Chapter 85: Essential Thrombocythemia

Essential thrombocythemia (ET), one of the myeloproliferative neoplasms (MPNs), is a clonal hematopoietic stem cell disorder characterized by thrombocytosis and associated with thrombotic and hemorrhagic complications. First recognized as a specific disease entity in 1934¹ and as a clonal disorder in 1981,² ET shares clinical and pathologic similarities with other MPNs, particularly polycythemia vera (PV) and primary myelofibrosis (PMF).

The annual incidence of ET is in the order of 1 to 2.5 per 100,000 per population and appears slightly more common in females.^3,4 Patients may present at any age, although ET is largely a disorder of later life with a peak incidence between the ages of 50 and 70 years. Presentation in childhood is rare but well recognized.

Little is known about the precise etiology of this disorder, although environmental factors such as exposure to radiation have been implicated in the genesis of other MPNs.⁵ Both registry data and kindred studies suggest a familial tendency to develop MPNs, including ET.^6,7 This predisposition appears to be explained in part by inheritance of a specific haplotype that contains the Janus family of tyrosine kinases type 2 (JAK2) gene.⁸

ET is characterized by hyperactive cytokine signaling which in 50 to 60 percent of cases is the result of somatic mutations targeting components of signaling pathways, including the JAK2 gene or the thrombopoietin receptor gene (MPL). Mutations in calreticulin gene (CALR) are present in the majority of JAK2/MPL–wild-type patients, leaving approximately 10 percent of ET patients without a mutation in any of these genes (JAK2/MPL/CALR–wild-type or “triple-negative” patients). A minority of ET patients also harbor mutations in transcriptional regulation pathways (Fig. 85–1).

A JAK2^V617F mutation is found in approximately 50 percent of patients with ET.⁹ JAK2, a cytoplasmic tyrosine kinase, forms a complex with and is essential for signaling by the erythropoietin and thrombopoietin receptors^10,11; JAK2 also contributes to signaling by the granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interferon-γ receptors.¹² Cytokine binding leads to a conformational change in the JAK2-receptor complex, with consequent activation of JAK2 kinase activity and recruitment of downstream signaling pathways.^10,13,14 The JAK2^V617F mutation alters a critical residue within the autoinhibitory pseudokinase (JH2) domain, resulting in increased JAK2 basal kinase and downstream signaling activity.¹⁵ The cellular consequences of mutant JAK2 expression include increased proliferation, cytokine hypersensitivity, cytokine-independent differentiation, and inhibition of apoptosis.⁹ The central role of JAK2 in erythropoiesis is highlighted by a JAK2 knockout mouse, which dies in midgestation from severe anemia.¹² In addition, mice engineered to express the JAK2^V617F allele recapitulate features of human ET or PV.¹⁶

Acquired mutations in MPL are found in 4 percent of ET patients, the majority of whom are JAK2–wild-type, and a similar proportion of those with PMF, but not in patients with PV.^17,18 These mutations alter residues in the juxtamembrane (MPL^W515) or transmembrane (MPL^S505N) regions and lead to constitutive activation of the receptor complex.^19,20 Expression of the MPL^W515L allele in a mouse model recapitulated features of human ET and PMF.²¹ Occasional patients with ET, as well as PV and PMF, harbor loss of function mutations in SH2B3 which encodes LNK, an important negative regulator of JAK/STAT (signal transducer and activator of transcription) signaling.²²

The majority of ET patients without a signaling pathway mutation harbor a somatic mutation in CALR (encoding calreticulin). CALR mutations are found in 15 to 35 percent of ET patients and a similar proportion of those with PMF but not in PV. Calreticulin is a key endoplasmic reticulum protein with calcium buffering and protein chaperone activity.²³ Although CALR-mutant patients generally lack mutations in JAK2 or MPL, they nonetheless show signaling pathway activation, suggesting an as yet undetermined role for CALR in cytokine signaling.^24,25,26

