271820'6 Prognosis and veximent of essental tembocybemia UpToDate’ Sissi! or ofotetsn @. Wolters Kluwer Prognosis and treatment of essential thrombocythemia Author Section Editor Deputy Editor Ayalew Teffed, MD Stanley L Schrier, MD Rebecca F Connor, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jul 2016. | This topic last updated: Dec 22, 2015. INTRODUCTION — The classic, Bcr/Abl-negative myeloproiiferative neoplasms (MPN, MPD) include polycythemia vera (PV), primary myelofibrosis (PMF, AMM, MMM, chronic idiopathic myelofibrosis), and essential thrombocythemia (ET, primary or essential thrombocytosis) [1]. Other members of MPN include chronic myeloid leukemia (CML), chronic neutrophilic leukemia, systemic mastocytosis, chronic eosinophilic leukemia-not otherwise specified and MPN- unclassifiable. ‘The MPD are themselves a subcategory of chronic myeloid disorders that also include chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), MDS/MPN and myeloid/lymphoid malignancies associated with eosinophilia and rearrangements of PDGFRA, PDGFRB or FGFR1. (See "Overviaw of the myeloproliferative neoplasms".) ET is neither a cytogenetically nor a morphologically defined disease entity, but rather is a diagnosis of exclusion. Thus, the diagnosis of ET requires that both reactive thrombocytosis and other chronic myeloid disorders have been excluded [2]. This review will discuss the prognosis and treatment of ET [3-6]. The general approach to the patient with an elevated platelet count and the diagnosis and clinical manifestations of ET are discussed separately. (See "Approach to the patient with thrombocytosis" and "Diagnosis and clinical manifestations of essential thrombocythemia.) PROGNOSIS — Most patients with essential thrombocythemia (ET) enjoy a normal life expectancy without associated disease-related complications [7.8]. In morphologically and cytogenetically defined ET (ie, patients in whom PV, CML, MDS, and PMF have been excluded), the delayed development of either acute myeloid leukemia (AML) or post-ET myelofibrosis (post-ET MF) is unusual [9.10]. As examples: ‘© Inalarge retrospective study of 435 patients with ET, the 15-year cumulative risks of thrombosis and clonal ‘evolution into either AML or post-ET MF were 17, 2, and 4 percent, respectively [Z] ‘* Inn intemational study of 891 patients with ET confirmed by the use of WHO criteria, 15-year cumulative risks of thrombosis, leukemic transformation, or overt fibrotic progression were 22, 2, and 9 percent, respectively [10} Overall survival (median survival: 14.7 years) was similar to that of the sex- and age-standardized European population. ‘© In two studies, patients with ET and calreticulin (CALR) mutations appeared to have a lower thrombotic risk than those with JAK2 or MPL mutations [11,12]. However, CALR mutations had no impact on overall survival or transformation to post-ET myelofibrosis. (See "Overview of the myeloproliferalive neoplasms", section on ‘Mutations in PV, ET, and PMF'.) ‘Survival — In our series of 605 patients with ET followed for a median of seven years, there were 185 deaths (26 percent). On multivariate analysis, risk factors for inferior survival included (13) ¢ Low hemoglobin level (<12 g/dl. in females and <13.5 g/dL. in males) ‘Age 260 years Leukocyte count 215,000/microL. ‘Smoking, diabetes mellitus, prior venous thrombosis, ‘A simplified model that included only age and white blood cell count at the time of diagnosis found the following three risk ‘groups and median survivals (flours 1) [14]: © Low risk (age <60 and WBC <15,000/microL) - 25 years © Intermediate risk (age 280 or WBC 215,000) - 17 years ‘* High risk (age 260 and WBC 215,000) - 10 years elpeuhwwn plod. comfcertenslpragnoss- anc realmer ssnial-brombocyhemiattopieKey=HEMES2F 44asselapsedTimeMs=4source=search «120271820'6 Prognosis and veximent of essental tembocybemia International Prognostic Score Overall survival — An Intemational Prognostic Score for Essential thrombocythemia (IPSET) was derived from £891 patients diagnosed strictly according to WHO criteria and was validated in two independent cohorts. Scoring was as follows: age 260: 2 points; white blood cell count >11,000/microL: 1 point; history of thrombosis: 1 point. Median survivals were as follows (15) ‘* Low risk (total score zero) — Not reached Intermediate risk (total score 1 or 2)— 24.5 years ‘¢ High risk (total score 3 or 4) — 13.8 years ‘The 10-year thrombosis free survival of those in the low, intermediate, and high risk groups were 89, 84, and 69 percent, respectively. The IPSET categories did not predict for evolution into myelofibrosis. ‘Thrombotic risk — Further evaluation of this cohort of 891 subjects with ET identified the following independent tisk factors for thrombosis (ie, the IPSET-thrombosis model) [ 16} ‘Age >60 years (HR 1.5; 1 point) History of thrombosis (HR 1.9; 2 points) Presence of cardiovascular risk factors (diabetes, hypertension, smoking, HR 1.6; 1 point) ‘* Presence of the JAK2 V617F mutation (HR 2.0; 2 points) Using this model, three thrombosis risk groups were determined: ‘* Low risk for thrombosis (total score zero or 1) ~ 1.03 percent/year risk of thrombosis ‘= Intermediate risk (Lotal score 2) - 2.96 