Essential thrombocythemia: Treatment and prognosis

INTRODUCTION — Essential thrombocythemia (ET) is a BCR::ABL1-negative myeloproliferative neoplasm (MPN) characterized by excessive clonal platelet production. While at least one-half of patients with ET are asymptomatic at the time of diagnosis, most will develop vasomotor, thrombotic, or hemorrhagic manifestations at some point during their disease. A small percentage of patients will progress to post-ET myelofibrosis or experience leukemic transformation. Nevertheless, ET has the most favorable prognosis among the BCR::ABL1 MPNs.

Management and prognosis of ET are reviewed here.

Clinical manifestations, evaluation, and diagnosis of ET are presented separately. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia".)

Evaluation of a patient with an elevated platelet count is discussed separately. (See "Approach to the patient with thrombocytosis".)

OVERVIEW — The goals of current management for patients with ET are to prevent thrombosis and bleeding and alleviate symptoms; current drug therapy has not been shown to prolong survival or prevent disease progression.

ET has the most favorable prognosis among the BCR::ABL1-negative myeloproliferative neoplasms (MPNs; ie, ET, polycythemia vera [PV], primary myelofibrosis [PMF]). Survival for patients diagnosed with ET is approximately 20 years, but it is 33 years for patients diagnosed at <60 years old [1]. Life expectancy for patients with ET is comparable to or slightly inferior to that of the general age- and sex-matched population [1,2].

●Clinical manifestations – Common ET-associated symptoms and complications include:

•Vasomotor symptoms – Vasomotor symptoms, including headache, lightheadedness, acral paresthesias, livedo reticularis, and erythromelalgia (burning pain of the hands or feet associated with erythema and warmth), (picture 1) are experienced by up to 40 percent of patients with ET. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Vasomotor symptoms'.)

Treatment with low-dose aspirin is effective for relieving vasomotor symptoms in most patients with ET, as discussed below. (See 'Low-dose aspirin' below.)

•Thrombosis – Thrombosis is the major cause of morbidity and mortality in patients with ET. There is increased risk for both venous thrombosis (eg, deep vein thrombosis, pulmonary embolus, superficial thrombophlebitis) and for arterial thrombosis (eg, cerebrovascular events, angina, myocardial infarction).

Approximately 20 percent of patients with ET present with major thrombotic events, and another 15 percent may experience recurrent thromboses [3,4]. Thrombosis is most common in patients of any age with a prior history of thrombosis and in patients >60 years with JAK2 V617F mutation and cardiovascular risk factors. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Thrombosis and hemorrhage'.)

Assessment of thrombotic risk, control of other risk factors for thrombosis (eg, smoking, elevated cholesterol), and risk-stratified treatment are key aspects of management for individuals with ET. (See 'Risk stratification' below.)

•Bleeding – Qualitative and quantitative platelet alterations contribute to bleeding in patients with ET.

Some patients with platelet counts >1,000,000/microL have excessive bleeding due to acquired von Willebrand syndrome (aVWS). Evaluation for aVWS is discussed below. (See 'Laboratory studies' below.)

Aspirin should be used with caution in patients with aVWS, as discussed below. (See 'Acquired von Willebrand syndrome' below.)

•Disease transformation – Transformation of ET to secondary myelofibrosis or acute myeloid leukemia occurs in <5 percent of patients after 10 to 20 years of disease. ET is the least likely of the BCR::ABL1-negative MPNs to undergo disease transformation.

Suspicion for disease transformation, diagnosis, and management are discussed below. (See 'Disease transformation' below.)

•Pregnancy loss – Patients with ET have an increased risk for complications of pregnancy (eg, thrombosis, hypertension, fetal loss). Management of pregnant patients with ET is discussed below. (See 'Pregnancy' below.)

●Management – Current treatments effectively control symptoms and reduce complications, but they have not been shown to extend survival, cure ET, or prevent disease transformation to post-ET myelofibrosis or leukemia.

Management of ET is stratified according to the risk for thrombotic complications. (See 'Risk stratification' below.)

PRETREATMENT EVALUATION — History and physical examination document ET-associated findings. Laboratory studies are used to assess hematologic findings and organ dysfunction that may influence management.

Clinical

●History – History should evaluate the following:

•Presence and severity of vasomotor symptoms, which may include headaches, dizziness, visual disturbances, burning dysesthesia of the palms and soles (erythromelalgia), paresthesias, acrocyanosis, and cutaneous ulcers. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Vasomotor symptoms'.)

•Prior venous thrombosis (eg, deep venous thrombosis, pelvic, mesenteric, hepatic, portal), arterial thrombosis (eg, cerebral, coronary, ophthalmic, or distal/extremities), first trimester spontaneous abortion, and history of hemorrhagic complications (eg, gastrointestinal, mucosal bleeding, epistaxis, urogenital, deep hematoma, hemarthrosis). (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Thrombosis and hemorrhage'.)

•Cardiovascular risk factors, including hypertension, diabetes mellitus, active tobacco use, and hyperlipidemia.

●Physical examination – The patient is evaluated for spleen and liver size and evidence of bleeding/bruising.

Laboratory studies — Blood tests include:

●Hematology – Complete blood count with leukocyte differential and review of the peripheral blood smear.

For patients with clinical bleeding or platelet count >1000 x 10⁹/L (1,000,000/microL), ristocetin cofactor activity should be measured. Patients with ristocetin cofactor activity <30 percent have acquired von Willebrand syndrome (aVWS). (See "Acquired von Willebrand syndrome", section on 'Laboratory testing'.)

Aspirin is contraindicated in patients with aVWS because of the increased risk for severe hemorrhage. (See 'Acquired von Willebrand syndrome' below.)

●Serum chemistries – Comprehensive metabolic panel, uric acid.

