Approach

Treatment for essential thrombocythaemia (ET) should be individualised (e.g., based on age, risk for thrombosis, mutation status, presence of symptoms).​[38]​​[45]​

The goals of treatment are to reduce the risk of thrombosis and bleeding complications, manage symptoms, and reduce the risk of progression (e.g., to myelofibrosis or leukaemia).​​[45]​​​​ Currently, there are no curative treatments for ET.

Cardiovascular risk factors (e.g., hypertension, hyperlipidaemia, diabetes, smoking) should be identified and managed in all patients with ET.​[38]​​

Give advice on lifestyle modification (e.g., smoking cessation, weight control) to reduce the risk of developing symptoms, or to moderate the severity of existing symptoms.[46]​ Offer supportive care to ensure optimum symptom management.

Monitor platelets regularly in all patients (including asymptomatic patients and those in a steady state after starting treatment).

Monitor for new thrombosis, acquired von Willebrand disease, and/or disease-related major bleeding.

Pregnant women require specialist management to avoid complications.[10][46]​​

Risk stratification

The International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) tool can be used to stratify patients into four risk groups to guide treatment.[38][39]​​​​[43][44]

  • Very low risk: age ≤60 years, no thrombosis history, no Janus kinase 2 (JAK2) JAK2 V617F mutation

  • Low risk: age ≤60 years, no thrombosis history, with JAK2 V617F mutation

  • Intermediate risk: age >60 years, no thrombosis history, no JAK2 V617F mutation

  • High risk: thrombosis history at any age, or age >60 years with JAK2 V617F mutation

Very low-risk, low-risk, or intermediate-risk patients

Very low-risk patients who are asymptomatic do not require treatment; observation is appropriate.​[38]​​[39]​​[45]​​​​​ These patients may receive low-dose (once-daily) aspirin if they have vascular symptoms (e.g., headaches, chest pain, erythromelalgia).​[38]​​[45]

Low-risk patients and intermediate-risk patients should receive low-dose (once-daily) aspirin, although observation may be an option for some low-risk patients. Clopidogrel may be considered for patients with major contraindications to aspirin (e.g., allergy or peptic ulcer disease).

Higher doses of aspirin may be appropriate in selected patients (e.g., with cardiovascular risk factors), as clinically indicated. For patients with aspirin-resistant symptoms, a twice-daily regimen of low-dose aspirin, or alternatively clopidogrel (alone or in combination with aspirin), may be considered, with close monitoring. The increased risk of bleeding with higher or more frequent doses of aspirin must be carefully weighed against the potential benefit (e.g., reduction in the presence and/or severity of vasomotor symptoms, including headache).​[38][47]​​​​​​

Aspirin should be used with caution and monitored closely in patients with acquired von Willebrand disease because of increased risk of bleeding.

Cytoreductive therapy

Very low-risk, low-risk, or intermediate-risk patients should be reviewed as clinically indicated, monitoring for signs and symptoms of disease progression and evaluating for indications of cytoreductive therapy.[38]​

Indications for cytoreductive therapy in symptomatic patients include:[38][48]

  • New thrombosis, acquired von Willebrand disease, and/or disease-related major bleeding

  • Splenomegaly

  • Progressive thrombocytosis and/or leukocytosis

  • Disease-related symptoms (e.g., pruritus, night sweats, fatigue)

  • Vascular symptoms (e.g., headaches, chest pain, and erythromelalgia) not responsive to aspirin (or other antiplatelet therapy)

Patients who are symptomatic and have indications for cytoreductive therapy should be treated with a cytoreductive agent (in addition to antiplatelet therapy).

Bone marrow aspirate and biopsy should be performed to rule out disease progression to myelofibrosis prior to the initiation of cytoreductive therapy.[38]

Hydroxycarbamide is the preferred cytoreductive agent in most patients.[45][46][49]​​​​​​ Doses are titrated up or down, balancing the desired effect on platelet count while minimising neutropenia and anaemia. Evidence-based guidelines regarding target platelet count are lacking; in low-risk ET it should be the level at which symptom relief is observed.[39]​​

Hydroxycarbamide should be used with caution as it is teratogenic and potentially leukemogenic.[50]​ It is relatively contraindicated in pregnancy, in women of childbearing potential, and in women who are breastfeeding. 