percent/year ‘¢ High risk (total score >2) - 3.56 percent/year Risk factors for thrombosis and hemorrhage — Risk stratification in ET is primarily based upon factors that influence the occurrence of thrombotic, rather than hemorrhagic, complications (lable 1). In a case-control study reported in 1990, the overall risk of thrombotic episodes in patients with ET was 6.6 percent/patient-year compared with 1.2 percent/patientyyear in the control group [17]. Corresponding risks for hemorrhagic complications were much lower, being 0.33 and zero percent/patient-year, respectively. Significant risk factors for thrombosis in this group of patients were: ‘¢ History of prior thrombosis (Fisk = 31.4 percent/patient-year) ‘© Age over 60 years (tisk = 15.1 percentipatient-year) ‘* Prolonged exposure to substantial degrees of thrombocytosis Prior thrombosis — Our subsequent experience as well as that of many other investigators supports the adverse prognostic value of a history of prior thrombosis in ET [7.18.20]. Our latest estimate of thrombotic risk, the |PSET- thrombosis model, includes prior thrombosis as a significant risk factor, although the observed thrombotic risk in this newer cohort (1.9 percent per year) is considerably lower than that reported in the 1990 study quoted above (6.6 percent per year) [17]. Recurrent thrombosis occurred in 45 and 13 percent of our series of young women with ET who had a Positive or a negative history of prior thrombosis, respectively [21]. The corresponding figures in an unselected group of 103 patients with ET were 57 and 16 percent, respectively [22]. ‘Age — The adverse prognostic value of increased age has not been uniformly appreciated [9,18,20,22]. In one study, for example, the risk of a thrombotic event was 1.7 and 15.1 percent/patient-year for patients <40 and >60 years of age, respectively [17], while in a second report, the hazard ratio for thrombosis in subjects >60, in comparison to those <60, was 2,99 (95% Cl 1.19-7.51) [19]. Age >60 years was found to be a significant risk factor for thrombosis in the IPSET- thrombosis model discussed above, Cardiovascular risk factors — The role of cardiovascular risk factors in the occurrence of thrombosis has been disputed in some studies [23,24], although smoking, diabetes, and hypertension were implicated as significant risk factors in the IPSET-thrombosis model Leukocytosis — Leukocytosis, either at baseline or developing over time, has been considered as an independent risk factor for thrombotic complications in some studies [14,19,25-32], although these observations are confounded by treatment effect, prior thrombotic history, and the presence of other risk factors [31.33.34] elpeuhwwn toda. comfcentenslpragnosis- anc realmer essential brombocythamiataicKoy IEMEMZF 4d868clapsedTimeMs=dBsource=soarch ¢ 220271820'6 Prognosis and veximent of essental tembocybemia ‘Thrombocytosis and platelet function — In contrast, neither the degree of thrombocytosis nor the presence of platelet function abnormalities has been corelated with thrombotic risk [9.19,20,22,25.35) Bleeding risk — The risk of major bleeding episodes during the entire clinical course of the disease is less than 5 Percent [9.17.21], and is probably not exacerbated following the use of low-dose aspirin (eg, 40 to 100 mg/day), especially if these doses are used in patients with a platelet count <1,000,000/microL, the absence of a prior history of bleeding, and/or acquired von Willebrand disease [36.37]. ‘Thrombo-hemorrhagic risk model — Based upon the above observations, we have developed a risk stratification model for ET for the development of thrombo-hemomhagic complications. All patients fall into one of the following two risk groups. (table 4) (21h Low risk — In order to qualify for low risk disease, the patient with ET must have all of the following characteristics: © Age <60 years ‘* No previous history of thrombosis ‘© Platelet count <1 million/microL Patients who are otherwise considered to be low risk but have a platelet count >1 million/microL should be screened for the presence of acquired von Willebrand disease by obtaining a ristocetin cofactor activity before treatment with low-dose aspirin is considered (see ‘Low risk patients with high platelet counts’ below) ‘A prospective study of 65 untreated low risk patients (criteria as above) has validated the low complication rate in this ‘group of patients [3]. The incidence of thrombosis over a median follow-up period of 4.1 years was 1.9 and 1.5 cases per 400 patient-years in the low risk group and the age- and sex-matched controls, respectively. Only three minor hemorrhagic episodes occurred in the patient group; pregnancy and surgery were not associated with thrombotic complications in these patients. High risk — Patients with ET are considered to be at high risk if they have one or both of the following characteristics: © Age 260 years ‘© A previous history of thrombosis Leukemic transformation — In our series of 605 patients with ET followed for a median of seven years, leukemic transformation (LT) was documented in 20 (3.3 percent) [13]. On multivariate analysis, risk factors for the development of LT included: ‘* Low hemoglobin level (<12 g/dL in females, <13.6 in males) ‘© Platelet count 21,000,000/microL. Increased age ‘A model for the risk of LT was devised using the first two of these factors. Patients with none, one, or both of these adverse factors had a risk of developing LT of 0.4, 4.8, and 6.5 percent, respectively. Use of cytoreductive therapy or presence of the JAK2 mutation did not affect the risk of LT, (See ‘Loukemogenicity’ below.) Once transformation to AML or myelodysplasia has occurred in a patient with MPN (eg, ET, PV, PMF), the long-term prognosis is poor, with median survivals in the range of two to seven months [35]. However, in one study in 21 patients with ET who developed MDS or AML and were treated with azaciticine (intial dose: 75 mg/m?