experienced recurrent abortions, yet have no other indication for these treatments. While there is unproven benefit with this approach, it is a reasonable option for some patients with ET [100,103,108].
Smoking and obesity — Studies in ET suggest that smoking is thrombogenic and alters inhibition of in vivo platelet activation by low-dose aspirin [12,109,110]. This should be emphasized to patients, especially if they wish to benefit from the use of aspirin [18,111].
Obesity has also been associated with thrombosis in ET [1,2,109]. We do not consider smoking or obesity alone to be indications for cytoreductive therapy in ET. These risk factors should be managed by lifestyle modifications.
Extreme thrombocytosis or bleeding — Extreme thrombocytosis (ie, platelets >1 million/microL) itself is not an indication for cytoreductive therapy. However, extreme thrombocytosis may promote a hemostatic defect due to the excessive adsorption of large von Willebrand factor multimers [89] and, accordingly, such patients should be screened for the presence of acquired von Willebrand syndrome (aVWS). (See "Acquired von Willebrand syndrome", section on 'Diagnostic evaluation'.)
aVWS due to extreme thrombocytosis in ET is associated with an increased risk of bleeding, especially when treated with aspirin [9,112,113]. Cytoreductive therapies are suggested to reduce the platelet count to 100,000 to 400,000/microL in the setting of aVWS [8]. Aspirin should be avoided by patients with ristocetin cofactor activity <30 percent due to the increased risk of hemorrhage. Low-dose aspirin (eg, ≤100 mg/day) is acceptable if the ristocetin cofactor level is ≥30 percent.
Limited lifespan — In clinical settings where comorbid illnesses are expected to limit lifespan (eg, to less than three to five years), or in situations where oral administration of medications is especially challenging (eg, severe dementia), 32P may be an effective means to control the platelet count, despite concern regarding longer term risk of leukemic transformation.
FOLLOW-UP
Assessing response to therapy — Patients should be followed longitudinally to assess symptom control, disease response to therapy, and to monitor for disease progression. We follow all patients with serial physical examinations (including an assessment of spleen size) and complete blood counts in order to assess hematologic improvement and toxicity. Serum chemistries (including electrolytes, liver and renal function) and hemostatic parameters may be monitored for patients who require cytoreductive therapy or systemic anticoagulation. We perform a bone marrow aspirate and biopsy if cell counts deteriorate more than anticipated, to evaluate possible progression to myelofibrosis or acute myeloid leukemia.
The frequency of visits is influenced by complications of the disease and the nature of therapeutic interventions.
●Low-risk and very low-risk patients who are observed without specific therapy or who receive aspirin alone may require only annual or semi-annual visits.
●Intermediate-risk and high-risk patients who are treated with cytoreductive therapy and/or systemic anticoagulation will require visits based on the response and stability of blood counts and anticoagulation.
Outside of the context of a clinical trial, response assessment depends upon the goals of therapy and how treatment decisions might change based upon the results.
Standardized response criteria that use bone marrow and peripheral blood analysis allow comparisons between published studies. Research response criteria created by the European LeukemiaNet (ELN) and International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) monitor resolution of disease symptoms, spleen and liver size, platelet count, leukocyte count, bone marrow histology, hemorrhagic or thrombotic events, and transformation to leukemia or post-ET myelofibrosis [3,114].
Transformation to acute leukemia — Patients with ET have a variable rate of transformation to acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Such patients have a very poor prognosis. The decision of when to treat a patient with AML-directed therapy is individualized, and may include standard induction therapy followed by allogenic hematopoietic cell transplantation or palliative therapy with a focus on management of symptoms. The treatment of AML is discussed in more detail separately. (See "Induction therapy for acute myeloid leukemia in medically-fit adults" and "Acute myeloid leukemia: Management of medically-unfit adults" and "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Transformation to acute leukemia'.)
Once transformation to AML or myelodysplasia has occurred in a patient with ET, the long-term prognosis is poor, with median survivals in the range of two to seven months [115]. However, in one study of 21 patients with ET who developed MDS or AML and were treated with azacitidine, the overall response rate was 71 percent, with a median survival of 16 months from the onset of treatment with this agent [115]. (See "Prognosis and treatment of polycythemia vera and secondary polycythemia".)
Post-ET myelofibrosis — ET can undergo delayed disease transformation into a fibrotic state called post-ET myelofibrosis (post-ET MF). The conversion rate after 10 to 20 years of disease is less than 5 percent. The management of patients with post-ET MF is the same as for patients with primary myelofibrosis. This is discussed in more detail separately. (See "Management of primary myelofibrosis" and 'Transformation to AML and post-ET myelofibrosis' below.)
OUTCOMES AND PROGNOSIS — Most patients with ET enjoy a normal life expectancy [50,116]. An important aspect of the management of patients with ET is discussion of prognosis and outcomes, including the risks of thrombotic and hemorrhagic disorders, and leukemic transformation or conversion to post-ET myelofibrosis.
