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How to Manage…

How to manage essential thrombocythemia

Abstract

I use the hematological, morphological and molecular criteria recently established by the World Health Organization to diagnose essential thrombocytemia. In these patients, major causes of morbidity and mortality are represented by thrombosis and bleeding, whereas progression to myelofibrosis and transformation to acute leukemia are more rare. Myelosuppressive therapy can reduce the rate of vascular complications, but there is some concern about treatment-related toxicity. Therefore, I follow a risk-oriented therapeutic approach to avoid inappropriate exposure to cytotoxic drugs on one side or suboptimal treatment on the other. Established predictors of cardiovascular events are represented by older age and previous thrombosis, whereas recent data suggest a prognostic role for novel risk factors, including leukocytosis and JAK2V617F mutational status. There is no indication for therapeutic intervention in asymptomatic, low-risk patients, while I treat high-risk patients with hydroxyurea (HU) first. Other therapeutic options, such as interferon alpha or anagrelide, may find place in selected patients including those who are resistant or intolerant to HU. I follow a risk-oriented approach also for management of pregnancy. Low-risk women are given low-dose aspirin throughout pregnancy and prophylactic low-molecular-weight heparin (LMWH) post partum, whereas LMWH throughout pregnancy and/or interferon-alpha can be required in high-risk cases.

Main

Among the chronic myeloproliferative neoplasms (MPN), essential thrombocythemia (ET) is characterized by longer median survival as well as lower transformation rates into acute leukemia or post-ET myelofibrosis.1 The clinical course is marked by thrombotic and hemorrhagic episodes that occur more frequently in older patients and those with previous vascular events.2 Recent advances in our understanding of molecular pathogenesis3 and histological features4 of this disease contributed to better define diagnostic criteria and risk factors for overall survival as well as for vascular and bleeding complications. A small number of randomized clinical trials showed that cytoreductive agents, particularly hydroxyurea (HU), are able to control the myeloproliferation and avoid vascular complications. However, short and long-term side effects of these drugs should be borne in mind. Hence, the best strategy is to limit the cytotoxic therapy to patients stratified on the basis of their risk for developing vascular events.5 In this article, I review the management of patients with ET by discussing diagnosis, risk stratification, current therapeutic options and updated treatment recommendations.

How I diagnose ET

The differential diagnosis of ET includes reactive thrombocytosis, polycythemia vera (PV), primary myelofibrosis (PMF), chronic myeloid leukemia and refractory anemia with ring sideroblasts and marked thrombocytosis.6 Accurate diagnosis is important for both prognostication and treatment, and I adopt the 2008 World Health Organization (WHO) classification system that include hematological, morphological and molecular criteria (Table 1).7 The presence of a clonal marker (for example, JAK2 or MPL mutation)3 reliably excludes the possibility of reactive thrombocytosis, but its absence does not define the diagnosis because up to 50% of patients with ET might be JAK2V617F negative.8 In addition, other chronic myeloid neoplasms, such as prefibrotic PMF9 and refractory anemia with ring sideroblasts and marked thrombocytosis,10 can be JAK2V617F positive and mimic ET in their presentation. Therefore, bone marrow examination is often necessary to distinguish ET from both reactive thrombocytosis (in JAK2V617F-negative patients) and other myeloid neoplasms (in JAK2V617F-positive cases).4

Table 1 Diagnostic criteria for ET according to the 2008 WHO classification7

Some investigators remain skeptical about the use of morphological criteria in distinguishing ET from prefibrotic PMF, maintaining that these criteria are subjective and difficult to apply reproducibly.11 However, a recent large international study confirmed the prognostic relevance of distinguishing ET from pre-fibrotic PMF.1 Out of 1104 enrolled patients, diagnosis was confirmed as ET in 891 (81%) and was revised to early/prefibrotic PMF in 180 (16%) patients; 33 cases were not evaluable. In early/prefibrotic PMF compared with ET, survival rates (59% and 80%, respectively), leukemic transformation rates (11.7% and 2.1%, respectively), and progression to overt myelofibrosis rates (16.9% and 9.3%, respectively) after 15 years were significantly worse. The respective death, leukemia and overt myelofibrosis incidence rates per 100 patient-years for early/prefibrotic PMF compared with ET were 2.7 and 1.3% (relative risk (RR), 2.1; P<0.001), 0.6 and 0.1% (RR, 5.2; P=0.001), and 1 and 0.5% (RR, 2.0; P=0.04). These findings indicate that hematological transformations are uncommon in patients with ET strictly diagnosed according to WHO 2008 criteria, and support current recommendations to focus management on risk stratification, prevention and treatment of thrombo-hemorrhagic complications.12