/day subcutaneously for 7 days every 28 days), the overall response rate was 71 percent, with a median survival of 16 months from the onset of treatment with this agent [39]. (See "P ‘TREATMENT ‘Treatment overview — While most patients with essential thrombocythemia (ET) enjoy a normal life expectancy, treatment is required for the following complications of ET [4.4042] © The most frequent symptoms are vasomotor, and are easily manageable with low-dose aspirin (ASA, 40 to 100 mg/day PO) [43.44], (See "Diagnosis and clinical mani ‘Masomotor symptoms.) Felpeuhwwn toda. comfcentenslpragnoss- and realmer /-ossomtia-eombocythemia?lopcKoy=HEMEMZF 4de6telapsedTimeMs=4Bsource=search & 20271820'6 Prognosis and veximent of essental tembocybemia ‘* Thrombotic events in low-risk patients with ET are too infrequent to justify the long-term use of potentially harmful agents [23,38]. The risk may be higher, however, in the presence of cardiovascular risk factors and/or extreme uncontrolled thrombocytosis [23.24.45]. Whether drug therapy is indicated in this particular situation remains controversial, On the other hand, approximately 20 percent of patients with ET present with major thrombotic events ‘and another 15 percent may experience recurrent thrombosis [9.23]; this complication is mast common in patients >60 years of age. Therefore, cyloreductive therapy is indicated in these highisk patients ([e, age >60 years or history of prior thrombosis). ‘© Bleeding complications are less frequent and may be prevented by the avoidance of doses of asvirin greater than 100 mg/day and avoiding the use of nonsteroidal antiinflammatory drugs (NSAIDs) [22.46]. In regard to spontaneous bleeding, control of thrombacytosis, especially in the presence of acquired von Willebrand disease, may alleviate a bleeding diathesis [47]. (See "Classification and pathophysiology of von Willebrand disease", section on ‘Acquired von Willebrand disease’) ‘The goals of treatment are to minimize the abnormal clinical, physical, and laboratory features while also minimizing the long-term complications of the disease (eg, thrombotic events, bleeding, myelofibrosis, acute leukemia, other malignancies) [48]. Criteria of response to clinical trials for the treatment of ET have been proposed by the European LeukemiaNet (ELN) [48-50]. Therapeutic agents available for the treatment of ET are discussed below. Hydroxyurea — In a randomized study involving 114 patients with ET, use of hydroxyurea (HU, Hydrea), compared with no treatment, was shown to reduce the risk of thrombosis in highsrisk patients from 24 percent to <4 percent at a median follow-up of 27 months [51]. In this study, there was only one episode of minor gastrointestinal bleeding in hydroxyurea treated patients. In a second trial, 809 patients with ET were randomly assigned to receive treatment with either hydroxyurea or anaarelide, both in combination with aspirin [52]. Results of this trial, which reported the superiority of hydroxyurea plus aspirin, are discussed below (see ‘Anaarelide versus hydroxyurea! below). Maintenance of the platelet count <400,000/microL may be associated with further reduction in thrombotic risk [9.53]. The controversy regarding the possible leukemogenic effect of HU is discussed in a separate section (see ‘Loukemogenicity’ below), ‘The recommended initial dose of HU is 15 mg/kg per day PO, taken in divided doses. Doses are then adjusted up or down depending upon the balance between the desired effect on the platelet count, which should be kept in the range of 100,000 to 400,000/microL, and undesired effects such as neutropenia and anemia, Toxicity — Side effects of HU are usually minimal and include oral ulcers, hyperpigmentation, skin rash, and nail changes [54]. A small percentage will develop leg ulcers, nausea, diarrhea, or alopecia (55). Ina study of 993 consecutive patients with myeloprolferative neoplasms treated with HU (50 percent with ET), mucocutaneous toxicity was reported in 51 (8.3 percent) [56]. This included painful skin ulcers mainly in the perimalleolar area, oral aphthous ulcers, or erythema and skin infiltration, Oral aphthous ulcers were found to be an early toxicity (median time to onset from start of HU therapy: 2.1 months), while skin ulcers and erythemalskin infiltration occurred late (median time to onset: 38 months). One-half of the affected patients required permanent drug discontinuation because of these side effects, Rare complications of HU include fever and abnormal liver function tests [54]. HU