Essential thrombocythemia: Disease and treatment overview

Essential thrombocythemia (ET) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) disease subtype characterized by excessive proliferation of platelets, pronounced thrombosis, a high frequency of thrombotic events, and hemorrhagic risk.¹ Compared with other MPN disease subtypes (myelofibrosis [MF], and polycythemia vera), ET has a favorable overall prognosis; however, the overall survival rate remains poor compared with the general population.¹ Here, we provide an overview of the epidemiology, pathophysiology, diagnosis, and management of ET.

Etiology

• Between 50–60% of patients harbor a mutation in the Janus kinase 2 (JAK2) gene,² with the JAK2^V617F mutation being the most common.²
• Other common driver mutations include the myeloproliferative leukemia virus oncogene, present in around 3% of patients; and calreticulin (CALR), present in 15–32% of patients.²
• These mutations cause constituent activation of the JAK/signal transducers and activators of transcription and phosphatidylinositol 3-kinase/mitogen-activated protein kinase signaling pathways, as well as hypersensitivity to thrombopoietin, resulting in uncontrolled thrombocyte proliferation.^2,3
• Risk factors include⁴:
  • working in agriculture and petroleum refineries;
  • benzene exposure; and
  • smoking.

Epidemiology

*Data from Accurso, et al.¹ and Li, et al.⁵

 Pathophysiology⁶

• The common JAK2^V617F mutation results from a valine-to-phenylalanine substitution at codon 617.
• Mutations in CALR are due to insertions or deletions resulting in a reading frame shift and the formation of a novel C-terminus.
• Point mutations in the myeloproliferative leukemia virus oncogene lead to hypersensitivity to the thrombopoietin receptor.
  • The subsequent gain in function primarily affects the JAK2 mutation, activating signaling pathways associated with hematopoietic cytokine receptors including erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor. (Figure 2).

This results in²:

• increased megakaryocyte mobility
• increased thrombocyte production
• deficiency of glycoprotein VI on the surface of platelets
• increased risk of thrombosis

JAK2, Janus kinase 2; RBC, red blood cell, TF, tissue factor.
*Adapted from Falchi, et al.¹⁰
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 Signs and symptoms

• The most frequently reported constitutional symptoms are fatigue, insomnia, dizziness, and headaches.¹ (Figure 3)
• However, most constitutional symptoms are experienced at a lower severity and frequency when compared with polycythemia vera and MF.¹
• The main complications of ET are increased risk and frequency of arterial and venous thrombotic events and transformation to either acute myeloid leukemia or secondary MF.²

*Adapted from Khodier and Gadó. ²
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 Diagnosis

• A complete blood count, a bone marrow biopsy, and genetic testing are essential for diagnostic confirmation.⁶
• Historically, the diagnosis of each MPN subtype has been defined by the World Health Organization (WHO) classification of MPN.
• However, the most recent revision has resulted in a new scheme, the International Consensus Classification of MPN and acute leukemias, with an emphasis on criteria refinement for easier distinction between subtypes (Figure 4).⁷
• For a confirmed subtype diagnosis, a patient must meet all major criteria defined in the classification, or most of the major criteria together with a minor criterion (Figure 4).⁷

BCR::ABL1, breakpoint cluster region::Abelson murine leukemia viral oncogene homolog 1; BM, bone marrow; CALR, calreticulin; CML, chronic myeloid leukemia; ET, essential thrombocythemia; Hb, hemoglobin; ICC, International Consensus Classification; JAK, Janus kinase; MPL, myeloproliferative leukemia virus oncogene; PMF, primary myelofibrosis; PV, polycythemia vera.
*Adapted from Arber, et al.⁷

 Prognostic analysis of ET employs two main risk stratification models¹

According to The International Prognostic Score for ET:

• Four factors are applied to calculate thrombosis risk: positive history of thrombosis (two points), presence of JAK2^V617F (two points), age >60 years (one point), and presence of cardiovascular risk (one point).
• Less than two points define low risk, two points define intermediate risk, and more than two points define high risk.

The more recent Revised International Prognostic Score for ET:

• Three factors are applied to calculate thrombotic risk: age, history of thrombosis, and presence of JAK2 mutation.
• Patients aged <60 years with no other factors are considered low risk, patients with either a history of thrombosis or a JAK2 mutation together with age >60 years are intermediate risk, and patients with all three factors are high risk.

Guidance on diagnosis may vary between countries (see key guidelines section).

Management²

• For most patients defined as low or very low risk, observation without therapeutic intervention is recommended; however, if any patients also present with cardiovascular risk, then low-dose aspirin is advised.
• The first-line of treatment for intermediate- and high-risk patients is hydroxyurea (HU).
  • This can be combined with aspirin if the patient has a positive history of thrombosis.
• For patients who become refractory or intolerant to HU, pegylated interferon alfa-2a is the preferred second-line treatment option.
• Anagrelide is an alternative second-line therapy; however, it is currently only recommended by European LeukemiaNet.
• Major drug classes/types of therapy and their cellular targets used in the treatment of ET are outlined in Figure 5.

*Adapted from Rumi and Cazzola. ⁸
ET, essential thrombocythemia.

• Treatment with aspirin is associated with a greater risk of bleeding, especially in patients diagnosed with ET.
• • Other more general side effects include gastrointestinal problems, such as abdominal pain and the development of stomach ulcers after long-term use.⁹
• HU treatment is associated with the development of anemia, leukopenia, and thrombocytopenia.
  • Treatment also increases the propensity for leukemic transformation.
• General adverse effects associated with interferon treatment include fever, fatigue, hair and weight loss, and flu-like symptoms.
• Anagrelide is typically well-tolerated by patients; however, common side effects include headache, diarrhea, fatigue, hair loss, and nausea.

Key Guidelines and organizations

• European LeukemiaNet
• Leukemia & Lymphoma Society
• World Health Organization
• MPN Research Foundation
• MPN Hub visual abstract on key updates to the 5th WHO Classification of MPN
• MPN Hub article on the International Consensus Classification 2022