Mutations targeting pathways implicated in the control of gene transcription are found in a minority of patients with ET, as well as those with PV, PMF and other myeloid neoplasms (see Fig. 85–1B). These mutations, which may coexist with mutations in JAK2, MPL, or CALR, target genes involved in DNA methylation (TET2, IDH1/2, DNMT3A), histone modification (EZH2) or RNA splicing (SF3B1).²⁷ In addition to its roles in cytokine signaling, JAK2 has also been shown to translocate to the nucleus where it acts as a mediator of gene transcription through the direct modification of histone proteins. Whereas nuclear translocation of wild-type JAK2 appears to be activation-dependent, JAK2 harboring a V617F substitution shows nuclear localization in the absence of cytokine stimulation.^28,29

SYMPTOMS AND SIGNS

ET is often diagnosed following the incidental finding of a high platelet count, although a proportion of patients present with thrombotic or hemorrhage complications. A detailed clinical history and physical examination are necessary to exclude causes for a reactive thrombocytosis. Approximately 10 percent of ET patients have a mild degree of palpable splenomegaly at diagnosis,³⁰ although significant splenic enlargement should raise the possibility of another MPN such as PMF or chronic myeloid leukemia (CML).

THROMBOSIS

Thrombotic complications are the major source of morbidity and mortality in ET, with a prospective study indicating a cumulative incidence of 24 percent over 27 months for untreated high-risk patients.³¹ Arterial thrombosis predominates, affecting the central nervous system (stroke, transient ischemic attack) and cardiovascular system (myocardial infarction, unstable angina, peripheral arterial occlusion).^30,31 Erythromelalgia, a distinct clinicopathologic syndrome caused by occlusion of small blood vessels, is manifest by discomfort and burning sensations in the fingers or toes, sometimes accompanied by mottling or discoloration of the skin.³² Venous events mainly comprise deep vein thrombosis and pulmonary embolism. Involvement of unusual sites such as hepatic, portal or mesenteric veins also occurs and may precede the onset of clinically overt ET (Fig. 85–2A). In one series, half of all patients presenting with hepatic vein thrombosis and a normal blood count tested positive for the JAK2^V617F mutation, and a quarter of these subsequently developed a clinically overt MPN, most commonly ET.³³

The strongest predictive factors for thrombotic complications are older than 60 years of age or a history of previous thrombosis.³⁴ The platelet count and leucocyte count at diagnosis are poor predictors of thrombotic risk.³⁵ Meta-analysis confirmed detection of a JAK2^V617F mutation as a risk factor for both arterial and venous thrombosis.^36,37 Other reported risk factors include predisposition to cardiovascular disease or increased marrow fibrosis at diagnosis.³⁸

HEMORRHAGE

Serious bleeding is less common than thrombosis and mainly affects the nasal and buccal mucosa and the gastrointestinal tract, although central nervous system hemorrhage may occur.^30,31 ET patients often demonstrate prolongation of the bleeding time and various abnormalities of in vitro coagulation studies, including abnormal platelet aggregation or loss of large von Willebrand factor multimers; however, the relationship of these findings to episodes of clinical bleeding is unclear.³⁹ In a prospective study, rates of major hemorrhage were increased in patients with increased marrow fibrosis at diagnosis³⁸ and in those with an increased platelet or leucocyte count during followup.³⁵

MYELOFIBROTIC TRANSFORMATION

Evolution to myelofibrosis is seen in a proportion of ET patients, although the reported prevalence varies widely, reflecting differences in study design, therapeutic intervention and diagnostic criteria for post-ET myelofibrosis (Chap. 86). Retrospective studies suggest that disease duration is a major predictor of progressive disease, with rates of myelofibrosis in the first decade after diagnosis of 3 to 10 percent rising to 6 to 30 percent in the second decade.^34,40 The presence of marrow fibrosis at diagnosis also appears to presage progression to myelofibrosis,³⁸ although the predictive value of other histologic features of early stage PMF, such as megakaryocyte dysplasia, remains controversial.⁴¹ Mutations in JAK2,^42,43 MPL,^17,18 or CALR^44,45 appear to lack prognostic significance. A prospective study of high-risk ET patients indicated increased progression to myelofibrosis with anagrelide therapy, with a 5-year cumulative incidence of 7 percent for anagrelide plus aspirin versus 2 percent for hydroxyurea plus aspirin-treated patients.³⁰ The clinical consequences of post-ET myelofibrosis are similar to de novo myelofibrosis, and the conditions are managed in the same way.