Incidence and type of thrombosis and hemorrhage

In uncontrolled studies, reported cumulative rates for thrombosis and hemorrhage during follow-up ranged from 7 to 17% and 8 to 14%, respectively.13 In one study that also evaluated a control population, the incidence of thrombotic episodes was 6.6% per patient-year in ET vs 1.2% in control subjects, and the rate of major hemorrhagic complications was 0.33% per patient-year in ET vs 0% in controls.2

The most frequent types of major thrombosis include stroke, transient ischemic attack, myocardial infarction, peripheral arterial thrombosis and deep venous thrombosis often occurring in unusual sites, such as hepatic (Budd–Chiari syndrome), portal and mesenteric veins.14 In addition to large vessel occlusions, ET patients may suffer from microcirculatory symptoms, including vascular headaches, dizziness, visual disturbances, distal paresthesia and acrocyanosis. The most characteristic of these disturbances is erythromelalgia, consisting of congestion, redness and burning pain to ischemia and gangrene of the distal portions of toes and fingers.15 The most frequent bleeding events are hemorrhages from the gastrointestinal tract followed by hematuria and other mucocutaneous hemorrhages. Hemarthrosis and large muscle hematomas are uncommon.14

Risk stratification according to thrombo-hemorrhagic risk

Age and previous thrombosis

Age over 60 and a previous thrombotic event were identified as major risk factors for thrombosis in most studies (Table 2). The age-related differences in the frequency of these events is mostly due to the coexistence of vascular disease in older patients. However, younger patients are not free of vascular thrombosis, sometimes in unusual sites, such as the portal or sagittal veins.16 Overall, the incidence of thrombotic and hemorrhagic complications in asymptomatic patients with ET younger than 60 years of age who had a platelet count of <1500 × 109/l is comparable to a normal control population.17

Table 2 Cohort studies of risk factors for thrombosis and bleeding in ET including at least 100 patients

Platelet count and function

Several large cohort studies have failed to define a relationship between the frequency of thrombotic complications and platelet number (Table 2). Thus, an elevated platelet count, per se, should not be considered as an indication for a myelosuppressive therapy aimed at preventing thrombotic complications. Supporting this view, in a retrospective study of 99 consecutive young patients (aged <60 years) who presented with extreme thrombocytosis (platelet count 1000 × 109/l) and without a previous history of thrombohemorrhagic complications, the incidences of major thrombosis and hemorrhage during the follow-up were similar between those who were treated with prophylactic cytoreductive therapy and those who did not receive such therapy.18

The relationship between frequency of bleeding episodes and high platelet counts is more consistent. Most studies have shown that the degree and duration of bleeding in this patient population correlate with the platelet count (Table 2). Bleeding events appear to occur when the platelet counts are excessively high and stop when the platelet count falls to normal. The clinical spectrum of bleeding in ET patients closely resembles that observed in von Willebrand disease.19 An increase in the number of circulating platelets appears to favor the adsorption of larger von Willebrand multimers onto platelet membranes, resulting in their removal from the circulation and their subsequent degradation. The laboratory features of acquired von Willebrand syndrome in ET is characteristic of a type II deficiency with prolonged bleeding time, normal factor VIII C:VWF Ag ratio, decreased ristocetin cofactor activity, and decrease or absence of large von Willebrand factor multimers.14, 19