should not be used in pregnancy, in women with childbearing potential, and in women who are breast-feeding (‘able 2). Monitoring — Varying degrees of neutropenia and anemia with megaloblastic features regularly accompany the plateletowering effect of HU. This is not strictly a side effect of HU, as its mechanism of action is through inhibition of DNA synthesis, resulting in a megaloblastic blood picture. In fact, if the patient's red blood cell mean corpuscular volume (MCV) does not rise significantly, this means that the patient is not taking the medication as prescribed. Therefore, a rising MCV is indicative of appropriate drug action, and is not, in and of itself, a reason to modify the dose of HU. (See 'Macrocytosis/Macrocytic anemia’) Since HU inhibits the enzyme ribonucleotide reductase, considerably downstream from the effect of vitamins B12 and folic acid, addition of these vitamins will not reverse HU-induced macrocytesis, anemia, neutropenia, or thrombocytopenia, and is not indicated Felpeuhwwn toda. comfcentenslpragnoss- and realmer essential brombocythamiataicKoy |EMEW2F4t868lopsedTimeMs=ABsource=search f.. 4/20271820'6 Prognosis and veximent of essental tembocybemia ‘The onset of action of HU is rapid, usually within three to five days of initiation of treatment. Similafy, its effect is short- lived once the medication is stopped. Accordingly, dose adjustments should not be made more frequently than once per ‘week in order to prevent wide fluctuations in the platelet count, It is also important to counsel patients taking HU to avoid missing drug doses. Complete blood counts and liver function tests should be obtained frequently within the first three months of initiation of treatment to monitor for rapid changes in blood counts as a result of drug dosage modifications, as well as to monitor for HU-induced alterations in liver function. Leukemogenicity — Both polycythemia vera (PV) and ET have an inherent tendency to evolve into acute myeloid leukemia (AML) [57-59]. For both disorders, a longer disease duration and the evolution into myelofibrosis significantly increase the risk of leukemic transformation [60]. However, there is, to date, no randomized study directly implicating HU as being more leukemogenic than any other therapeutic strategy, either in PV or ET. Several nonrandomized studies have either supported or refuted a significant increase in leukemic conversion associated with the long-term use of HU, Reported incidence rates of leukemic conversion, when HU is used alone in ET, range from 0 to 5 percent [55,61-64]. In one series of 357 patients followed for a median of eight years, the incidence of conversion to myelodysplastic syndrome (MDS) or AML was 4.5 percent [61]. This risk was 3.5 percent in patients treated with HU alone and 14 percent in patients receiving HU in combination with 32P, busulfan, or pipobroman. Similar results have been ‘obtained by other investigators (51.64-67) In a large retrospective study of 435 patients with ET, the 15-year cumulative risk of either AML (2 percent) or MMM (4 Percent) was not significantly influenced by single-agent chemotherapy of any kind, including use of hydroxyurea (7). Consistent with this observation, the risk of leukemic transformation in two randomized trials was not adversely affected by the use of hydroxyurea alone [51,52]. Therefore, at present there is no hard evidence to implicate hydroxyurea use in ET as being leukemogenic, while new information suggests that anaarelide may increase the risk of transformation into MMM (see ‘Anaarelide! below). Nevertheless, it is legitimate to be concemed about a potential risk of mutagenicity with HU, and to avoid use of this agent in situations where the benefit of HU is unproven [44]. One study has revealed a high frequency of 179 chromosomal deletions (41 percent) in acutely transformed patients with ET treated with HU [61]. The majority also had p53 mutations and a specific type of dysgranulopoiesis (17p- syndrome) [68]. However, 17p deletions also occur in other hematologic disorders, including both de novo and treatment-related cases of AML and MDS [69,70]. The 17p deletion in this setting may represent a nonspecific late clonal event that may or may not require the presence of antecedent chemotherapy, including HU. Based upon current understanding of the clonal myeloid disorders, it is not unexpected that the risk of clonal evolution is higher with aggressive, treatment-requiring disease and longer follow-up, Thus, although current information does not clearly implicate HU as being leukemogenic in patients with ET, the use of 32P or alkylating agents in patients failing treatment with HU should be discouraged [55], HU is being used increasingly in non-hematologic conditions (eg, sickle cell disease and cyanotic congenital heart disease) with no reports of associated acute leukemia [71.72]. In a study of 64 patients with cyanotic congenital heart disease (mean age, 25.2 years, range: 8 to 47 years) receiving HU for a mean treatment duration of 5.6 years (range: 2 to 415 years), no cases of AML or any other malignancy were observed [72]. (See "Hydroxyurea and other disease-modifying therapies in sickle cell disease”, section on Use of