LEUKEMIC TRANSFORMATION

Progression to acute myeloid leukemia (AML) occurs in a small minority of patients, with retrospective studies suggesting a prevalence of 1 to 2.5 percent in the first decade after diagnosis, 5 to 8 percent in the second decade, and continuing to rise thereafter.^34,40,46 Therapeutic heterogeneity in these studies, however, renders their findings difficult to interpret. Studies in PV demonstrated a significantly increased risk of AML in patients receiving genotoxic agents such as radioactive phosphorus, chlorambucil, or busulphan.^47,48 The potential leukemogenicity of hydroxyurea remains controversial (see “Choice of Cytoreductive Agent” below). Importantly, transformation to leukemia has been reported in the absence of any cytoreductive therapy,^49,50 indicating that AML is part of the natural history of this disorder.

Therapy of post-ET AML is often limited by the older age of the affected patients, in whom palliative treatment may be the most appropriate strategy. Overall the prognosis of secondary AML is poor (Chap. 88). Younger patients who do achieve remission with AML induction therapy may be considered for allogeneic hematopoietic stem cell transplantation.

An unexplained and persistently raised platelet count generally warrants further investigation (Fig. 85–3). Establishing a diagnosis of ET requires exclusion of both reactive conditions and other myeloproliferative or myelodysplastic disorders that may present with an isolated thrombocytosis (Tables 85–1 and 85–2).

HEMATOLOGIC AND BIOCHEMICAL PARAMETERS

An elevated platelet count is invariably present and may be only slightly increased (e.g., ≥ 400 × 10⁹/L) or massively elevated into the millions × 10⁹/L. Thus, the degree of thrombocytosis varies markedly between patients. The white count may be slightly to mildly elevated but usually not above 20 × 10⁹/L as a result of neutrophilia. The hemoglobin concentration may be normal or mildly reduced. If occult bleeding has been present, the hemoglobin may be further decreased and indications of iron deficiency may be evident in the red cells (microcytosis and hypochromia; see “Differential Diagnosis” below). Examination of the blood film often reveals large platelets which may stain poorly, and is useful in excluding features of PMF such as teardrop cells (dacryocytes) or circulating immature granulocyte precursors.

SERUM CHEMICAL FINDINGS

Levels of thrombopoietin are normal or slightly elevated in ET and have no diagnostic utility. ET patients may show a spurious increase in serum potassium level as a result of in vitro activation of platelets and leukocytes during processing of serum; this phenomenon can be circumvented by using a plasma sample for biochemical analysis.

MOLECULAR TESTING

Molecular testing for genetic mutations has become the investigation of choice for patients with an unexplained and persistent increase in platelet count (see Fig. 85–3). A reasonable approach is to screen all patients for the JAK2^V617F mutation, following by screening for mutations in CALR and uncommon MPL in negative cases. Suitable techniques include allele-specific or real-time polymerase chain reaction (PCR) for JAK2^V617F, pyrosequencing or high-resolution melt curve analysis for MPL, and fragment length analysis for CALR exon 9.^25,51 In the absence of marrow cytogenetic analysis, molecular testing for the BCR-ABL1 fusion gene is also recommended to exclude CML. Screening for additional mutations (e.g., TET2) is currently of uncertain utility in routine clinical practice.

MARROW STUDIES

Marrow aspiration and trephine biopsy is particularly recommended in suspected cases of ET that are negative for a relevant somatic mutation. Marrow studies may also be useful in cases showing atypical clinical or laboratory features (for example, palpable splenomegaly, unexplained anemia or blood film abnormalities) or in the context of a clinical study. The marrow aspirate in ET often shows large hyperlobulated megakaryocytes (see Fig. 85–2B), and iron staining may be helpful in excluding iron deficiency or the presence of ringed sideroblasts (see “Differential Diagnosis” below). The marrow trephine biopsy typically shows an increase in megakaryocyte frequency with megakaryocyte clustering and nuclear hyperlobulation in the absence of significant reticulin fibrosis (see Fig. 85–2C). Cellularity is usually normal or slightly increased, but occasional cases may show a hypocellular marrow, for example, a proportion of those with mutations in MPL.^17,18