The following agents are alternatives to hydroxycarbamide.[38][39]​​​​​​​​​

  • Peginterferon alfa-2a: effective for treating patients with JAK2-mutated ET or calreticulin (CALR)-mutated ET.[51][52]​​​ Peginterferon alfa-2a may be preferred to hydroxycarbamide in younger patients, particularly women of childbearing age and pregnant patients, because it is non-teratogenic and non-leukemogenic.[53]

  • Busulfan: typically used as a second-line option (after hydroxycarbamide) in older patients (i.e., aged ≥65 years).[39]​​[54]​​​ Busulfan may be associated with a significant rate of transformation to acute myeloid leukaemia, although the leukemogenicity of busulfan is debated.[39] Sequential use of busulfan and hydroxycarbamide has been reported to significantly increase the risk of second malignancies.[55]​ The National Comprehensive Cancer Network (NCCN) guidelines do not recommend the use of busulfan for ET.[38]​

  • Anagrelide: can be considered for second-line use after failure of other cytoreductive agents (e.g., hydroxycarbamide, peginterferon alfa-2a). Careful evaluation is recommended before starting treatment because of the risk of adverse effects (e.g., cardiotoxicity), especially in older patients.[38][49][53] Some studies suggest that anagrelide may increase the risk of progression to myelofibrosis and decrease survival.[39][49][56]​​​ 

High-risk patients

High-risk patients should receive low-dose (once-daily) aspirin and cytoreductive therapy as initial treatment.​[38][39]​​​​​​​​[45]

Hydroxycarbamide is the preferred cytoreductive agent in most patients.​[38]​​​​​​​[45][49]​​​

Peginterferon alfa-2a may be considered as an alternative option for younger patients (age <65 years), particularly women of childbearing age and pregnant patients, or for those who do not wish to start hydroxycarbamide.[38]

In high-risk patients experiencing intolerance or resistance to first-line therapy, anagrelide or busulfan (for older patients) may be considered as second-line agents.[57] The NCCN guidelines do not recommend the use of busulfan for ET.[38]​​

The management goal is to adequately control myeloproliferation and keep platelet and leukocyte counts in the normal range (platelet count 150 × 10⁹/L to 400 × 10⁹/L [150,000 to 400,000/microlitre]; leukocyte count 4.5 × 10⁹/L to 10 × 10⁹/L [4500 to 10,000/microlitre]), without significant clinical toxicity or suppression of other marrow elements.[58]​ 

Patients should be reviewed as clinically indicated to monitor for signs and symptoms of disease progression.[38]​ If the response to treatment is adequate, it should be continued. If the response is inadequate or there is a loss of response, an alternative cytoreductive agent should be tried. If there is clinical or laboratory-based suspicion of progression to myelofibrosis, perform bone marrow aspirate and and biopsy.[38]

Potential indications for a change of cytoreductive therapy include:[38]

  • Intolerance or resistance to first-line cytoreductive therapy

  • New thrombosis, acquired von Willebrand syndrome, or disease-related major bleeding

  • Leukocytosis

  • Thrombocytosis

  • Splenomegaly

  • Disease-related symptoms (e.g., pruritus, night sweats, and fatigue)

  • Vascular symptoms (e.g., headaches, chest pain, erythromelalgia) not responsive to aspirin

Second-line options, if not already tried, may include peginterferon alfa-2a, hydroxycarbamide, anagrelide, or busulfan (for older patients), or the patient may be considered for a clinical trial.[38][39]​​ The NCCN guidelines do not recommend the use of busulfan for ET.[38]​​

Patients with a history of thrombosis

A twice-daily regimen of low-dose aspirin may be considered for high-risk patients with a history of arterial thrombosis or with cardiovascular risk factors.[39][47]​​​​

Systemic anticoagulation (combined with aspirin and cytoreductive therapy) may be considered for high-risk patients with a history of venous thrombosis.[39]​​ Use of systemic anticoagulation in high-risk patients should be individualised, balancing bleeding risk and benefits.