Platelets in patients with ET have been known for a considerable time to be qualitatively abnormal.6 Although both increased and decreased platelet reactivities have been described, these findings have not been definitively associated with thrombohemorrhagic complications with two noteworthy exceptions; erythromelalgia, where the prompt relief of symptoms by cyclooxygenase inhibitors provides direct evidence that prostaglandins have a role in the development of vascular occlusion,15 and acquired von Willebrand syndrome, which is a major cause of bleeding in patients with ET.19

Leukocyte number and function

A prognostic role for leukocytosis in ET has been advocated.20 Three large cohort studies reported that an increased baseline leukocyte count was an independent risk factor for both thrombosis and inferior survival.21, 22, 23 The role of WBC count in ET was mostly observed on the occurrence of myocardial infarction,24 as also shown in patients with PV.25 In ‘low-risk’ ET patients, (that is, below 60 years and without previous thrombosis) leukocytosis conferred a thrombotic risk comparable to that of treated ‘high-risk’ patients without leukocytosis.22 These findings were not confirmed in a retrospective study of 407 low-risk patients with ET.26 Leukocytosis at the time of diagnosis, defined by a cut-off level of either 15 or 9.4 × 109/l, did not appear to be predictive of either arterial or venous thrombosis during follow-up. However, in an analysis of 194 low-risk ET patients, the increase in leukocyte count within 2 years of diagnosis (observed in 9% of patients), rather than leukocytosis at diagnosis, was associated with an higher risk of vascular complications during follow-up.27

In ET, an in vivo leukocyte activation has been consistently documented in association with signs of activation of both platelets and endothelial cells. Interestingly, the presence of the JAK2 mutation is associated with higher platelet and leukocyte activation in these patients.28 Thus, platelet and leukocyte activation may have a role in the generation of the pre-thrombotic state that characterizes ET.29 However, whether leukocytosis should be simply considered a marker for vascular disease or whether elevated WBC levels actually contribute directly to causing such disorders should be matter of prospective studies.

Other risk factors

The presence of the JAK2V617F mutation in about 60% of ET patients raised the question whether mutated and non-mutated patients differ in terms of thrombotic risk. The largest prospective study on 806 patients suggested that JAK2 mutation in ET was associated with anamnestic venous but not arterial events.30 An increased risk of thrombosis in JAK2-mutated patients was retrospectively observed by other investigators.31, 32 However, the rate of vascular complications was not affected by the presence of the mutation in two relatively large retrospective studies, including 150 and 130 ET patients respectively.8, 33 A systematic literature review was carried out to compare the frequency of thrombosis between JAK2V617F-positive and wild-type patients with essential thrombocythemia.34 This study showed that JAK2V617F patients have a two-fold risk of developing thrombosis (odds ratio (OR) 1.92, 95% confidence interval (CI) 1.45–2.53) but a significant heterogeneity between studies has been pointed out. In addition to the prognostic role of JAK2 mutation for the first thrombotic episode, recent data would indicate that the mutation has also a role to predict recurrent thrombotic episodes in patients with ET.35

Bone marrow histology is important for an accurate morphologic diagnosis of ET according to WHO criteria and for predicting survival and hematological transformations to myelofibrosis or acute leukemia.1 However, its role as a risk factor for thrombosis is controversial. Campbell et al.36 have identified increased bone marrow reticulin fibrosis at diagnosis as an independent predictor of subsequent thrombotic and hemorrhagic complications. At variance, a recent analysis comparing 891 patients with WHO-diagnosed ET vs 180 patients clinically presenting like ET but with an histological picture of prefibrotic PMF did not show any difference in the rates of arterial (1.2–1.4% patient-year, respectively) and venous (0.6% patient-year in both groups) thrombotic complications.1 Instead, prefibrotic PMF was a significant predictor of major bleeding, together with leukocytosis, previous hemorrhage and aspirin use.37

The role of inflammation among the possible prognostic factors in MPN has been recenly highlighted.38, 39 Barbui et al. correlated vascular complications with plasma levels of high-sensitivity C-reactive protein and pentraxin-3 in 244 ET and PV patients. Major thrombosis rate was higher in the highest C-reactive protein tertile (P=0.01) and lower at the highest pentraxin-3 levels (P=0.045). These associations remained significant in multivariable analysis and indicate that these inflammatory biomarkers independently and in opposite ways modulate the risk of cardiovascular events in patients with MPN.38

