Essential thrombocythemia D47.3

Essential thrombocythemia" (ET), also called primary thrombocythemia, belongs to the chronic myeloproliferative neoplasms (MPN) along with primary myelofibrosis (PMF) and polycythaemia vera (PV). It is characterized by increased proliferation of the megakaryocytic cell line. The leading finding is a constant and usually slowly progressive increase in the peripheral platelet count. In the bone marrow, the megakaryocytes are greatly increased, often markedly enlarged. They are stored in loose groups. The nuclei are hyperlobulated or have deer antler-like changes.

ET is a disease of the hematopoietic stem cell. It is characterized by a cytokine-independent increase in megakaryopoiesis in the bone marrow and by the increased release of platelets into the peripheral blood. Due to the possibility of disease-associated gene mutations(driver mutations), several molecular subtypes with prognostic relevance and different therapeutic approaches can be distinguished. It can be assumed that the driver mutations are already acquired in childhood. This means that the latency until the onset of MPN can be several decades (Williams N et al. 2020).

The most common genetic aberration is the JAK2V617F(Janus kinase 2 - in 50 - 60%) mutation, followed by CALR(Calreticulin -in 30 - 35%) and Thrombopoietin receptor(MPL in 3%) mutations (Tefferi A et al. 2018). The overlap of genetic aberrations in the different entities of "chronic myeloproliferative neoplasms (MPN)" confirms the pathogenetic and clinical relatedness of these diseases. In individual patients, JAK2 (e.g. R683G) or MPL mutations (e.g.S204P) are found outside the hotspots (Grinfield J et al. 2018).

In 10-12% of ET patients, none of the three mutations (JAK2, CALR, MPL) can be detected(triple negative).

In addition to the diagnostically relevant "driver" mutations, other mutations may be associated with essential thrombocythemia: these involve the genes TP53, ASXL1, IDH1/2, RAS, EZH2, PPM1D, among others. They may affect individual prognosis but are not MPN specific (they are found in a whole range of myeloid neoplasms (Grinfield J et al 2018).

In addition to the laboratory pathologies, microcirculatory disorders in the area of the fingers and toes (erythromelalgia) or the brain (visual or speech disorders, dizziness, migraine) are characteristic of ET. ET may progress to myelofibrosis (post-ET MF). The percentage is probably very low in so-called true (histologically confirmed) ET. In individual JAK2-positive patients, ET progresses to polycythaemia vera. The first sign is the slow increase in hematocrit during regular blood count checks. At the same time, some patients report the first occurrence of the aquagenic pruritustypical of PV.

The transition of ET into MDS/acute leukemia is rare. Since drug therapies such as hydroxyurea or busulfan may increase the risk of transition, they should be used with caution (Lengfelder E et al.2007).

The most common and most feared complication of ET is thrombosis in the venous and arterial systems. Arterial: mainly occlusion of the coronary arteries (myocardial infarction) and of the arteries supplying the brain (stroke).

Venous: venous thrombosis of the lower extremities; also venous thrombosis of the large vessels of the upper abdomen (portal, hepatic, splenic, mesenteric veins) and cerebral thrombosis (e.g. sinus vein thrombosis. Concurrent hemorrhagic complications are possible (due to secondary von Willebrand factor deficiency).

ET and skin:

PVmay be associated with aquagenic pruritus.

After exclusion of a secondary thrombocythaemia, a molecular genetic mutation analysis is carried out (examination of a JAK2V617F mutation; if present, an MPN is proven to be the cause of the thrombocyte increase; if not proven, examination of a calreticulin mutation; if negative, examination of an MPLW515K/L.). If these are also not present, exclusion of CML (which in rare cases may initially manifest as thrombocythaemia) by checking the bcr-abl oncogene.

Since JAK2-, CALR- or MPL-positive thrombocythaemia may be due to ET, but also to myelofibrosis, the subsequent bone marrow aspiration is used for the differential diagnosis of essential thrombocythaemia, prefibrotic myelofibrosis and myelofibrosis in the fibrotic stage. In the peripheral blood smear, the platelets are morphologically altered in over 90% of patients, i.e. enlarged and of varying size.