Plateletpheresis

Plateletpheresis is rarely used in treating ET, but may be considered in certain emergency situations (e.g., life-threatening thrombosis, severe thrombocytosis-related neurological complications, or severe bleeding).[38]​​[59] It may help rapidly reduce the platelet count and relieve acute symptoms associated with ET.[60]​​

Plateletpheresis involves removing whole blood from a patient, separating the blood into its components, removing the platelets, and then returning the remaining blood components to the patient.

Pregnant women

Treating women with ET during pregnancy is challenging due to the increased risk for first trimester spontaneous abortion, and thrombotic and obstetric complications.[10] Patients who become pregnant should be under the joint care of a haematologist and an obstetrician experienced in high-risk care.​​

Treatment is similar to that for non-pregnant patients. Aspirin has been reported to be effective in reducing pregnancy complications, especially in patients with JAK2-mutated ET.[61]​ One systematic review reported a higher live birth rate among women with myeloproliferative neoplasms who were treated with aspirin alone or in combination with interferon.[62]

Peginterferon alfa-2a may be considered if cytoreduction is indicated; other cytoreductive agents (e.g., hydroxycarbamide, busulfan, and anagrelide) cross the placenta and are potentially harmful to the fetus. Hydroxycarbamide, busulfan, and anagrelide should be avoided during pregnancy, particularly in the first trimester.

Very low-risk, low-risk, or intermediate-risk patients: pregnant

  • Low-dose (once-daily) aspirin should be the initial therapy to reduce the risk of placental thrombosis, spontaneous abortion, and other complications (e.g., pre-eclampsia).[10]

  • Aspirin should be used with caution and monitored closely in patients with acquired von Willebrand disease because of increased risk of bleeding.

  • Clopidogrel can be considered for pregnant patients if aspirin is contraindicated (e.g., due to allergy or peptic ulcer disease).

  • Cytoreductive therapy with peginterferon alfa-2a may be considered in certain situations (e.g., history of recurrent fetal loss; pre-eclampsia; uncontrolled leukocytosis/thrombocytosis; prominent splenomegaly).[10][38]​​

High-risk patients: pregnant

  • Cytoreductive therapy with peginterferon alfa-2a can be considered for high-risk patients who are pregnant.[10]

  • Patients who are receiving hydroxycarbamide before pregnancy should be switched to peginterferon alfa-2a. Hydroxycarbamide is excreted in breastmilk and should be avoided in women who are breastfeeding.

  • Pregnant high-risk patients with a history of arterial thrombosis should receive low-dose (once-daily) aspirin in combination with peginterferon alfa-2a.[10]​ Clopidogrel can be considered if aspirin is contraindicated.

  • Pregnant high-risk patients with a history of venous thrombosis should receive systemic anticoagulation in combination with peginterferon alfa-2a.[10]​ Low molecular weight heparin (LMWH; e.g., enoxaparin) is the preferred anticoagulant for pregnant women.[10][38]​​​​​ LMWH does not cross the placenta and, in pregnant women, is associated with a lower risk of osteoporosis and heparin-induced thrombocytopenia (HIT) than unfractionated heparin (UFH).[63]​

Patients requiring surgery

Patients with ET who have undergone surgery are at high risk for bleeding and thrombotic complications.[64]​ 

A careful preoperative review should be carried out in patients with ET who require surgery, taking into consideration individual patient factors as well as the thrombotic and bleeding risk of the surgical procedure.

Antiplatelet agents are typically stopped 7 to 10 days before major surgery, or surgery to critical sites, and reintroduced as soon as feasible with surgeon input (typically 24 hours after surgery).[38]

For patients receiving cytoreductive therapy who are undergoing elective surgery, the blood count is optimised preoperatively, and interruptions in therapy should be kept to a minimum.[65]​ For patients not receiving cytoreductive treatment, temporary therapy should be considered on an individualised basis.[65]

Postoperative thromboprophylaxis is recommended according to usual guidelines for the specific procedure.

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