Chromosomal analysis, by G-banding or in situ fluorescent hybridization, is helpful in suspected cases of ET lacking a relevant somatic mutation, primarily to exclude lesions associated with other myeloid disorders such as t(9:22) (CML) or deletions of chromosome 5q (“5q-minus syndrome”; Chap. 87). Other karyotypic abnormalities, mainly comprising deletions of chromosomes 20q or 13q or additional copies of chromosomes 8 or 9, are found in approximately 5 percent of ET patients and establish the existence of clonal hematopoiesis.

REACTIVE THROMBOCYTOSIS

A secondary increase in platelet count, initiated by cytokines such as interleukin-6 and directly driven by the induction of hepatic thrombopoietin production is associated with a number of infectious, inflammatory and malignant disorders (see Table 85–2; Chap. 119). In reports of unselected patients attending various hospital departments, an increased platelet count was attributable to reactive causes in more than 80 percent of cases; the degree of thrombocytosis did not permit distinction between a clonal versus a reactive pathogenesis.^52,53

FAMILIAL THROMBOCYTOSIS

Familial thrombocytosis is a rare disorder caused by mutations in the thrombopoietin gene, MPL, or other unknown genes. Changes in the 5´-untranslated region or splice donor/acceptor sites of the thrombopoietin gene are associated with increased translation of thrombopoietin and consequent thrombocytosis.⁵⁴ These alleles are dominantly inherited and have not been seen in clonal MPNs.⁵⁵ A dominantly inherited, activating MPL allele (MPL^S505N) has been reported in Japanese and Italian kindreds.⁵⁴ Of interest, this allele has also been reported as a somatic mutation in patients with a clonal MPN.¹⁷ Several different inherited JAK2 alleles have been reported in families with autosomal dominant thrombocytosis (including JAK2^R564Q, JAK2^V617I, JAK2^R867Q, and JAK2^S755R/R938Q).^56,57 Although complicated by occasional thrombotic or bleeding episodes, the clinical phenotype of familial thrombocytosis is relatively mild, although exceptions occur.⁵⁴ The genetic cause underlying a subset of familial cases remains to be elucidated.

POLYCYTHEMIA VERA

PV (Chap. 84) is often associated with thrombocytosis, and may present with a normal hemoglobin level in the presence of iron depletion, mimicking ET, although in such cases the mean corpuscular volume is usually decreased. In addition, ET and PV form a phenotypic spectrum, resulting in diagnostic difficulties in a subset of patients. There are inherent limitations to the utility of continuous variables, such as hematocrit, to make this distinction, as the group of patients with intermediate values will inevitably include both disorders (Fig. 85–4). Controversy persists over how to best distinguish these two conditions.⁵⁸

PRIMARY MYELOFIBROSIS

PMF may present with an isolated thrombocytosis, but palpable splenomegaly, circulating teardrop red cells and progenitor cells, and marrow fibrosis are usually present (Chap. 86). An area of ongoing controversy relates to the 15 to 20 percent of ET patients who harbor distinct marrow morphology, coined prefibrotic PMF, at diagnosis in the absence of other features to indicate PMF. Although such patients have higher rates of myelofibrotic transformation, thrombosis, and hemorrhage, their overall survival is not different from other patients with ET.⁵⁹ A second area of controversy relates to the suggestion that marrow trephine appearances can distinguish ET and prefibrotic PMF from the early stages of PMF⁶⁰; however, the reproducibility and clinical utility of this distinction is unclear.^41,58

CHRONIC MYELOID LEUKEMIA

Occasional patients with CML present with an isolated thrombocytosis. Such cases are predominantly female with absent or minimal splenomegaly and a normal or marginally elevated white cell count, often without basophilia or circulating myeloid progenitors.⁶¹ Marrow studies, however, are usually informative, showing small hypolobulated megakaryocytes typical of CML, and not the large hyperlobulated forms observed in ET. Given the significant impact of tyrosine kinase inhibitors on the prognosis of CML, it is important that this unusual presentation is not overlooked. It is therefore recommended that suspected cases of ET that are negative for a relevant somatic mutation undergo molecular analysis of blood for the BCR-ABL1 fusion gene. Marrow aspiration, biopsy and G-banding cytogenetic analysis, may be useful in a specific case.