In conclusion, a clinically oriented scheme is proposed to stratify patients with ET in a ‘high-risk’ or ‘low-risk’ category according to their age and previous history of thrombosis (Table 3).12 Putative novel variables, such as leukocytosis and JAK2V617F mutational status, might be incorporated in the risk classification, possibly allowing better definition of the low-risk group, once more information is available and when they have been eventually validated in prospective studies.

Table 3 Risk stratification in ET based on thrombohemorrhagic risk

How I manage ‘low-risk’ patients

I avoid cytoreduction in low-risk ET patients (Figure 1). The natural history of such patients left untreated was prospectively evaluated in a controlled study that compared 65 low-risk patients with 65 age- and sex-matched normal controls.17 Patients were followed up and cytoreductive therapy was introduced as soon as a major clinical event was recorded. After a median follow-up of 4.1 years, the incidence of thrombosis was not significantly higher in patients than in controls (1.91% vs 1.5% per patient-year; age- and sex-adjusted risk ratio 1.43, 95% CI 0.37–5.4). No major bleeding was observed. These findings were confirmed in a cohort of 74 young women followed untreated for more than 9 years who showed 1.2% per patient-year incidence of vascular events.40 Thrombotic deaths seem very rare in low-risk ET subjects, and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Admittedly, this policy is based on studies with relatively small samples, and further data from large clinical trials are needed.

Figure 1
figure1

How I manage patients with ET

Low-dose aspirin

In ET, aspirin, 100 mg daily, has been found to control microvascular symptoms, such as erythromelalgia, and transient neurological and ocular disturbances including dysarthria, hemiparesis, scintillating scotomas, amaurosis fugax, migraine and seizures.15. Higher doses, up to 500 mg daily, may be necessary in the acute phase of erythromelalgia. Translating evidence from the ECLAP randomized study in PV,41 the use of low-dose aspirin as primary prophylaxis of vascular events can be considered. However, formal clinical trials addressing this issue in ET have not been produced so far. In a randomized study comparing HU vs anagrelide in high-risk patients with ET discussed in detail below, low-dose aspirin was given to both groups.42 An increased rate of major bleeding was registered in the anagrelide plus aspirin arm and this may be due to a synergistic effect of the two drugs on platelet function inhibition.

A recent publication from Alvarez-Larran et al.43 questions the benefit of low-dose aspirin in low-risk ET. These authors retrospectively assessed the incidence rates of arterial and venous thrombosis in 300 low-risk ET patients either treated with antiplatelet drugs as monotherapy (n=198, follow-up 802 person-years) or subjected to observation only (n=102, 848 person-years). They reported that overall rates of thrombotic events did not differ between these patient groups, whereas an increased risk of major bleeding was observed in patients with platelet count >1000 × 109/l treated with antiplatelet therapy (incidence rate ratio (IRR): 5.4; 95% CI 1.7–17.2; P=0.004). Subgroup analysis also showed that two types of patients did worse with observation only: JAK2 V617F-positive patients had an increased risk of venous thrombosis (IRR: 4.0; 95% CI 1.2–12.9; P=0.02), and patients with cardiovascular risk factors had increased rates of arterial thrombosis (IRR: 2.5; 95% CI 1.02–6.1; P=0.047).

Taking into account all these data, I currently do not use aspirin as primary anti-thrombotic prophylaxis in all ET patients, but I reserve the drug for patients with microvascular symptoms or severe, uncontrolled cardiovascular risk factors (Figure 1).

How I treat high-risk patients

The cytoreductive drugs most commonly used for the treatment of high-risk ET include HU, alpha-interferon and anagrelide. Practical recommendations for their management and dosing are reported in Table 4 and main results from randomized clinical trials comparing these drugs are summarized in Table 5.