hydroxyurea’) Anagrelide — Anaarolide is an oral imidazoquinazoline derivative which inhibits platelet aggregation via platelet anti-cyclic AMP phosphodiesterase activity, and also has a platelet lowering effect in humans [Z3]. Three groups of investigators have studied the mechanism of anagrelide-induced platelet underproduction in the various myeloprolferative disorders [74.75]. Their observations suggest drug interference with megakaryocyte proliferation and maturation, resulting in platelet nderproduction. The platelet function inhibitory activity of anagrelide Is seen only at doses higher than those used for controlling thrombocytosis and should not be a concem in patients with ET [75] Since 1985, thousands of patients with clonal thrombocytosis (eg, CML, PV, ET, and AMM) have been treated with anaarelide [77-80]. In general, the drug is capable of reducing the platelet count to less than 600,000/microL. in more than 80 percent of previously treated and untreated patients, including children [81]. The initial adult dose is 0.5 mg, taken two to four times daily. This dose is then adjusted according to the platelet count response and symptomatology. The usual Felpeuhwwn toda. comfcentenslpragnoss- and realmer {ossental-brombocyhemia?tapckey=HEMENIF 44868elapsedTimeMs=ABsourcessearch f... 720271820%6 Prognosis and veximent of essental tembocybemia ‘oral maintenance dose is in the range of 1 to 4 mg/day, with a median maintenance dose of 2.5 mg/day in a group of ‘young patients with ET [82]; tachyphylaxis does not develop. Ina separate study, which included 79 patients with ET, treatment with anaorelide resulted ina significant reduction in the Platelet count, as well as a reduction in both major and minor arterial and venous thromboembolic complications [83]. Bleeding complications were common only in those patients who were taking anagrelide along with low dose aspirin. (See 0 nical ations of al hrombooyth ection on "Thrombosis and h ) ‘Two randomized studies that compared the use of anaarelide versus hydroxyurea in previously untreated patients with ET are discussed below. (See ‘Anaarelide versus hydroxyurea’ below.) Toxicity — Toxicity of anacrelde is mainly related to the drug's direct vasodilatory and inotropic effects observed in both humans and animals (84.85). Side effects during the first three months of treatment in a group of 35 young patients {ages 17 to 48 years) with ET included headache (34 percent), palpitations/tachycardia (23 percent), fuid retention (14 percent), and ciarhea (8 percent) [82]. The incidence ofthese side effects was reduced to 6,8, 6, and zero percent, respectively, following long-term use in the same group of patients. A reduction in hemoglobin concentration more than 3 g/dL was seen in 24 percent following long-term treatment. Side effects resulted in discontinuation of anagrelide in three of the 35 patients (9 percent). In a series of 577 patients treated with anaqrelide for thrombocythemic states including ET, 24 percent had fluid retention and 2 percent were diagnosed with heart failure [77]. Anagrelide use in patients with ET and polycythemia vera has been associated with acquired idiopathic cardiomyopathy [86], and must be given with caution in patients with known or suspected heart disease, which may limit its utility in the older patient [87]. Anagrelide therapy has also been reported as a potential cause of high output heart failure, (See "High-output heart failure", ther complications after a median treatment duration of 11 years included 10 episodes of thrombosis and seven episodes ‘of major bleeding [82]. Each of these 17 events was associated with a platelet count >400,000/microL, 12 of which (71 percent) were associated with a platelet count >600, 000/microL. These events were probably a result of incomplete control of the disease, rather than a side effect of therapy (see ‘Hiah risk patients’ below), Anagrelide versus hydroxyurea — Two randomized trials have compared the efficacy, safely, and tolerability of anagrelide versus hydroxyurea for the treatment of ET. United Kingdom Medical Research Council Primary Thrombocythemia 1 Study — In this trial, 809 patients with ET diagnosed according to the Polycythemia Vera Study Group (PVSG) Criteria and considered to be at high risk for vascular events were randomly assigned to receive treatment with either hydroxyurea (initial dose 0.5 to 1.0 g/day orally) or anaarelide (Initial dose 0.5 mg twice per day orally); both groups also received treatment with aspirin (75 to 100 mg/day PO) [52]. The doses of hydroxyurea and anagrelide were adjusted to maintain the patient's platelet count at <400,000/microL. Patients were classified as being at high risk for vascular events if they met one or more of the following criteria: © Age 260 years ‘© Current or prior platelet count 21,000,000/microL © Abistory of ischemia, thrombosis, or embolism ‘* Hemorthagic events caused by ET ‘¢ Hypertension requiring therapy ‘* Diabetes mellitus requiring treatment with a hypoglycemic agent Equivalent long-term control of the platelet count was achieved in both groups. After a median follow-up of 39 months, the ‘composite risk of arterial thrombosis, venous thrombosis, serious hemorrhage, or death