MYELODYSPLASIA

Thrombocytosis, usually in association with anemia, may be seen in the myelodysplastic disorder associated with an isolated deletion of chromosome 5q (“5q-minus syndrome”). Although often increased in number, the megakaryocytes are generally small and hypolobulated,⁶⁰ in contrast to the large hyperlobulated forms typical of ET. A raised platelet count is also a feature of refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T), and may be associated with thrombotic complications. Approximately half of patients with RARS-T harbor a JAK2^V617F mutation or, rarely, a mutation in MPL.

PATHOGENETIC RELATIONSHIP OF ESSENTIAL THROMBOCYTHEMIA TO OTHER MYELOPROLIFERATIVE NEOPLASMS

Polycythemia Vera

The same JAK2^V617F mutation is present in the vast majority of patients with PV (Chap. 84) and in approximately half of those with ET, raising questions as to how a single mutation is commonly associated with apparently distinct clinical phenotypes. Clones that are homozygous for the JAK2^V617F mutation (arising by a mitotic recombination event termed uniparental disomy; Fig. 85–5) are larger and more frequent in patients with PV compared with ET,^62,63 suggesting a role for increased JAK2-STAT5 signaling in driving erythrocytosis. In support of this hypothesis, in both mouse and human model systems strong JAK2-STAT5 activation drives erythropoiesis whereas weaker activation favors a megakaryopoiesis.^16,64,65 Other contributing factors include the effects of patient gender⁶³ and modulation of STAT1 signaling.⁶⁶

Myelofibrosis and Accelerated Phase Disease

A proportion of patients diagnosed with ET experience progression to an accelerated phase characterized by increasingly disordered hematopoiesis. The phenotypic manifestations are variable and include hyperproliferation, myelodysplasia, or, most commonly, myelofibrosis. Myelofibrotic transformation of ET, characterized by marrow fibrosis, extramedullary hematopoiesis and marrow failure, is clinically indistinguishable from PMF (Chap. 86), suggesting PMF may represent presentation with accelerated phase disease. Consistent with this, patients with PMF may have thrombocytosis for many years prior to diagnosis, suggestive of undiagnosed ET.⁵⁸

The prevalence of mutations in JAK2, CALR, or MPL is similar in ET compared to myelofibrosis; however, karyotypic abnormalities are present in up to 50 percent of myelofibrosis patients (Chap. 86) compared to only approximately 5 percent of patients in ET, indicating a greater degree of genetic instability. In addition, mutations in genes implicated in transcriptional regulation (including ASXL1, IDH1/2, and EZH2) appear more common in patients with PMF compared with ET. Together, these findings suggest that progression to advanced phase disease arises through a process of clonal evolution driven by the acquisition of additional genetic events or epigenetic alterations; to date, however, no combination of genetic events has been shown to reliably distinguish ET from PMF. Constitutive activation of JAK2 has been implicated as a driver of clonal progression, as expression of mutant JAK2 leads to the accumulation of reactive oxygen species, increased DNA damage, and aberrant DNA repair.^67,68,69,70

Blastic Phase Disease

For a minority of patients with ET, their disease terminates in AML, also referred to as blastic phase. In some patients, the disease phenotype shows a stepwise transition from ET to PMF to AML, thus mimicking the triphasic disease pattern of CML observed in the preimatinib era (Chap. 89). In other cases, AML arises directly following ET.⁷¹

The mutational profile of blastic phase disease shares some similarities with de novo AML. Mutations in transcriptional control pathways (including TET2, ASXL1, EZH2, and IDH1) are more common in blastic phase than in the early disease phases. In addition, mutations are seen in DNA repair and cellular differentiation pathways (including TP53, RUNX1, and IKZF1) which are rarely mutated in early stage MPNs. In contrast to de novo AML, balanced chromosomal translocations are rare in post-MPN AML.^72,73,74 Of note, patients with JAK2^V617F-positive ET may develop AML that is negative for the JAK2 mutation.^49,71

MODIFICATION OF CARDIOVASCULAR RISK FACTORS

Established risk factors for cardiovascular disease, such as hypertension, diabetes, smoking, hypercholesterolemia, and obesity, should be identified and treated appropriately. The broad efficacy of the cholesterol-­lowering statin drugs in the prevention of atherosclerotic disease has raised the possibility that such agents may be useful in ET, although this has yet to be tested in a prospective study.