Table 4 Management and dosing of cytoreductive therapy in ET
Table 5 Randomized clinical trials in high-risk patients with ET

Hydroxyurea

HU has emerged as the treatment of choice in high-risk patients with ET because of its efficacy in preventing thrombosis, as demonstrated in a seminal randomized clinical trial.44 One hundred and fourteen patients were randomized to long-term treatment with HU (n=56) or to no cytoreductive treatment (n=58). During a median follow-up of 27 months, 2 thromboses were recorded in the HU-treated group (1.6%/patient-year) compared with 14 in the control group (10.7% patient-year; P=0.003). Notably, the anti-thrombotic effect of HU may recognize additional mechanisms of action besides panmyelosuppression, including qualitative changes in leukocytes, decreased expression of endothelial adhesion molecules and enhanced nitric oxide generation.45 Some long-term follow-up studies revealed that a proportion of ET patients treated with HU developed acute leukemia, particularly when given before or after alkylating agents or radiophosphorus.46 In other studies, however, the use of this drug as the only cytotoxic treatment was rarely associated with secondary malignancies; in an analysis of 25 ET patients younger than 50 years and treated with HU alone for a high risk of thrombosis, no case of leukemic or neoplastic transformation occurred after a median follow-up of 8 years (range 5–14 years).47 Interestingly, in a recent, large population-based nested case-control study in Sweden, the risk of AML/MDS in MPNs was strongly associated with P32 (RR 3.39, 95% CI 1.28–8.99, P=0.01) and alkylator treatments (RR 4.46, 95% CI 1.22–16.31, P=0.03). In contrast, in this survey HU (>1000 mg) did not significantly increase the risk for transformation to AML/MDS (RR 1.01, 0.28–3.6).48 Further support to the low, if any, leukemogenic potential of HU comes from a systematic review of the efficacy and safety of this drug in sickle cell disease. This study analyzed HU toxicities not only in patients with sickle cell disease but also in patients with other diseases, including MPNs, and concluded that, albeit limited, current evidence suggests that HU treatment in adults does not increase the risk for leukemia.49

Major side effects of HU include hematopoietic impairment, leading to neutropenia and macrocytic anemia, and mucocutaneuos toxicity, most frequently presenting as oral and leg ulcers, and skin lesions. In addition, it is estimated that about 10% of patients receiving HU do not achieve the desired reduction in blood cell counts using recommended doses. Recently, an international working group in the frame of the European Leukemia Net was convened to develop a consensus formulation of clinically significant criteria for defining resistance/intolerance to HU in ET.50 The Working Group proposed that the definition of resistance/intolerance should require the fulfillment of at least one of the following criteria: platelet count >600 000/μl after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count >400 000/μl and WBC count <2500/μl or Hb count<10 g/dl at any dose of HU; presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HU; HU-related fever.

Interferon alpha (IFN-alpha)

IFN-alpha was considered for the treatment of patients with MPDs because this agent suppresses the proliferation of hematopoietic progenitors, has a direct inhibiting effect on bone marrow fibroblast progenitor cells and antagonizes the action of platelet-derived growth factor, transforming growth factor-beta and other cytokines, which may be involved in the development of myelofibrosis.51 Published reports concern small consecutive series of patients in whom hematological response and side effects were evaluated. The results of several cohort studies of ET patients, reviewed in Lengfelder et al.,52 indicate that reduction of platelet count below 600 × 109/l can be obtained in about 90% of cases after about 3 months with an average dose of 3 million IU daily. IFN-alpha is not known to be teratogenic and does not cross the placenta. Thus, it has been used successfully throughout pregnancy in some ET patients with no adverse fetal or maternal outcome.53 The main problem with IFN-alpha therapy, apart from its costs and parental route of administration, is the incidence of side effects. Fever and flu-like symptoms are experienced by most patients and usually require treatment with paracetamol. Signs of chronic IFN-alpha toxicity, such as weakness, myalgia, weight and hair loss, severe depression, and gastrointestinal and cardiovascular symptoms, make it necessary to discontinue the drug in about one third of patients.