●Molecular studies – If not previously performed, test blood for JAK2 V617F mutation; if negative, test for mutations of CALR exon 9 and MPL exon 10.

Mutations associated with ET are discussed separately. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Genetic features'.)

RISK STRATIFICATION — Assessment of thrombotic risk is a key aspect of management for patients with ET. We calculate the revised International Prognostic Score for thrombosis in ET (revised IPSET-thrombosis) score to assess thrombotic risk for patients with ET [5]. The revised IPSET-thrombosis categories are:

●High-risk disease – History of thrombosis or age >60 with JAK2 V617F. (See 'High-risk ET' below.)

●Intermediate-risk disease – Age >60, no JAK2 mutation, and no history of thrombosis. (See 'Intermediate-risk ET' below.)

●Low-risk disease – Age ≤60, JAK2 V617F, and no history of thrombosis. (See 'Low-risk ET' below.)

●Very low-risk disease – Age ≤60, no JAK2 mutation, and no history of thrombosis. (See 'Very low-risk ET' below.)

HIGH-RISK ET — Patients with a high-risk International Prognostic Score for thrombosis in ET (revised IPSET-thrombosis) score are best managed with a cytoreductive agent plus low-dose aspirin. The choice of cytoreductive agent is informed by the patient’s age and potential to become pregnant.

Age ≥40 years and no potential for pregnancy — For most patients with high-risk ET, we suggest low-dose aspirin plus hydroxyurea. Pegylated interferon alfa (IFNa) is a reasonable alternative for cytoreduction based on patient preference and drug tolerance.

Low-dose aspirin should be used carefully, and sometimes not at all, in patients with clinically significant acquired von Willebrand syndrome (aVWS), as discussed below. (See 'Acquired von Willebrand syndrome' below.)

Hydroxyurea, IFNa, and anagrelide have comparable efficacy for ameliorating symptoms, controlling platelet counts, and lessening thrombotic risk, but hydroxyurea is associated with less toxicity. Some patients may favor IFNa because it more effectively reduces the size of the malignant clone, but this has not been proven to be associated with longer survival.

Administration of hydroxyurea is discussed below. (See 'Hydroxyurea' below.)

Treatment for patients with limited life expectancy is discussed below. (See 'Frail or limited lifespan' below.)

The choice of hydroxyurea for patients with high-risk ET is based on randomized clinical trials:

●Hydroxyurea versus no cytoreductive agent – In a phase 3 trial of patients with high-risk ET, compared with no cytoreductive treatment, hydroxyurea reduced arterial and venous thrombotic events [6]. The 114 patients were randomly assigned to hydroxyurea versus no hydroxyurea, and with a median follow-up of 27 months, there were fewer thrombotic events in those who received hydroxyurea (4 versus 24 percent). The untreated patients had platelet counts from 892,000/microL to 986,000/microL at six months, compared with <600,000 platelets/microL in all patients treated with hydroxyurea. Multivariate analysis indicated that use of antiplatelet agents (only three patients were taking aspirin and two were taking ticlopidine) had no effect on thrombosis or bleeding. Hydroxyurea was not associated with cytopenias or other serious adverse effects (AEs).

●Hydroxyurea versus interferon alfa – A phase 3 trial in 168 patients with treatment-naïve, high-risk ET or polycythemia vera (PV) reported that hydroxyurea and pegylated IFNa achieved similar rates of complete response (CR), but IFNa was associated with greater toxicity [7]. Among patients with ET, CR rates at 12 months were similar for hydroxyurea (45 percent in 42 patients) and IFNa (44 percent in 39 patients); platelet control at 12 months was also similar (45 and 46 percent, respectively). CR rates also did not differ after 24 and 36 months (25 and 17 percent with hydroxyurea, respectively; 38 and 33 percent with IFNa). Thrombohemorrhagic complications did not differ between treatments. The two agents reduced JAK2 V617F variant allele frequency (VAF) comparably; however, with IFNa, JAK2 V617F VAF decreased consistently through month 24 while it increased after month 12 with hydroxyurea. Grade ≥3 AEs were significantly more frequent with IFNa than with hydroxyurea (46 versus 28 percent). Mucositis and anorexia were more common with hydroxyurea, while hypertension, leukopenia, flu-like symptoms, fatigue, and depression were more common with IFNa.

●Hydroxyurea versus anagrelide – Both hydroxyurea and anagrelide were effective for controlling thromboses, but their effects and toxicity differed.

•A phase 3 trial that compared hydroxyurea with anagrelide reported that hydroxyurea more effectively reduced arterial thrombosis, bleeding, and fibrotic progression, while anagrelide was more effective for preventing venous thrombosis [8]. The trial included 809 patients with high-risk ET; the primary end point was a composite of death from thrombosis or hemorrhage, arterial or venous thrombosis, and serious hemorrhage. Long-term control of platelet counts was similar with both drugs. After five years, anagrelide was associated with a higher rate of the composite end point (16 versus 11 percent; odds ratio [OR] 1.57 [95% CI 1.04-2.37]); patients taking anagrelide also had more arterial thromboses (OR 2.16 [95% CI 1.27-3.69]), transient ischemic attacks (OR 5.72 [95% CI 2.08-15.73]), serious hemorrhage (OR 2.61 [95% 1.27-5.33]), transformation to myelofibrosis (OR 2.92 [95% CI 1.24-6.86]), and a trend toward more myocardial infarctions, unstable angina, and thrombotic stroke. However, patients treated with anagrelide had a lower risk for venous thromboses (OR 0.27 [95% 0.11-0.71]) and deep vein thrombosis (OR 0.20 [95% 0.06-0.71]). Treatment withdrawal for AEs was more frequent with anagrelide (88 versus 43 patients), but those treated with hydroxyurea had more leg ulcers and mouth ulcers.