ANTIPLATELET THERAPY

A large randomized trial in PV demonstrated a reduction in thrombotic events in those taking low-dose aspirin (100 mg daily) without a concomitant increase in the risk of hemorrhage.⁷⁵ Although retrospective studies have suggested a similar protective effect in ET,³² prospective trials have not been performed. Based on current evidence, aspirin is recommended for all ET patients unless contraindicated. Although there are few data concerning the use of newer antiplatelet agents such as clopidogrel in ET, their proven track record in preventing complications of atherosclerotic disease suggests they may be appropriate for patients unable to tolerate aspirin.

CYTOREDUCTIVE THERAPY

Indications to Treat

A prospective randomized trial demonstrated a clear role for cytoreductive therapy with hydroxyurea in reducing thrombotic events in high-risk ET patients (age >60 years or history of prior thrombosis), approximately 70 percent of whom were also receiving antiplatelet agents.³¹ Although retrospective studies suggest that thrombotic complications in those younger than 60 years of age without additional risk factors may be no higher than controls, prospective data are lacking. Patients with ET are currently stratified on the basis of their risk of thrombotic complications (Table 85–3), with cytoreductive therapy likely to benefit high-risk patients. Patients without high-risk features can be divided into low risk (age less than 40 years) and intermediate risk (age 40 to 60 years). Cytoreductive therapy is unlikely to offer a significant protective effect for those with low-risk disease, in whom the a priori risk of thrombosis is small. There is currently little evidence available to guide treatment decisions in the intermediate-risk group. The ongoing PT-1 trials (http://www.haem.cam.ac.uk/primary-thrombocythaemia/), comprising a randomized trial of hydroxyurea and aspirin versus aspirin alone for intermediate-risk patients and an observational study of low-risk patients treated with aspirin alone, will provide prospective data to help clarify therapeutic decisions for these patients. Although the degree of thrombocytosis is not a reliable indicator of thrombotic risk, many physicians consider cytoreductive therapy in patients with a very high platelet count (e.g., greater than 1500 × 10⁹/L).

Once cytoreductive therapy is instituted, dose adjustment is recommended to keep the platelet and leucocyte counts within the normal range.³⁵

Choice of Cytoreductive Agent

Choices of first and second line therapies for patients with ET are summarized in Table 85–4) (Table 85–4). Hydroxyurea, a ribonucleotide reductase inhibitor also known as hydroxycarbamide, is widely regarded as first-line therapy for patients requiring treatment, and is the only cytoreductive agent proven to reduce thrombotic events in a randomized controlled trial.³¹ Major complications of this drug include reversible myelosuppression and ulceration of the buccal mucosa or lower leg. Although hydroxyurea appears nonleukemogenic when used to treat sickle cell disease,⁷⁶ controversy remains about potential leukemogenicity in the MPNs. Some studies suggest an increased risk of acute leukemia in hydroxyurea-treated ET patients,^77,78 but others have failed to observe this association.^79,80 Problems with these studies include small patient numbers, inclusion of patients who have received multiple cytotoxic agents, lack of proper controls, retrospective data collection, and relatively short followup. Of note, analysis of blood cells from sickle cell and MPN patients receiving hydroxyurea showed equivalent rates of DNA mutations to normal controls, suggesting that the mutagenic potential of hydroxyurea is low.⁸¹ At present it is not clear whether hydroxyurea used as a single agent is associated with an increased risk of acute leukemia; however, any increased risk is likely to be small and should be balanced against the reduction in thrombotic complications.