from vascular causes was significantly greater in patients treated with anaarelide plus aspirin (odds ratio 1.6, 95% Cl 1.0-2.4). Anagrelide-treated patients also experienced a significantly greater increase in bone marrow reticulin [88], and a higher rate of transformation into myelofibrosis at five years (7 versus 2 percent, odds ratio 2.9, 95% Cl 1.2-6.9). There were no significant differences between the two treatment arms in regard to the subsequent development of myelodysplasia and/or acute myeloid leukemia telpeuhwwn toda. comfcentenslpragnosis- anc realmer essential brombocythamiataicKoy |EMEN2Fat868lopsedTimeMs=ABsource=search f... 620271820'6 Prognosis and veximent of essental tembocybemia ‘Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia study — The non- inferiority ANAHYDRET Study involved 259 previously untreated patients with ET at high risk for thrombohemorthagic ‘events, Subjects were randomly assigned to receive either hydroxyurea (intial dose 1500 mg/day) or anaarelide (initial dose 0.5 mg twice per day); only 28 percent of the patients in either treatment arm were taking aspirin during ths trial (89) After a follow-up of 730 patient-years, the investigators concluded that anaarelide was not inferior to hydroxvurea in Preventing thrombohemorrhagic complications in patients with WHO-defined ET. Infectious events, leukopenia, and ‘anemia were significantly more common in those taking hydroxyurea, while cardiac events (eg, hypertension, palpitations, tachycardia) were significantly more common in those taking anagrelide. No comments were made conceming the long- term risk of myelofibrosis. Conclusions — Our concems about the ANAHYDRET study include the non-use of aspirin in the majority of Patients, the severity of cardiac events in those taking anagrelide, and the lack of information about the long-term risk of myelofibrosis. Accordingly, we and others recommend the use of hydroxyurea and aspirin as first line therapy in high-isk ET patients (20) Alpha interferon — Alpha interferon controls the thrombocytosis associated with all myeloprolferative disorders, including ET. An overview of the reported literature indicates a 75 to 88 percent hematologic response rate, associated with a 32 Percent rate of reduction in spleen size [21-96]. Average starting doses were 3 to 5 milion units SQ daily, although doses as high as § million units/m2 per day have been used, Despite significant reduction in megakaryocyte mass, clonal hematopoiesis persists and alpha interferon is not curative (97) Pegylated interferon — Similar efficacy along with marginally less toxicity has been observed with the use of the pegylated interferons alpha-2b and alpha-2a, which provide prolonged activity compatible with once weekly dosing [96,98- 4101], (See "Prognosis and treatment of polyeythemia vera", section on 'P inter As an example, after a median follow-up of 42 months, the complete hematologic response rate was 77 percent in 40 patients with advanced ET treated with pegylated interferon alpha-2a, while the complete molecular response rate for the 19 subjects with the JAK2V617F mutation was 17 percent [100,102]. The tolerability of this agent at a starting dose of 90 mog/week was considered to be excellent, although some grade 3 toxicities were noted at that dose. ‘The overall benefit to patients, compared with current treatment that usually consists of hydroxyurea and low dose aspirin, is unknown, Considering the higher cost and increased toxicity associated with interferon therapy, a controlled study is needed before endorsing treatment with interferon as standard therapy in ET. Accordingly, because of these cost and toxicity issues, we have restricted the use of alpha interferon in ET to high-risk women of childbearing age, to those who are pregnant, and for controlling thrombocytosis in patients failing treatment with HU (65,103) Pipobroman — Pipobroman is an oral piperazine derivative, structurally classified as an alkylating agent [104]. The drug is not available in the United States; itis used widely in Europe for the treatment of PV and ET. Initial dose is 0.8 to 1.0 mg/kg per day PO; anticipated side effects include nausea, abdominal cramps, diarthea, stomatitis, and dry skin. In ‘studies with short-term follow-up, acute leukemia has not been associated with the use of pipobroman in ET [61.105] However, a small risk may exist with long-term therapy [106,107]. The risk of developing AML increases significantly when pipobroman is used with other agents, such as hydroxyurea [61], Low dose aspirin — The use of aspirin (ASA) in ET had been discouraged because of a previously demonstrated ‘association with an increased incidence of gastrointestinal hemorrhage when ASA was used in high doses (900 mg/day) in combination with another platelet antiaggregant (Jiovridamole, 225 mg/day) in patients with polycythemia vera [105]. However, lower doses of ASA (75 to 325 mg/day) have been shown to be effective in preventing recurrent vascular events. ‘among various high-risk population groups [109]. Similarly, low-dose ASA may be safe and possibly effective in preventing thrombosis in ET [36.27]. Low-dose ASA is especially effective in treating the vasomotor symptoms of ET and