The leading finding is the constant and often slowly progressive increase in the peripheral platelet count.

Bone marrow: marked proliferation of megakaryocytes; these are often markedly enlarged with hyperlobulated or staghorn-like nuclei; they are stored in loose groups.

The diagnosis of ET is made on the basis of the current WHO criteria (2016), supplemented by the new molecular genetic results (Arber DA et al.2016).

WHO criteria for the diagnosis of essential thrombocythaemia (Arber DA et al.2016).

Main criteria:

• Sustained platelet count > 450,000/µl.
• Bone marrow histology: Proliferation mainly of megakaryocyte lineage with increased numbers of enlarged mature hyperlobulated megakaryocytes. No significant increase or left shift in granulopoiesis or erythropoiesis. No or slight increase (grade 0-1) in reticulin fibers.
• WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, or other myeloid neoplasms are not met.
• Evidence of a JAK2V617F, calreticulin, or MPL mutation.

Ancillary Criteria:

• Presence of another clonal marker
• No evidence of reactive thrombocytosis

The diagnosis of ET requires all 4 major criteria or the first 3 major criteria and 1 minor criterion.

When clarifying a persistent platelet elevation, first exclude inflammation- or iron deficiency-related secondary thrombocytosis by determining CRP and ferritin levels.

Molecular genetic differentiation of ET from prefibrotic myelofibrosis (Patients with ET have a near-normal life expectancy; they have fewer transformations to myelofibrosis or MDS or AML and a lower bleeding tendency with acetylsalicylic acid (ASA) than patients with prefibrotic myelofibrosis (Barbui T et al (2012). Other MPNs should also be included in the differential diagnosis, especially PV (measurement of erythropoietin levels, bone marrow histology) or the rare entity MDS/MPN with ring sideroblasts and thrombocytosis (previously called refractory anemia with ring sideroblasts and thrombocytosis (RARS-T)) if JAK2 positive.

In 'triple' negative RT cases, exclude rarer forms of myeloid neoplasms (e.g. MPN unclassifiable, myelodysplastic/myeloproliferative neoplasm unclassifiable, mastocytosis and others). Furthermore, also reactive blood count changes.

A curative therapy is not yet available. The choice of treatment for ET is always a compromise between the reduction of ET-related symptoms or complications (primary or secondary prophylaxis) on the one hand and the occurrence of drug-related side effects on the other. Due to the very different individual clinical course, treatment is based on the presence of risk factors.

In principle, a distinction is made between anti-aggregating and cytoreductive therapy:

• Anti-aggregating treatment with ASS (50-100 mg/day)
• Cytoreductive treatment with hydroxyurea (inhibition of the formation of platelets, erythrocytes and granulocytes)

Platelet-reducing treatment with anagrelide (inhibition of platelet formation)

Cytoreductive treatment with pegylated interferon-alpha (off label)

Anti-aggregant therapy is indicated for microcirculatory disorders. Subgroups of ET patients may benefit from therapy with ASA for prophylaxis of thrombosis.

Cytoreductive therapy aims to reduce the platelet count below 400,000/µl. With all forms of therapy, long-term therapy is usually required. The dosage is adjusted according to the individual.

Platelet aggregation inhibitors: ASA in a dosage of 50 to 100 mg/day in the presence of microcirculatory disorders such as erythromelalgia, visual disturbances, etc. Contraindications to aspirin therapy are a hemorrhagic diathesis or a history of gastrointestinal ulcer disease.

Aspirin is not recommended for very high platelet counts (> 1,000,000/µl to 1,500,000/µl or higher) because the frequently observed loss of high molecular weight von Willebrand factor multimers may lead to an increased bleeding tendency. The vWF deficiency is quantified by determining the ristocetin cofactor or vWF activity. Aspirin should not be taken below a level of 30%.

Risk- and age-adapted cytoreductive therapy options.

High-risk ET: In high-risk patients, there is an indication for cytoreductive treatment. Hydroxyurea is approved as first-line therapy (initial dose of 20 mg/kg bw; maximum dose of 40 mg/kg bw). Therapy-induced anemia and/or leukocytopenia may be limiting factors.