•There was no difference in thrombohemorrhagic complications among 259 patients with high-risk ET who were randomly assigned to hydroxyurea versus anagrelide in the ANAHYDRET trial [9]. There was no significant difference between trial arms in major arterial or venous thrombosis, severe bleeding, or rates of treatment discontinuation. Hydroxyurea was associated with more infectious events, leukopenia, and anemia, while anagrelide was associated with more cardiac events (eg, hypertension, palpitations, tachycardia). Conclusions from this study are limited because there was a high rate of discontinuation and crossover between drugs, only one-third of patients received aspirin, and duration of follow-up was limited.

Age <40 years or potential for pregnancy — For cytoreduction in younger patients (eg, <40 years) and in those with potential to become pregnant, we suggest low-dose aspirin plus IFNa based on efficacy and safety of IFNa in this setting. Hydroxyurea and anagrelide are contraindicated in pregnant patients.

Aspirin should be used carefully, or not at all, in patients with clinically significant aVWS. (See 'Acquired von Willebrand syndrome' below.)

IFNa effectively controls vasomotor symptoms, platelet counts, and thrombohemorrhagic complications, but it may cause mild to moderate AEs. IFNa treatment is associated with reduction in the size of the malignant clone in patients with ET, but this molecular effect does not predict longer survival or less transformation to secondary myelofibrosis or acute myeloid leukemia (AML). Outcomes of a phase 3 trial that included IFNa are described above. (See 'Age ≥40 years and no potential for pregnancy' above.)

Administration of IFNa is discussed below. (See 'Interferon alfa' below.)

IFNa can be used safely in pregnant patients. (See 'Pregnancy' below.)

Prior thrombotic events — Management of patients with a previous thrombotic event is influenced by the type of prior thrombosis.

History of arterial thrombosis — For patients with ET and a prior arterial thrombosis, we suggest twice-daily aspirin plus a cytoreductive agent.

Selection of a cytoreductive agent is discussed above. (See 'High-risk ET' above.)

Aspirin should be used carefully, or not at all, in patients with clinically significant aVWS. (See 'Acquired von Willebrand syndrome' below.)

A retrospective analysis of 300 patients (<60 years) with ET who had cardiovascular (CV) risk factors but no prior arterial events (ie, low-risk and very low-risk ET) reported that aspirin reduced the risk for subsequent arterial thrombotic events [10]. Compared with low-dose aspirin, observation was associated with an increased risk for arterial thrombosis (relative risk [RR] 2.5 [95% CI 1.02-6.1]).

No studies have directly compared aspirin dosing schedules for prevention of arterial events in patients with ET. The suggestion for twice-daily dosing of low-dose aspirin is based on more effective inhibition of cyclooxygenase 1 (COX-1) using divided doses [11], as described below. (See 'Low-dose aspirin' below.)

History of venous thrombosis — Patients with ET and a prior venous thrombosis should be treated with a cytoreductive agent plus systemic anticoagulation.

Selection of a cytoreductive agent is discussed above. (See 'High-risk ET' above.)

Some experts also add low-dose aspirin for patients with previous venous thrombosis and mutated JAK2 or CV risk factors. This decision should be individualized, based on joint decision-making about the balance of risks and benefits. Aspirin should be used carefully, or not at all, in patients with aVWS. (See 'Acquired von Willebrand syndrome' below.)

Systemic anticoagulation for treatment of venous thrombosis and prophylaxis are discussed separately. (See "Venous thromboembolism: Anticoagulation after initial management" and "Risk and prevention of venous thromboembolism in adults with cancer".)

Resistance or intolerance to cytoreductive agent — For patients with refractory disease or intolerance to the initial cytoreductive agent, we suggest changing to an alternate cytoreductive agent.

The preferred agent depends on prior treatments, comorbid conditions, toxicity, and patient preference. The most common options are hydroxyurea, IFNa, and anagrelide. (See 'Treatments' below.)

●Treatment resistance – We consider that ET is refractory to initial cytoreductive therapy based on any of the following conditions [12]:

•Platelet count >600,000/microL with maximal tolerated dose of the cytoreductive agent

•Platelet count >400,000/microL with white blood cell (WBC) count <2500/microL or hemoglobin <10 g/dL

•Persistent, severe vasomotor symptoms despite platelet count <400,000/microL

●Incidence – Up to one-quarter of patients with ET who are treated with hydroxyurea demonstrate resistance or intolerance. In a study of hydroxyurea for treatment in 166 patients, resistance occurred in 15 patients and intolerance in 21 patients [13]. Patients with resistance to hydroxyurea had a median survival of 2.4 years from onset of resistance; hydroxyurea resistance was associated with sixfold higher risk of death from any cause and eightfold higher rate of developing myelofibrosis.

●Outcomes – Studies that reported outcomes of treatment of hydroxyurea-refractory ET include:

•A multicenter study that included 65 patients who were treated with pegylated IFNa for hydroxyurea-resistant ET reported a 69 percent overall response rate (including a 26 percent CR) at 12 months [14]. Grade ≥3 AEs included cytopenias, myalgia/arthralgia, depression, dyspnea, and headache (all in <10 percent of patients); toxicity led to treatment discontinuation in 14 percent of patients.

•A phase 2 study that randomly assigned 110 patients with hydroxyurea resistance/intolerance to ruxolitinib versus physician's choice of best available therapy (BAT; primarily anagrelide, interferon, or resumption of hydroxyurea) reported comparable response rates and no difference in thrombohemorrhagic complications or leukemic progression at two years [15]. Ruxolitinib was superior by some measures of symptom relief but was associated with higher rates of AEs, including anemia, thrombocytopenia, and infections. Conclusions from this study are limited because of its nonstandardized diagnostic processes, substantial switching between BAT agents, and frequent use of hydroxyurea in patients who were previously found to be intolerant or resistant.