It is important to firmly establish the morphologic diagnosis of ET because the risk of transformation to leukemia or to post-ET myelofibrosis is considerably different for other disorders that may be confused with ET (eg, early/prefibrotic primary myelofibrosis) [42]. (See "Diagnosis and clinical manifestations of essential thrombocythemia", section on 'Diagnosis'.)
Overall survival — Most patients with ET enjoy a normal life expectancy, although survival is affected by disease features used for risk stratification [50,116]. (See 'Risk stratification' above.)
Large studies that assessed survival in ET include the following:
●An International Prognostic Score for Essential Thrombocythemia (IPSET) was derived from 891 patients diagnosed strictly according to World Health Organization criteria and was validated in two independent cohorts [117]. The median overall survival of 14.7 years was similar to that of the sex- and age-standardized European population.
Patients were assigned a total score based on the following three features: age ≥60 years (2 points), white blood cell (WBC) count ≥11,000/microL (1 point), history of thrombosis (1 point).
Median survivals were as follows:
•Low risk (total score 0; 48 percent of patients) – Not reached
•Intermediate risk (total score 1 or 2; 47 percent of patients) – 24.5 years
•High risk (total score 3 or 4; 5 percent of patients) – 13.8 years
●A single institution study of 605 patients with ET followed for a median of seven years, reported 155 deaths (26 percent) [43]. In multivariate analysis, the following were identified as independent risk factors for predicting inferior survival:
•Low hemoglobin level (<12 g/dL in females and <13.5 g/dL in males)
•Age ≥60 years
•Elevated leukocyte count (≥15,000/microL)
•Smoking
•Diabetes mellitus
•Prior venous thrombosis
Risk stratification based on age, low hemoglobin, and leukocytosis identified median survival in three distinct risk groups, as follows:
•Low risk (none of the risk factors; 43 percent of patients) – 23 years
•Intermediate risk (one risk factor; 41 percent of patients) – 17 years
•High risk (two or three risk factors; 17 percent of patients) – 9 years
●A study of 322 patients from the same institution developed a simplified model that included only age and WBC count at the time of diagnosis [118].
This study found the following three risk groups and median survivals (figure 1):
•Low risk (age <60 and WBC count <15,000/microL) – 25 years
•Intermediate risk (age ≥60 or WBC count ≥15,000) – 17 years
•High risk (age ≥60 and WBC count ≥15,000) – 10 years
Thrombosis — Risk stratification in patients with ET is primarily based upon factors that influence the occurrence of thrombotic complications. Arterial thrombotic events are more common than venous thrombotic events [1].
More recent studies indicate lower overall thrombotic risk compared with that seen in some older studies (eg, 1.8 versus 6.6 percent of patients per year), presumably due to improved management and refinement of prognostic models [1,14].
Numerous studies have shown that the most important adverse risk factors for thrombotic complications in ET are a history of prior thrombosis and age >60 years [29,50,119,120]. The presence of JAK2 V617F mutation and other clinical factors also confer thrombotic risk, as illustrated below:
●The IPSET-thrombosis model was derived from a cohort of 891 subjects with World Health Organization-defined ET, as follows [1]:
•Age >60 years (hazard ratio [HR] 1.5; 1 point)
•Presence of cardiovascular risk factors (hypertension, diabetes, active tobacco use, HR 1.6; 1 point)
•History of thrombosis (HR 1.9; 2 points)
•Presence of the JAK2 V617F mutation (HR 2.0; 2 points)
Using this model, three thrombosis risk groups were identified:
•Low risk for thrombosis (total score 0 or 1) – 1 percent/year incidence of thrombosis
•Intermediate risk (total score 2) – 2.4 percent/year incidence of thrombosis
•High risk (total score >2) – 3.6 percent/year incidence of thrombosis
The 15-year thrombosis-free survival of those in the low- and high-risk IPSET groups were 89 and 50 percent, respectively. The thrombotic risk for the intermediate-risk group was close to the low-risk category for the first 10 years, but progressively reached the high-risk curve in the subsequent five years [1].
●Further revisions to this IPSET-thrombosis model defined 'very low risk' and 'low risk' groups, and are described separately [2]. (See 'Risk stratification' above.)
Using this model, the rate of thrombotic events was influenced by the presence of cardiovascular risk factors. In each risk category, the presence of cardiovascular risk factors was associated with a moderate increase in thrombotic risk that did not reach statistical significance.
Hemorrhage — The risk of major bleeding episodes during the clinical course of the disease is less than 5 percent, and this risk is lower than the risk of thrombotic events [9,14,112]. Bleeding is probably not exacerbated by the use of low-dose aspirin (eg, 40 to 100 mg/day), especially if these doses are used in patients without a history of bleeding and/or acquired von Willebrand syndrome (aVWS) [18,19]. (See 'Low-dose aspirin' above and 'Extreme thrombocytosis or bleeding' above.)
Patients who are otherwise considered to be low risk but have a platelet count >1 million/microL should be screened for the presence of aVWS by obtaining testing for aVWS including ristocetin cofactor activity before treatment with low-dose aspirin is initiated. (See 'Extreme thrombocytosis or bleeding' above.)