PV, such ‘as acral paresthesias and erythromelalgia [43.110]. Additional retrospective studies in ET support the value of low-dose ASA, as was also shown in a controlled study in patients with polycythemia vera [111,112]. (See "Diagnosis and clinical manifestations of essential thrombocythemia", section on ‘Vasomotor symptoms.) Low-dose aspirin (once or twice daily) should not be used in patients with ET and acquired von Willebrand disease. (See ‘Low risk patients with high platelet counts’ belaw.) {essental-brrombocythemiaMtapicKey telpeuhwwn toda. comfcentenslpragnosis- anc realmer IEMEV2F4de6slapsedTimeMs=ABsource=search 7120amerore Prognosis and treatment of essential trombocytemia ‘Twice daily low dose aspirin — The optimal dosing of aspirin in ET is not known. Whereas low-dose aspirin given ‘once daily is known to inhibit platelet thromboxane A, (TXAz) synthesis by approximately 97 to 99 percent in healthy ‘subjects through the irreversible inhibition of platelet cyclooxygenase-1 (COX-1) [113], the same aspirin regimen is unable to fully inhibit TXA, production in approximately 80 percent of patients with ET [114.115]. This may be due to increased platelet turnover in ET, with the emergence of young platelets with intact COX-1 activity in the 24 hours between aspirin doses. ‘This supposition has been supported in patients with ET in that giving the same total dose of aspirin (200 mg/day) in two divided doses was more effective in normalizing the functional platelet response to aspirin than when this same dose was given once daily [114]. Although the clinical benefit of the use of divided doses has not yet been shown in a definitive tral, this measure could be reserved at present for the following groups of patients: ‘* Those with clear evidence (ie, continuation of microvascular symptoms) of low-dose once daily aspirin treatment failure [37,116] ‘© Those with cardiovascular risk factors and JAK2 V617F, a group shown to be at high risk for thrombosis [6]. (See “Thrombotic risk’ above.) Radiophosphorus — The manufacturer of chromic phosphate P-32 (Phosphocol P 32) has discontinued production of this therapeutic radiopharmaceutical. It is no longer available in the United States or elsewhere. Plateletpheresis — Removal of platelets by pheresis techniques has been employed in patients with ET who have extreme degrees of thrombocytosis. However, neither the degree of thrombocytosis nor the presence or absence of platelet function abnormalities consistently correlates with the clinical presentation, Although prospective randomized trials ‘of plateletpheresis have not been conducted, this technique has generally been reserved for those with acute, serious, thrombotic or hemorrhagic events [117,118]. Because plateletpheresis lowers the platelet count only transiently, such treatment needs to be followed by the use of a myelosuppressive agent in order to maintain a platelet count within the recommended range (ie, <400,000/microL}. Patients most likely to benefit from plateletpheresis include the following: Severe or life-threatening organ dysfunction (eg, stroke, pulmonary embolism, ischemic digital necrosis) [119-122] Acute bleeding due to acauired von Willebrand disease [123,124] ‘There is less information conceming the value of perioperative plateletpheresis [125.126] Plateletpheresis has been effective in reducing the platelet count in those refusing myelosuppressive agents, but this Use is not recommended. Clinical settings in which patients with ET and high platelet counts are least likely to benefit from plateletpheresis include: ‘* When used in pregnancy to reduce the incidence of first trimester spontaneous abortions [117,127] ‘* When used in those with platelet counts >1,000,000/microL. who are asymptomatic ‘© There is litle oF no evidence that plateletpheresis is effective in patients with reactive thrombocytosis. TREATMENT RESULTS —A diagnosis of essential thrombocythemia (ET), based on a careful pathologic and ‘cytogenetic review, is associated with a very low risk of either leukemic transformation or occurrence of other life- threatening complications, (See "Diagnosis and clinical manifestations of essential thrombocythemia’, section on ‘Diaanosis'.) As a result, life expectancy in ET is minimally affected [8,21] and the indiscriminate use of potentially harmful treatment agents is not warranted [2]. Once the diagnosis is adequately established, the next step is to evaluate the presence or absence of risk factors for thrombohemorhagic complications (lable 1). The treatment of patients in each risk group, as well as management during or before pregnancy, are discussed below [41]: Low risk patients — Young patients with ET (age <60 years) with no history of thrombosis or hemorrhage and a platelet ‘count <1.5 million/microL were prospectively followed and evaluated for thrombohemorthagic events [38]. The incidence of thrombosis in the study patients (1.9/100 patient-years) was not significantly different from that of an age- and sex- matched control population (1.5 cases/100 patient-years) [38]. Similarly, minor bleeding episodes occurred rarely (1.1 ‘cases/100 patient-years). Of practical importance was the observation by the authors that the occurence