INTERMEDIATE-RISK ET — For patients with intermediate-risk ET, we suggest either low-dose aspirin alone or low-dose aspirin plus hydroxyurea.

Management should be individualized, with consideration of cardiovascular (CV) risk factors, bleeding history, and patient preference. For patients with clinically significant acquired von Willebrand syndrome, we favor hydroxyurea alone. (See 'Hydroxyurea' below.)

Administration of low-dose aspirin is discussed below. (See 'Low-dose aspirin' below.)

No randomized trials have directly evaluated the effect of adding a cytoreductive agent to low-dose aspirin in patients with intermediate-risk ET. In the retrospective study that led to the development of the International Prognostic Score for thrombosis in ET (IPSET-thrombosis) score, the risk for thrombosis in intermediate-risk patients was 2.35 percent/year, which is distinct from the risk for patients with a high-risk score (3.56 percent/year) and a low-risk score (1.03 percent/year) [16]. In a subsequent analysis of this patient population, the presence of CV risk factors was not significantly associated with increased thrombotic risk [5].

LOW-RISK ET — Low-risk ET includes patients ≤60 years with JAK2 V617F mutation but no history of thrombosis. (See 'Risk stratification' above.)

Initial treatment — For initial treatment of low-risk ET, we suggest low-dose aspirin rather than cytoreductive therapy. This approach is considered standard therapy for patients with low-risk disease because of the favorable prognosis and to avoid potential adverse effects (AEs) of cytoreductive agents.

Aspirin should be used carefully, or not at all, in patients with clinically significant acquired von Willebrand syndrome, as discussed below. (See 'Acquired von Willebrand syndrome' below.)

Studies of initial treatment of patients with low-risk ET or very low-risk ET include:

●In a phase 3 trial of patients with low-risk ET, there was no difference in outcomes when hydroxyurea was added to low-dose aspirin, compared with low-dose aspirin alone [17]. The trial randomly assigned these treatments to 382 patients (40 to 59 years) who had no history of ischemia, thrombosis, embolism, hemorrhage, platelets ≥1,500 x 10⁹/L, hypertension, or diabetes. With a median follow-up of 73 months, hydroxyurea did not affect overall survival; disease transformation; or a composite endpoint of arterial or venous thrombosis, serious hemorrhage, or death from vascular cause. The incidence of significant vascular events in the entire cohort of enrolled patients was <1 per 100 patient-years. There was no difference in AEs between trial arms.

●Low-dose aspirin was associated with fewer venous thromboses than observation alone in patients with low-risk ET in a retrospective analysis of 300 patients; however, the analysis also included patients with very low-risk ET, and there was no benefit of aspirin across the entire study population [10]. For patients <60 years with JAK2-mutated ET, compared with those taking aspirin, observation was associated with a higher risk for venous thrombosis (relative risk [RR] 4.0 [95% CI 1.2-12.9]). For patients with low-risk ET and cardiovascular risk factors, compared with low-dose aspirin, observation was associated with an increased risk for arterial thrombosis (RR 2.5 [95% CI 1.02-6.1]). Patients with platelets >1000 x 10⁹/L had an increased risk of major bleeding (RR 5.4 [95% CI 1.7-17.2]).

Persistent symptoms in low-risk patients — For patients with inadequate control of vasomotor symptoms while taking a single dose of low-dose aspirin, we suggest twice-daily low-dose aspirin, using no more than 100 mg total per day.

It is important to use ≤100 mg total daily aspirin dose (eg, aspirin 42 mg twice daily by mouth) to avoid excessive bleeding that may be exacerbated by ET-associated platelet function abnormalities.

There is no proof that divided dosing is more effective for controlling vasomotor symptoms than a single daily dose, but some individuals have better symptom control with twice-daily dosing. Additionally, there is biochemical evidence that divided doses are more effective for suppressing platelet cyclooxygenase 1 (COX-1) activity (the target of action), as described below. (See 'Low-dose aspirin' below.)

For symptoms that persist despite twice-daily low-dose aspirin, we suggest adding cytoreductive therapy, as described for patients with high-risk ET. (See 'High-risk ET' above.)

VERY LOW-RISK ET — For patients with very low-risk ET, we suggest either observation or low-dose aspirin alone.

Management of patients with very low-risk ET should be individualized, with consideration of the degree of vasomotor symptoms, cardiovascular (CV) risk factors, risk of bleeding, and patient preference. The risk of thrombosis in these patients is very low, and survival is comparable to that of the general population [2].

Aspirin should be used carefully, or not at all, in patients with clinically significant acquired von Willebrand syndrome. (See 'Acquired von Willebrand syndrome' below.)

Aspirin did not reduce the risk of thrombosis in patients with very low-risk ET in a retrospective analysis of 300 patients with ET [10]. By contrast, aspirin was associated with improved outcomes for patients with low-risk ET (ie, those who had either JAK2 V617F or CV risk factors), as described above. (See 'Initial treatment' above.)

Patients with very low-risk ET who develop vasomotor symptoms should be managed as discussed above. (See 'Low-risk ET' above.)

TREATMENTS — Treatments for ET are used to alleviate vasomotor symptoms, control splenomegaly, and reduce thrombohemorrhagic complications. No treatment has been proven to reduce transformation to secondary myelofibrosis or leukemic progression.

Low-dose aspirin — Low-dose aspirin can reduce vasomotor symptoms and thrombohemorrhagic complications in most patients with ET.

●Administration – Low-dose aspirin refers to doses of 40 to 100 mg per day. It can be taken once or twice daily, but the total daily dose should be ≤100 mg.

Aspirin should be used carefully, or not at all, in patients with clinically significant acquired von Willebrand syndrome. (See 'Acquired von Willebrand syndrome' below.)