Anagrelide, a quinazoline derivative, reduces the platelet count by inhibition of megakaryocyte differentiation. Although the white cell count is unaffected, anemia is common and often progressive.³⁸ Up to a third of patients cannot tolerate anagrelide because of side effects, many of which result from its vasodilatory and positive inotropic actions including palpitations and arrhythmias, fluid retention, heart failure and headaches. Use of this drug requires particular caution in elderly patients or those with preexisting cardiac disease. Although anagrelide is not cytotoxic, and therefore unlikely to be leukemogenic, the PT-1 randomized trial demonstrated that anagrelide plus aspirin was inferior to hydroxyurea plus aspirin in high-risk ET patients. In this study, anagrelide-­treated patients experienced reduced event-free survival (p = 0.03) with higher rates of arterial thrombosis (p = 0.004), major hemorrhage (p = 0.008) and progression to myelofibrosis (p = 0.01), despite equivalent control of the platelet count, although rates of venous thrombosis were decreased (p = 0.006).³⁰ In contrast to hydroxyurea, anagrelide therapy was also associated with an increase in marrow reticulin over time.³⁸ Comparison of patients in the PT-1 (comparison of hydroxyurea versus anagrelide) and Italian (comparison of hydroxyurea versus no cytoreductive therapy) prospective studies suggests that anagrelide does provide partial protection from thrombosis,⁸² and therefore may be suitable as second-line therapy for patients in whom hydroxyurea therapy is inadequate or not tolerated. It has been suggested that the results of the ANAHYDRET trial (comparing hydroxyurea to anagrelide) show that anagrelide is not inferior to hydroxyurea in the treatment of ET.⁸³ However, the number of patients enrolled, duration of followup, and primary end points recorded were relatively small (Table 85–5) and as such this trial was not powered to see the differences observed in the PT-1 study. In addition, the ethical basis for performing noninferiority trials may be questioned.⁸⁴

Recombinant interferon-α is effective at controlling the platelet count in ET, although there is little direct evidence of efficacy in prevention of thrombosis. Treatment is often associated with significant side effects, including flu-like symptoms and psychiatric disturbance that may mandate cessation of therapy. As this agent is free from leukemogenic or teratogenic effects,⁸⁵ interferon-α is often used for younger patients or during conception and pregnancy. The adverse side-effect profile, however, means that it is generally avoided in older patients. Pegylated interferon-α, for which less-frequent administration is required, may be more convenient but the side-effect profile appears similar to the native compound.

Radioactive phosphorus and alkylating agents such as busulphan are effective at controlling the platelet count, but are associated with an increased risk of progression to acute leukemia, particularly when used sequentially with hydroxyurea, and thus should be avoided in younger patients. Both radioactive phosphorus and busulphan can be given intermittently with long intervals between doses, and may be useful in treating older patients who are unable to attend the clinic on a regular basis. Pipobroman, a piperazine derivative, is effective at reducing the platelet count in ET, although there is little direct evidence for efficacy in thrombosis prevention. However, studies of patients with PV have indicated that long-term use of this agent is associated with an increased risk of developing leukemia.^80,86

The identification of mutations in JAK2 and studies highlighting a central role for increased JAK2 activity in the pathogenesis of the MPNs have driven the rapid development of targeted JAK2 inhibitors (e.g., ruxolitinib). Randomized trials indicate a role for these agents in relieving symptoms and possibly prolonging survival in patients with PMF.^87,88 Although early phase clinical trials have demonstrated efficacy in reducing the platelet count in patients with ET, their place in routine management has yet to be defined.