Alternative: various anagrelide preparations. Anagrelide preparations in a daily dosage of 0.5 to 2.0 mg. Anagrelide has been used for the treatment of ET for 30 years. Side effect rate (headache, palpitations) is limited.

Pat < 60 years: rather cautious therapy regime (under hydroxyurea treatment potential increase of risk of secondary leukemia or other neoplasms (e.g. basal cell carcinoma, keratoacanthoma, squamous cell carcinoma). Use of non-leukaemogenic agents such as anagrelide or interferon-alpha.

Pat: <40years (about 20% of ET patients): characterized by frequently higher platelet counts, more pronounced splenomegaly, more frequent calreticulin mutations and fewer arterial complications (Szuber N et al. 2018). There is a tendency for venous thrombosis in unusual locations (Budd-Chiari syndrome, mesenteric vein thrombosis, cerebral vein thrombosis) in this cohort (Ianotto JC et al 2019).

Interferon-alpha: Interferon-alpha is also cytoreductive and has been used for many years in ET. Pegylated interferon-alpha is preferable to conventional interferon-alpha in terms of its spectrum of side effects and efficacy. Interferon-alpha is not approved for the treatment of ET and can only be used in 'off label use'.

Ruxolitinib: The JAK-2 inhibitor ruxolitinib is not approved for the treatment of ET. Currently used in trial protocols.

Low-risk ET: In low-risk patients with ET, an increased risk of thromboembolic complications with 2 events per 100 patient-years has not been proven. The benefit of cytoreductive therapy or ASA use is not established. Wait-and-watch therapy is recommended.

Intermediate-risk ET: In the absence of contraindications, the use of low-dose ASA is recommended.

In order to determine an adequate treatment strategy for the individual patient, a risk stratification is first performed. Risk factors (one point for each risk factor) for the occurrence of thromboembolic and hemorrhagic complications are currently considered according to the conventional risk score used in several ET studies:

• History of known thromboembolic complications or major bleeding.
• Age greater than 60 years (there is discussion of raising the age to 65 years, i.e., taking more account of biological age)
• Platelet counts higher than 1,500,000/µl

High-risk patients are considered ET patients with at least one of the 3 factors mentioned (age over 60 years, thromboembolic or severe bleeding complications, platelet count >1,500,000/µl). Patients are considered low-risk if none of these risk factors are present (with the exception of microcirculatory disorders).

In addition, intermediate-risk patients are defined as those who cannot be assigned to the high-risk group but have other vascular risk factors (arterial hypertension, diabetes mellitus, hypercholesterolemia, nicotinic abuse, positive thrombophilia markers). Molecular characterization of MPN (including ET) over the past years shows that molecular parameters can influence clinical presentation and prognosis. For example, in ET, CALR-positive patients generally have higher platelet counts but lower risk of thrombosis than JAK2V617F-positive patients (Nangalia J et al.2013). Genetic factors (somatic mutations) that may adversely affect survival of patients with ET include SH2B3, SRSF2, U2AF1, TP53, IDH2, and EZH2.

Clinical (questioning of the patient regarding ET-specific symptoms) and laboratory examinations, complete blood count: intervals depend on the form of therapy and the phase of therapy as well as the individual course of the disease. In the initial phase of therapy, short-term, every 1-2 weeks; after reaching a stable phase, usually between 4 and 12 weeks.

Later, semi-annual checks of the clinical status and laboratory findings (including blood smear morphology), taking into account expected therapy side effects and complications of the disease.

Annual ultrasound examination of the abdomen (with measurement of the spleen in 3 planes for spleen volume determination).

Bone marrow progression examinations to detect the rare transitions to acute leukaemia or myelofibrosis are based on the individual course (blood count, spleen size). They are useful if acceleration of the disease course is suspected.

SARS-COV2: A current problem concerns SARS-COV2 (corona infection) in the concomitant presence of an MPN: according to the data of a retrospective study, ET patients have the highest risk of thrombosis among MPN patients if they suffer a COVID infection (Barbui T et al.(2021).

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