There is no persuasive evidence that twice-daily dosing more effectively controls vasomotor symptoms or reduces thrombotic risk. However, twice-daily low-dose aspirin was more effective than single-daily dosing for inhibiting cyclooxygenase 1 (COX-1; the target of action for aspirin) in a randomized trial of 245 patients with ET [11]. This effect may be due to accelerated turnover of platelet COX-1 in patients with ET [18,19]. Some patients with persistent vasomotor symptoms while taking single-daily low-dose aspirin respond better to twice-daily low-dose aspirin.

Higher-dose aspirin (eg, 900 mg/day) is discouraged because of increased gastrointestinal bleeding when high-dose aspirin was used in combination with dipyridamole in patients with polycythemia vera (PV) [20,21].

●Toxicity – Low-dose aspirin is well-tolerated and has no major adverse effects (AEs).

There was no increase in major bleeding episodes in patients taking low-dose aspirin compared with no aspirin in a randomized trial of patients with ET [22].

Management of aspirin-resistant symptoms in patients with low-risk ET or very low-risk ET is discussed above. (See 'Persistent symptoms in low-risk patients' above.)

Hydroxyurea — Hydroxyurea is an oral agent that effectively reduces platelet counts, controls vasomotor symptoms and splenomegaly, and reduces thromboses in patients with ET. Hydroxyurea inhibits deoxyribonucleic acid (DNA) synthesis by acting on ribonucleotide reductase.

●Administration – The initial dose of hydroxyurea is 15 mg/kg per day by mouth. We generally begin treatment with either one or two 500 mg tablets daily. Patients should be advised to avoid missing doses.

The dose of hydroxyurea should be reduced by 50 percent in patients with creatinine clearance <60 mL/min. Because the effect of hydroxyurea may resemble that of folic acid deficiency, folic acid supplementation should be considered (to avoid masked folate deficiency); folic acid does not reverse the effects of hydroxyurea on symptoms or blood counts.

Hydroxyurea is contraindicated in pregnant individuals, and it should be avoided in patients who are breastfeeding or with childbearing potential. (See 'Pregnancy' below.)

●Response monitoring – The dose of hydroxyurea is adjusted to achieve a target platelet count of 100,000/microL to 400,000/microL while limiting neutropenia and anemia [3,23].

Complete blood counts are initially obtained weekly, but the frequency may be reduced as blood counts stabilize. Treatment is accompanied by varying degrees of neutropenia and anemia with megaloblastic features (eg, increased mean cell volume).

Liver function tests should be obtained periodically to monitor for hydroxyurea-induced alterations in liver function.

The onset of action is rapid, and blood counts generally decline within three to five days of beginning treatment; similarly, the effect of hydroxyurea is short-lived when it is stopped. Dose adjustments should not be made more than once per week to prevent wide fluctuations in the platelet count.

●Toxicity – Hydroxyurea is well-tolerated. AEs include oral ulcers, hyperpigmentation, skin rash, and nail changes but are usually mild (table 1) [24]. Some patients experience fever, nausea, diarrhea, abnormal liver function tests, or alopecia; rare cases of severe (including fatal) pulmonary toxicity have been reported [13,24,25].

In a study of 993 patients treated with hydroxyurea for myeloproliferative neoplasms (one-half with ET), mucocutaneous toxicity (eg, erythema, perimalleolar or oral aphthous ulcers) was reported in 8 percent; one-half of affected patients required permanent drug discontinuation [26].

●Outcomes – Response rates to hydroxyurea have varied among studies because of different diagnostic criteria and target platelet levels. Among 166 patients treated with hydroxyurea with a target platelet count <400,000/microL, the complete response rate was 81 percent and partial response rate was 15 percent, using the European LeukemiaNet (ELN) and International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria [13].

Randomized trials in ET that included hydroxyurea are described above. (See 'Age ≥40 years and no potential for pregnancy' above.)

●Leukemogenesis – There is no persuasive evidence that hydroxyurea is associated with increased risk for leukemia in patients with ET. Other treatments that are now rarely used (eg, busulfan, ³²P) are clearly associated with increased rates of malignant transformation.

The incidence of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) in patients with ET has generally been estimated to be 0 to 5 percent in most long-term studies [2,8,27-35].

•Among 357 patients followed for a median of eight years, the incidence of MDS or AML was 4.5 percent [27]. This risk was 3.5 percent in patients treated with hydroxyurea alone but 14 percent in patients receiving hydroxyurea in combination with ³²P, busulfan, or pipobroman.

•A retrospective study of 435 patients with ET reported a 2 percent cumulative incidence of AML after 15 years; the risk for developing AML was not associated with the use of hydroxyurea [36].

Long-term treatment with hydroxyurea has not been associated with an increased leukemia in nonhematologic conditions (eg, sickle cell disease), as discussed separately. (See "Hydroxyurea use in sickle cell disease", section on 'Adverse effects'.)

Interferon alfa — Interferon alfa (IFNa) is a pharmaceutical product obtained from human leukocytes that contains several naturally occurring subtypes of interferon alpha. Pegylated IFNa provides a more favorable toxicity profile than conventional IFNa, and its prolonged activity is compatible with once-weekly dosing [37-39].

●Administration – The initial dose of pegylated IFNa is 45 mcg/week subcutaneously for the first two weeks. The dose is increased, as tolerated, to a maximal dose of 180 mcg/week.

Use of mono-pegylated IFNa-2b (ropeginterferon) 100 mcg every two weeks, increased by 50 mcg every two weeks to a maximum of 500 mcg, is also acceptable.

The dose of IFNa is titrated to maintain the platelet count between 100 x 10⁹/L and 400 x 10⁹/L.