Pegylated forms of IFN-alpha allow weekly administration, potentially improving compliance and possibly providing more effective therapy. In patients with PV, pegylated IFN-alpha-2a therapy was able to reduce the malignant clone as quantitated by the percentage of the mutated allele JAK2V617F.54 More limited effects on JAK2 mutational status have been reported after therapy with pegylated IFN-alfa-2b in a small group of patients with PV and ET.55 In a phase II study of pegylated IFN-alfa-2a in 79 patients with PV and ET, an overall hematologic response rate was observed in 80% of PV and 81% of ET (complete in 70% and 76% of patients, respectively).56 The molecular response rate was 38% in ET and 54% in PV, being complete (undetectable JAK2 V617F) in 6% and 14%, respectively. The JAK2V617F mutant allele burden continued to decrease with no clear evidence for a plateau in PV patients, whereas this pattern was less clear in ET patients. The tolerability of PEG-IFN-alpha-2a at 90 μg weekly was excellent. Thus, this agent may have an important role in the treatment of clonal MPN, particularly PV.

Anagrelide

Anagrelide, a member of the imidazoquinazolin compounds, has a potent platelet reducing activity devoid of leukemogenic potential and appeared to be the option to HU for reducing platelet counts in younger ET patients at high risk for thrombosis. The largest analysis reported so far comprised 3660 patients (2251 with ET).57 With maximum follow-up of 7 years, anagrelide achieved platelet control in over 75% of patients and did not increase the conversion to AL. However, other complications of the drug include palpitations, congestive heart failure, headache and depression.

HU and anagrelide (plus aspirin in both groups) have been compared head to head in a randomized clinical trial (PT-1) including 809 ET patients.42 Patients in the anagrelide arm showed an increased rate of arterial thrombosis (OR 2.16, 95% CI 1.04–2.37, P=0.03), major bleeding (OR 2.61, 95% CI 1.27–5.33, P=0.008) and myelofibrotic transformation (OR 2.92, 95% CI 1.24–6.86, P=0.01) but a decreased incidence of venous thrombosis (OR 0.27, 95% CI 0.11–0.71, P=0.006) compared with HU. In addition, anagrelide was more poorly tolerated than HU and presented significantly greater rates of cardiovascular (P<0.0001), gastrointestinal (P<0.02), neurological (P<0001) and constitutional (P<0.001) side effects. Transformation to AL was comparable between the two arms (4 anagrelide vs 6 HU), although the small number of transformations and short follow-up prevented firm conclusions about leukemogenicity.

Therapy with anagrelide, but not with HU, was also associated with progressive anemia and an increase in bone marrow fibrosis.36 The increased fibrosis was reversible in a small number of patients upon withdrawal of anagrelide, and follow-up trephine biopsies are therefore recommended for patients receiving this agent, perhaps every 2–3 years. It is important to note that the diagnosis of ET in the PT-1 trial was made according to the PVSG classification and it remains questionable if these recommendations can be applied to ET patients diagnosed according to the WHO classification.

In this connection, useful information is expected from the Anahydret trial.58 The Anahydret was a randomized single blind international multicenter phase III study designed to evaluate the non-inferiority of anagrelide vs HU in 258 high-risk ET patients diagnosed according to the 2008 WHO diagnostic criteria. This classification, at variance of PVSG criteria required in the PT-1 trial, included a more homogenous category of patients excluding those with early myelofibrosis. During the whole study period, 11 major ET-related complications occurred in the anagrelide group (5 arterial events, 2 venous thrombotic complications and 4 bleedings) and 12 major events were seen in the HU arm (5 arterial events, 5 venous thrombotic events and 2 bleedings). Transformations to myelofibrosis were not reported. This study provides preliminary evidence for non-inferiority of anagrelide compared with HU in the treatment of ET diagnosed according to the WHO classification. However, compared with PT-1, the number of patients enrolled was small, duration of follow-up relatively short and considerably fewer end-point events were recorded. It is therefore questionable whether this study has the statistical power to detect the differences observed in the PT-1 study.