SPECIAL CONSIDERATIONS

Conception and Pregnancy

First trimester fetal loss complicates up to 50 percent of pregnancies in ET patients, with other complications such as intrauterine growth retardation, stillbirth, and preeclampsia also occurring more frequently. Such complications occur irrespective of the platelet count prior to conception but may be more prominent in those with JAK2^V617F-positive disease. Whether the use of aspirin or cytoreductive agents can improve pregnancy outcome is uncertain, with studies reporting contradictory results.⁸⁹ However, a large meta-analysis of preeclampsia patients without ET suggested that aspirin use in pregnancy is safe for both mother and fetus,⁹⁰ and it therefore seems reasonable to consider its use for all pregnant ET patients. Although hydroxyurea has been used during pregnancy, usually without adverse effects for mother or fetus, it is teratogenic in various non-human mammals⁹¹ and should be avoided if possible. Anagrelide can cross the placenta with unknown effects on fetal development and should also be avoided. Interferon-α is nonteratogenic⁸⁵ and is the agent of choice for patients with high-risk disease should cytoreductive therapy be required during pregnancy. Although studies in ET patients are lacking, thromboprophylaxis appears safe in pregnancy (e.g., with low doses of low-molecular-weight heparin),⁹² and may be considered for patients with a history of thrombosis or pregnancy loss; in those with prior thrombosis, treatment should be continued for 6 weeks postpartum. Pregnant ET patients should ideally be managed in a center where regular fetal monitoring can be performed, with good communication between the obstetric, hematology, and anesthetic departments. Pregnancy does not appear to affect the natural history of the disease, although the platelet count often falls during gestation. In animal studies, hydroxyurea is associated with reduced spermatogenesis and genetic damage to spermatogonia.⁹¹ Male patients requiring cytoreductive treatment should therefore consider interferon-α therapy prior to attempted conception.

Surgery

Although thrombotic and bleeding complications appear increased in ET patients undergoing surgical procedures, it is not clear whether these risks can be ameliorated by specific therapeutic interventions. In general, antiplatelet agents should be stopped 7 to 10 days prior to major surgery or surgery to critical sites, and recommenced as soon as the surgeon is confident of secure hemostasis. Postoperative thromboprophylaxis should be administered according to local protocols. For patients receiving cytoreductive therapy, control of blood counts should be optimized preoperatively and interruptions in therapy kept to a minimum. For patients not receiving treatment, temporary cytoreductive therapy may be considered on a case-by-case basis, taking into account the individual’s thrombotic risk profile, the degree of thrombocytosis, and the nature of the surgery.

Splenectomy in ET patients generally results in an increase in the platelet count and also in increased thrombotic and hemorrhagic complications. Normalization of the platelet count is therefore advisable for all ET patients prior to elective splenectomy. Thromboprophylaxis and daily monitoring of bloods counts is recommended during the postoperative period.

There is a lack of good quality prospective data concerning long-term survival in ET. Data from cancer registries and retrospective studies indicate that overall survival is reduced compared with population controls.^93,94,95 This excess mortality results from disease complications such as thrombosis and transformation to PMF or AML. However, management paradigms have changed significantly over the last 10 to 20 years, including more aggressive intervention to prevent thrombosis and decreasing use of leukemogenic agents. These changes, which may be related to observed improvements in patient outcomes in recent years,⁹⁴ render some long-term followup studies difficult to interpret.

A number of predictive factors for thrombotic complications have been identified (Table 85–6), the best established of which are age older than 60 years or a history of previous thrombosis. Factors independently associated with decreased overall survival in ET include history of prior thrombosis, anemia and leukocytosis,⁹³ the latter two factors likely representing markers of more advanced disease. Additional factors associated with an increased risk of thrombosis include predisposition to atherosclerotic disease (diabetes, hypertension, hypercholesterolemia, or tobacco use), presence of a JAK2^V617F mutation or increased marrow fibrosis at diagnosis (see section “Thrombosis”). At the present time, age older than 60 years or history of previous thrombosis are generally considered to mandate cytoreductive therapy in ET patients. Whether additional factors, such as presence of a JAK2 mutation, can be used to improve patient stratification is yet to be tested formally in a clinical trial.

In contrast to thrombotic complications, there are few identifiable factors that predict for progression to PMF or acute leukemia. The incidence of both complications increases progressively with disease duration. Choice of therapy also plays a role, with anagrelide increasing the risk of myelofibrotic transformation compared to hydroxyurea³⁰ and genotoxic agents increasing the risk of leukemia, especially when used sequentially with hydroxyurea. Marrow fibrosis at diagnosis was associated with an increased risk of subsequent PMF in a prospective study,³⁸ but other markers, including the presence of different somatic mutations, have failed to show a consistent association with either myelofibrotic or leukemic transformation.