We favor pegylated IFNa rather than nonpegylated IFNa because of comparable efficacy, ease of administration, and the more favorable toxicity profile [37,38,40-43]. If pegylated IFNa is not available, the usual starting dose of nonpegylated IFNa is 3 million units subcutaneously three times per week.

●Toxicity – Treatment with pegylated IFNa in a phase 3 trial caused grade ≥3 AEs in nearly one-half of patients; the most common grade ≥3 AEs were fatigue (7 percent), hypertension (7 percent), and headache (4 percent) [7]. Grade 1 to 2 AEs occurred in one-half of patients and included fatigue (49 percent), flu-like symptoms (22 percent), headache (22 percent), peripheral sensory neuropathy (20 percent), pain in extremities (20 percent), and depression (15 percent).

Studies using nonpegylated IFNa reported treatment discontinuation in up to one-quarter of patients due to treatment-related AEs [40,44-46].

●Outcomes – Treatment with IFNa was associated with a hematologic response in all 31 patients with CALR-mutated ET and reduced CALR mutant allelic burden (from 41 percent at baseline to 26 percent; two patients had a complete molecular response) [42].

A randomized trial that compared IFNa with hydroxyurea for patients with high-risk ET is discussed above. (See 'Age ≥40 years and no potential for pregnancy' above.)

Anagrelide — Anagrelide is an oral imidazoquinoline that effectively lowers platelet counts and reduces ET-related symptoms. Anagrelide also inhibits platelet aggregation (by reducing platelet anti-cyclic AMP phosphodiesterase activity), but its effect on platelet function is only seen with doses that are higher than those used for controlling thrombocytosis [47-49]. Use of anagrelide for ET has been limited by concerns about the potential for cardiac toxicity and post-ET myelofibrosis.

●Administration – The initial dose is 0.5 mg by mouth, two to four times daily.

The dose is titrated to maintain the platelet count between 100 x 10⁹/L and 400 x 10⁹/L. The usual maintenance dose is 1 to 4 mg/day.

Anagrelide must be given with caution to patients with known or suspected heart disease; this may limit its use in older patients [50].

Anagrelide is contraindicated in patients who are pregnant or may become pregnant.

●Toxicity – The most common AEs are headache, palpitations/tachycardia, and fluid retention; these effects are thought to be related to its vasodilatory properties. Anagrelide has been associated with acquired idiopathic cardiomyopathy and high output heart failure [51].

Treatment of 577 patients with anagrelide for thrombocythemia, including ET, reported 24 percent fluid retention, and 2 percent of patients had heart failure [52].

●Outcomes – Randomized trials that compared anagrelide with hydroxyurea for prevention of thrombosis in patients with ET reported similar efficacy, but anagrelide was associated with greater toxicity. (See 'High-risk ET' above.)

Alternative approaches — Other agents can be used when hydroxyurea, IFNa, and anagrelide do not provide relief of ET-related symptoms or fail to control thrombocytosis without significant leukopenia.

Treatment choice for treatment resistance or intolerance are discussed below. (See 'Resistance or intolerance to cytoreductive agent' above.)

●Ruxolitinib – Response rates were comparable between ruxolitinib versus best available therapy in hydroxyurea-unresponsive/intolerant patients with high-risk ET in a randomized phase 2 study [53]. The two study arms were associated with comparable rates of complete response at one-year and two-year rates of thrombosis, hemorrhage, and leukemic/fibrotic transformation.

●Pipobroman – Pipobroman is an oral piperazine derivative that is classified as an alkylating agent [54]. It is used for treatment of ET in Europe, but it is not available in the United States.

The initial dose of pipobroman is 0.8 to 1 mg/kg per day by mouth. AEs include nausea, abdominal cramps, diarrhea, stomatitis, and dry skin.

In studies with a short-term follow-up, pipobroman was not associated with an increased risk of AML in ET, but a small risk may exist with long-term therapy [27,55-57]. The risk of developing AML increases significantly when pipobroman is used with other agents, such as hydroxyurea [27]. (See 'Hydroxyurea' above.)

●Other approaches – Historically, ³²P and busulfan were used to control platelet counts and reduce the risk of thrombosis in ET. However, both agents 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 life-shortening comorbidities that make medication administration unusually difficult, as discussed below. (See 'Frail or limited lifespan' below.)

●Apheresis – Apheresis can transiently reduce extreme thrombocytosis in association with acute, severe thrombotic or hemorrhagic events. However, this must be followed by treatment with a cytoreductive agent to maintain control of the platelet count.

Apheresis is discussed separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

RESPONSE MONITORING — Patients are monitored to assess symptoms, splenomegaly, bleeding, thrombosis, blood counts, and disease progression.

We do not perform routine scheduled bone marrow examinations outside of a clinical trial. However, we perform a bone marrow examination if there is an unexpected change in blood counts or other evidence of disease transformation.

The frequency of visits is influenced by the presence and severity of symptoms and disease complications, the type of treatment, and concerns of the patient or clinician.

●Low risk or very low risk – Patients who are observed or treated with low-dose aspirin may require only annual or semiannual visits.

●High risk or intermediate risk – Patients treated with cytoreductive therapy and/or systemic anticoagulation are seen based on the treatment response and stability of blood counts and anticoagulation.

The European LeukemiaNet (ELN) and International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) published criteria for monitoring symptoms, spleen and liver size, platelet count, leukocyte count, bone marrow histology, hemorrhagic or thrombotic events, and transformation to leukemia or post-ET myelofibrosis [58,59].

SPECIAL POPULATIONS — Distinctive management is needed for ET in certain populations of patients.

Acquired von Willebrand syndrome — Acquired von Willebrand syndrome (aVWS) is thought to be caused by adsorption of von Willebrand factor to the expanded population of platelets or by increased proteolysis from platelet proteases. (See "Acquired von Willebrand syndrome".)