Transformation to AML and post-ET myelofibrosis — The risk of leukemic transformation to acute myeloid leukemia (AML) or post-ET myelofibrosis is considerably lower than the risk of thrombosis in ET, as illustrated by the following studies:
●In a retrospective study of 435 patients with ET, the 15-year cumulative risks of thrombosis, AML, and post-ET myelofibrosis were 17, 2, and 4 percent, respectively [50].
●In the IPSET study of 891 patients with ET, 15-year cumulative risks of AML and overt fibrotic progression were 2 and 9 percent, respectively [42].
●In a single institution study of 605 patients with ET followed for a median of seven years, AML was documented in 20 (3.3 percent) [43]. Multivariate analysis revealed low hemoglobin level (<12 g/dL in females, <13.5 in males) and platelet count ≥1 million/microL as risk factors for AML. Patients with none, one, or both of these adverse factors had a risk of AML of 0.4, 4.8, and 6.5 percent, respectively. Presence of JAK2 V617F mutation and use of cytoreductive therapy did not affect the risk of AML.
CLINICAL TRIALS — Often, there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).
Agents under active investigation include combinations of drugs currently used in essential thrombocytosis, those approved for other myeloproliferative neoplasms, and other novel agents. As an example, imetelstat is an investigational antisense oligonucleotide directed against telomerase. In a pilot study, all 18 patients with essential thrombocytosis treated with imetelstat achieved a hematologic response and 16 achieved a complete hematologic response [121]. The most common toxicities were myelosuppression, and elevations in liver enzymes, which were usually reversible.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 2), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myeloproliferative neoplasms".)
SUMMARY AND RECOMMENDATIONS
●Evaluation and diagnosis – Evaluation of thrombocytosis and diagnosis of essential thrombocythemia (ET) are described separately. (See "Approach to the patient with thrombocytosis" and "Diagnosis and clinical manifestations of essential thrombocythemia".)
●Pretreatment evaluation
•Clinical – History and examination for venous or arterial thrombosis, hemorrhage, vasomotor symptoms (eg, headache, dizziness, visual disturbances, erythromelalgia, acrocyanosis), hepatosplenomegaly, and cardiovascular (CV) risk factors (eg, hypertension, diabetes mellitus, tobacco use, hyperlipidemia). (See 'Pretreatment evaluation' above.)
•Laboratory – Pretreatment studies include:
-Complete blood count (CBC) with differential count, review of blood smear, liver and kidney function tests
-For platelet count >1 million/microL on CBC or clinical bleeding, we measure ristocetin cofactor (RCo) activity; RCo <30 percent is considered acquired von Willebrand syndrome (vWS). (See 'Extreme thrombocytosis or bleeding' above.)
-JAK2 V617F; if no JAK2 mutation is found, we test for mutations of CALR exon 9 and MPL exon 10.
●Risk stratification – Calculate International Prognostic Score of Thrombosis (IPSET). (See 'Risk stratification' above.)
•High-risk – History of thrombosis or age >60 years with JAK2 V617F mutation
•Intermediate-risk – No prior thrombosis, age >60, and no JAK2 mutation
•Low-risk – No prior thrombosis, age ≤60, JAK2 V617F detected
•Very low-risk – No prior thrombosis, age ≤60 years, and no JAK2 mutation
●Management – All patients should discontinue smoking, control weight, and modify other CV risk factors.
•History of thrombosis or acquired vWS – For patients with a history of venous or arterial thrombosis or acquired vWS (ie, RCo <30 percent), we recommend treatment with a cytoreductive agent (Grade 1B). (See 'Cytoreductive therapies' above.)
We favor hydroxyurea, rather than anagrelide or interferon, and adjust the dose to maintain the platelet count of 100,000 to 400,000/microL.
Our approach follows:
-Venous thrombosis – Treat with hydroxyurea plus life-long systemic anticoagulation.
-Arterial thrombosis – Treat with hydroxyurea plus life-long low-dose aspirin.
-Acquired vWS – Treat with hydroxyurea alone (ie, no aspirin or anticoagulation).
•No prior thrombosis with high- or intermediate-risk IPSET score – We suggest treatment with hydroxyurea plus low-dose aspirin, rather than other approaches (Grade 2C).
•No prior thrombosis with low- or very low-risk IPSET score – We suggest observation alone or aspirin, rather than cytoreductive therapy (Grade 2C). (See 'Low-dose aspirin' above.)
We manage these patients as follows:
-JAK2 V617F mutation plus CV risk factors – Twice daily low-dose aspirin.
-Either JAK2 V617F or CV risk factors – Once daily low-dose aspirin.
-For no JAK2 mutation and no CV risk factors – We observe without initial treatment.
●Pregnancy – For pregnant patients (or those who desire to become pregnant) who require a cytoreductive agent, we recommend interferon (IFN) rather than hydroxyurea or other cytoreductive agents (Grade 1C). (See 'Pregnant women or those who desire to become pregnant' above.)
●Hydroxyurea resistance/intolerance – For hydroxyurea resistance/intolerance, we suggest IFN rather than anagrelide or other agents (Grade 2C). (See 'Resistance/intolerance to hydroxyurea' above.)
ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