JAK2 inhibitors

To date, clinical studies of new drugs with JAK2 inhibitory activity have mainly included patients with PMF or PV. A small group of 39 patients with ET, refractory or intolerant to HU, is currently treated with Ruxolitinib (INCB018424). At the latest study update,59 after a median follow-up of 15 months (range 4–21), 49% of enrolled subjects had platelet counts normalized to the upper limit of normal for a median duration of 3.5 months and 82% maintained platelet counts <600 × 109/l for a median duration of 9.8 months. Palpable spleens were resolved in three out of four subjects and reductions in patient-reported symptom scores for pruritus, night sweats and bone pain were observed. Grade 3 adverse events potentially related to study medication included leukopenia (two patients), gastrointestinal disorder and peripheral neuropathy (one patient each). No grade 4 drug-related adverse event have occurred. Clinical responses were unrelated to the presence/absence of JAK2V617F mutation at entry or to the allele burden changes following treatment. Although interesting, these results are too preliminary to draw any conclusion on the current role of JAK2 inhibitors in the management of ET.

Practical recommendations

My current practice for the treatment of patients with ET is summarized in Figure 1 and largely overlaps with the recommendations of a panel of experts recently appointed by the ELN.12 Several areas of uncertainties still remain and call for appropriate clinical trials. In order to uniform the criteria to be used in clinical studies, a definition of response to treatment in PV and ET has been proposed.60 Clinico-hematologic, molecular and histologic response were selected and are expected to provide a means to compare the results from different patient cohorts and to facilitate communication within the scientific community.

How I manage pregnant patients with ET

I take a detailed personal and family history, and I put the patient also under the care of an obstetrician experienced in the management of patients with high-risk pregnancies. The patient should stop any possibly teratogenic drugs at least 3 months before conception. Depending on the risk of maternal vascular events and pregnancy morbidity, treatment options range from no therapy, aspirin alone, low-molecular-weight heparin (LMWH) to cytoreductive therapy (Table 6).

Table 6 How I manage pregnancy in ET

In the absence of clear contraindications, I give aspirin (100 mg daily) throughout pregnancy and LMWH 4000 U daily for 6 weeks post partum to all women with ET. However, not all studies agree on the value of aspirin therapy in reducing miscarriage rates. Low-dose aspirin is considered safe in pregnancy and should preferably be started before conception to facilitate placental and fetal development. Bleeding complications are rare, but particular attention should be paid to patients with platelet count above 1000–1500 × 109/l because the risk of bleeding may increase significantly.

LMWH throughout all pregnancy is indicated for prophylaxis of deep venous thrombosis and to reduce fetal morbidity in selected high-risk ET women. The suggested dose of enoxaparin is 4000 U (40 mg) once daily, increasing to 4000 U twice daily for 16 weeks and dropping to 4000 U daily for 6 weeks postpartum. To increase the antithrombotic efficacy in very high-risk situations LMWH can be used in combination with low-dose aspirin.

Cytoreductive therapy in pregnant women with ET is a controversial area. During pregnancy, platelet count may undergo a natural fall and this could reduce the need of cytoreductive drugs. The target of platelet-lowering therapy is uncertain, because the available data did not indicate a relation between platelet count and adverse pregnancy outcome. According to recent guidelines12 and expert judgement,53, 61 candidates for platelet-lowering drugs are high-risk women, such as those with a previous history of major thrombosis or major bleeding, particularly when platelet count is >1000–1500 × 109/l, or when familial thrombophilia or cardiovascular risk factors are documented. If cytoreduction has to be given, IFN-alpha is probably the safest option. Generally, patients should not be receiving HU when they conceive or in the first trimester. Anagrelide may cause fetal harm by crossing the placenta and result in severe thrombocytopenia. It is therefore not recommended in pregnancy.

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Finazzi, G. How to manage essential thrombocythemia. Leukemia 26, 875–882 (2012). https://doi.org/10.1038/leu.2011.306

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Keywords

  • chronic myeloproliferative neoplasms
  • essential thrombocythemia
  • hydroxyurea
  • low-dose aspirin
  • alpha-interferon
  • anagrelide

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