The syndrome should be suspected in patients with ET who have bleeding and/or >1000 x 10⁹ platelets/L (>1,000,000/microL). Diagnosis of aVWS is based on ristocetin cofactor activity <30 percent. (See "Acquired von Willebrand syndrome", section on 'Diagnostic evaluation'.)

Aspirin should be used carefully, or not at all, in patients with clinically significant aVWS. For patients with low-risk ET and very low-risk ET, cytoreductive therapy can be used to control vasomotor symptoms and reduce thrombotic risk, as described for patients with high-risk ET. (See 'High-risk ET' above.)

The risk of hemorrhage is significantly increased by low-dose aspirin in patients with aVWS. In a retrospective study of 300 patients with low-risk ET, patients with platelets >1000 x 10⁹/L had an increased risk of major bleeding (relative risk [RR] 5.4 [95% CI 1.7-17.2]) [10].

Pregnancy — Management of ET in pregnant patients or those who desire to become pregnant is guided by the need to relieve symptoms and reduce complications while avoiding treatments that may harm the developing fetus.

●Risk-based management – Pregnant patients with ET are treated according to the risk for thrombosis, as described above. (See 'Risk stratification' above.)

•Lower-risk ET – Patients with low-risk or very low-risk ET are generally treated with low-dose aspirin to relieve ET-associated symptoms and to reduce pregnancy loss. (See 'Low-risk ET' above.)

We do not routinely treat pregnant patients with interferon alfa (IFNa) unless there are other indications for its use. However, some experts offer IFNa for patients with ET who have had recurrent spontaneous abortions [60-62].

•Higher-risk ET – IFNa is the preferred cytoreductive agent because both hydroxyurea and anagrelide are contraindicated in pregnant and lactating individuals. (See 'Age <40 years or potential for pregnancy' above.)

For pregnant patients with uncontrolled thrombocytosis who cannot tolerate IFNa, a decision to use hydroxyurea or anagrelide should be made using joint decision-making.

We do not consider inadvertent exposure to hydroxyurea or anagrelide a reason to terminate a pregnancy. Successful pregnancies have been reported after exposure to hydroxyurea in the first trimester in patients with ET and other conditions [63]. Similarly, no ill effects to the fetus were observed following exposure to hydroxyurea in the second and third trimesters [60,62,64-66].

●Thromboprophylaxis – We do not routinely offer thromboprophylaxis to pregnant patients unless there are other indications, such as prior venous thrombosis or cesarean delivery.

No prospective studies have evaluated thromboprophylaxis in pregnant patients with ET. Thromboprophylaxis for pregnant patients is discussed separately. (See "Venous thromboembolism in pregnancy: Prevention".)

●Recurrent spontaneous abortions – Patients with ET have a higher rate of fetal loss compared with the general population. Studies evaluating the risk of spontaneous abortion in women with ET have reported mixed results, but aspirin and IFNa may be associated with a higher probability of live birth.

There is no consensus for the use of aspirin and/or IFNa for patients with ET and recurrent spontaneous abortions.

A meta-analysis of 1210 pregnancies in 767 patients with myeloproliferative neoplasms (most with ET) reported a 3.1 percent incidence of pre-eclampsia and a 71.3 percent rate of live births without significant maternal or fetal adverse effects (AEs; compared with 80 percent in the general population) [67]. The odds ratio (OR) for a live birth without significant maternal or fetal AEs was higher in the 227 patients taking aspirin (OR 8.6 [95% CI 4.0-18.1]) and in the 90 patients taking IFNa (OR 9.7 [95% CI 2.3-41.0]).

Frail or limited lifespan — In 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 can be effective for controlling the platelet count, despite concern regarding longer-term risk of leukemic transformation.

Disease transformation — ET progresses to post-ET myelofibrosis (MF) or secondary acute myeloid leukemia (AML) in a small subset of patients.

ET transformation should be suspected in patients with unexpected cytopenias, circulating blasts and other immature forms, and exacerbation of ET-associated symptoms. Bone marrow examination is required to evaluate these conditions.

Details of evaluation and diagnosis of MF and secondary AML are presented separately. (See "Clinical manifestations and diagnosis of primary myelofibrosis" and "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

The risk of disease transformation in ET is considerably lower than the risk of thrombosis, as illustrated by the following studies:

●In a retrospective study of 435 patients with ET, the 15-year cumulative risks of thrombosis, secondary AML, and post-ET MF were 17, 2, and 4 percent, respectively [36].

●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 [2].

●In a single-institution study of 605 patients with ET followed for a median of seven years, AML was documented in 3.3 percent [28]. Low levels of hemoglobin (<12 g/dL in females, <13.5 in males) and platelet count ≥1000 x 10⁹/L were risk factors for the development secondary AML in multivariate analysis. Patients with none, one, or both risk factors had 0.4, 4.8, and 6.5 percent incidence of AML, respectively. Risk for secondary AML was not associated with JAK2 V617F mutation treatment with a cytoreductive agent.

Management of post-ET MF is described separately. (See "Myelofibrosis (MF): Management of primary MF and secondary MF".)

Management of post-ET secondary AML is discussed separately. (See "Therapy-related myeloid neoplasms: Management and prognosis".)

PROGNOSIS — Increased age and prior thrombosis are associated with shorter survival and increased thrombotic risk in patients with ET.

Survival — Most patients with ET enjoy a normal life expectancy, but survival is inferior in patients with increased age, prior thrombosis, and other factors.

●Multivariable analysis of 891 patients with ET reported that age >60 years, history of thrombosis, elevated white blood cell (WBC) count, and anemia were associated with survival [2]. Overall survival (OS) at 10 years was 89 percent, and the 15-year OS was 80 percent. Hazard ratios (HRs) for death were age >60 years (HR 6.7 [95% CI 4.34-10.3]), previous thrombosis (HR 2.81 [95% CI 1.95-4.06]), hemoglobin <12 g/dL (HR 2.95 [95% CI 1.73-5.04]), and WBC >11 x 10⁹/L (HR 2.01 [95% CI 1.39-2.90]). Survival of patients with ET was comparable to that of the sex- and age-standardized European population.

●A single-institution study of 605 patients with ET also identified age ≥60 years, prior venous thrombosis, leukocytosis (≥15,000 WBC/microL), and anemia (<12 g/dL in females; <13.5 g/dL in males) as being independently associated with inferior survival [28].

Thrombosis — Prior thrombosis, age >60 years, JAK2 V617F mutation, and cardiovascular (CV) risk factors (hypertension, diabetes, active tobacco use) are associated with increased thrombotic risk in patients with ET.

The revised International Prognostic Score for thrombosis in ET (IPSET)-thrombosis model was derived from a cohort of 891 subjects with ET [16]. This study reported the following associations with thrombosis: age >60 years (HR 1.50), history of thrombosis (HR 1.93), CV risk factors (HR 1.56), and JAK2 V617F (HR 2.04).

Similar findings were reported in other studies [36,68-70].

Use of the revised IPSET-thrombosis model is discussed above. (See 'Risk stratification' above.)

Disease transformation — The risk of leukemic transformation to acute myeloid leukemia (AML) or post-ET myelofibrosis (MF) 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 MF were 17, 2, and 4 percent, respectively [36].

●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 [2].

●In a single-institution study of 605 patients with ET followed for a median of seven years, AML was reported in 3.3 percent [28]. Multivariate analysis revealed low hemoglobin levels, and platelet count ≥1,000,000/microL were identified as risk factors for AML, while JAK2 V617F and cytoreductive therapy were not associated with risk for AML.

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

●Description – Essential thrombocythemia (ET) is a BCR::ABL1-negative myeloproliferative neoplasm characterized by excessive clonal platelet production. ET may be asymptomatic at presentation or may manifest vasomotor symptoms (eg, erythromelalgia, acrocyanosis, headaches, cutaneous ulcers), thrombosis, or bleeding.

Diagnosis of ET is discussed separately. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia".)

●Pretreatment evaluation – Evaluate vasomotor findings, organomegaly, thrombosis, bleeding, and blood counts. (See 'Pretreatment evaluation' above.)

Patients with bleeding or platelets >1000 x 10⁹/L (>1,000,000/microL) should be tested for acquired von Willebrand syndrome (aVWS).

●Risk stratification. (See 'Risk stratification' above.)

•High risk

•Intermediate risk

•Low risk

•Very low risk

●High risk – Treatment includes a cytoreductive agent plus low-dose aspirin, but aspirin should be used with caution in patients with aVWS. (See 'High-risk ET' above.)

•Choice of cytoreductive agent

-Age ≥40 years and not pregnant – For most patients with high-risk ET, we suggest aspirin plus hydroxyurea rather other cytoreductive agents (Grade 2C). (See 'Age ≥40 years and no potential for pregnancy' above.)

-Age <40 years and/or potential for pregnancy – We suggest aspirin plus interferon alfa (IFNa) rather than aspirin alone (Grade 2C); hydroxyurea and anagrelide are contraindicated in pregnancy. (See 'Age <40 years or potential for pregnancy' above.)

•Patients with prior thrombosis

-Prior arterial thrombosis – We suggest adding twice-daily low-dose aspirin to cytoreduction (Grade 2C). (See 'History of arterial thrombosis' above.)

-Prior venous thrombosis – Systemic anticoagulation is added to cytoreduction. (See 'History of venous thrombosis' above.)

•Resistance/intolerance to initial therapy – For resistance or intolerance to hydroxyurea, we suggest changing to IFNa (Grade 2C). Parameters for defining resistance are discussed above. (See 'Resistance or intolerance to cytoreductive agent' above.)

●Intermediate-risk ET – In most patients, we suggest either low-dose aspirin alone or low-dose aspirin plus hydroxyurea (Grade 2C). (See 'Intermediate-risk ET' above.)

However, aspirin should be used with caution in patients with aVWS. (See 'Acquired von Willebrand syndrome' above.)

●Low-risk ET. (See 'Low-risk ET' above.)

•Initial therapy – In most patients, we suggest low-dose aspirin rather than cytoreduction (Grade 2C). (See 'Low-risk ET' above.)

However, for patients with aVWS, we favor cytoreductive therapy rather than aspirin. (See 'Acquired von Willebrand syndrome' above.)

•Persistent symptoms – For inadequate symptom control, we suggest twice-daily low-dose aspirin (≤100 mg total per day) (Grade 2C). (See 'Persistent symptoms in low-risk patients' above.)

Add cytoreduction if symptoms persist with twice-daily low-dose aspirin.

●Very low-risk ET – We suggest either observation or low-dose aspirin rather than cytoreduction (Grade 2C). (See 'Very low-risk ET' above.)

●Response monitoring – Assess symptoms, bleeding, thrombosis, and platelet count. (See 'Response monitoring' above.)

●Special populations

•Acquired von Willebrand syndrome – We weigh the risk of bleeding with aspirin against the degree of symptoms in patients with aVWS. (See 'Acquired von Willebrand syndrome' above.)

•Pregnancy – Low-dose aspirin and pegylated IFNa can be used safely in pregnancy. (See 'Pregnancy' above.)

•Frail or limited lifespan – Options include hydroxyurea, anagrelide, busulfan, or ³²P. (See 'Frail or limited lifespan' above.)

•Disease transformation – Evaluate bone marrow for unexpected changes in blood counts or abnormal circulating cells that suggest disease transformation. (See 'Disease transformation' 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.