of pregnancy or surgical intervention in the study population was not associated with significant thrombohemorrhagic risk. telpeuhwwn toda. comfcentenslpragnosis- anc realmer essential brombocythamiataicKoy |EMEN2Fat86tlopsedTimeMs=ABsource=search f.. 20amerore Prognosis and treatment of essential trombocytemia Our experience with young women with ET is similar [21]. In the absence of a history of thrombosis and regardless of the platelet count, the risk of recurrent thrombosis in our patients was only 1.2 cases/100 patient-years. These data support the practice of observation without cytoreductive therapy in young, low-risk asymptomatic patients with ET, even in those with extreme thrombocytosis [128] ‘The use of low-dose ASA (40 to 100 mg/day PO) in low risk patients is encouraged in the presence of vasomotor symptoms or general indications for ASA use. Low risk patients with high platelet counts — The use of cytoreductive therapy in those patients with ET who have Platelet counts >1 million/microL. is based on the association with an increased risk of hemorthage [9.21.35]. In addition, ‘extreme thrombocytosis may promote the abnormal adsorption of large von Willebrand factor (VWF) multimers and result ina hemostatic defect [123]. Accordingly, such patients should be screened for the presence of acquired von Willebrand disease (VW). Low-dose asoitin therapy (eg, $100 mg/day) is acceptable if the ristocetin cofactor level is at least 30 percent; if less than 30 percent, all aspirin should be avoided. (See "Classification and pathophysiology of von Willebrand disease", section on ‘Acquired von Willebrand disease'.) Further, we have recognized an association of extreme thrombocytosis and recurrent venous, but not arterial, thrombosis [21]. Despite these observations, the incidence of major bleeding episodes, in the absence of ASA abuse, remains very low, and the episodes are often not life-threatening, ‘Therefore, while it is reasonable to consider cytoreductive therapy in patients with extreme thrombocytosis, itis equally ‘acceptable to manage those patients who do not have acquired VW with clinical observation and/or low-dose aspirin, as long as they avoid tobacco and doses of ASA >100 mg/day. This is especially true, as will be discussed below, for young ‘women of childbearing potential High risk patients — The risk of recurrent thrombosis is unacceptably high in patients with a previous history of thrombosis or age >60 years. In the only randomized study that evaluated the benefit of cytoreductive therapy in high-risk patients with ET, treatment with HU was compared with observation alone [51]. At a median follow-up of 27 months, the incidence of recurrent thrombosis was significantly lower in the HU group (3.6 versus 24 percent). This benefit was maintained after a median follow-up of 73 months [67]. Results of this randomized study are supported by numerous uncontrolled studies that have shown reduced risk of thrombosis associated with adequate control of thrombocytosis in ET [2.17.53]. Of importance in the selection of a platelet-lowering agent, a prospective study involving over 800 patients with ET has noted a superiority of hydroxyurea over anaarelide in terms of prevention of both thrombosis and transformation into myelofibrosis [129] In choosing a particular platelet-lowering agent, one has to consider several patient factors including age, childbearing potential, anticipated life-expectancy, the presence of other comorbid conditions, and drug cost [130]. Because of its toxicity profile, we do not use interferon alpha in patients with ET unless in the setting of either treatment failure with other agents or pregnancy (see ‘Preanant women or those who desire to become preanant’ below). It is reasonable to consider the use of radioactive phosphorus in older patients with an anticipated life-expectancy of <10 years. In all other settings, we use HU as first line therapy. We strive for a target platelet count of <400,000/microl. [9.53.82]. Although generally safe, the benefit of adding low-dose ASA (40 to 100 mg/day PO) to HU therapy in high risk patients is not clear (51.131) ‘Smoking — Smoking is probably thrombogenic in ET [24,51] and has been reported to alter the inhibition of in vivo Platelet activation by low-dose ASA [132]. This should be emphasized to patients, especially if they wish to profit from the possible benefit of low-dose ASA [35.133]. Obesity is the only other cardiovascular risk factor that has been associated with thrombosis in ET [24]. We do not recommend cytoreductive therapy in ET based solely on the presence of smoking ‘or obesity; these risk factors should be managed by life-style modifications. Pregnant women or those who desire to become pregnant — In an updated review of 43 pregnancies that have ‘occurred in 20 patients seen at our institution, 21 (49 percent) did not result in live births, primarily because of first trimester spontaneous abortions (16 cases) [21,127]. This rate of pregnancy loss is more than what is expected in the general population (15 percent). We were not able to demonstrate significant correlations between preconception clinical features (eg, platelet count, thrombohemorthagic history, spontaneous platelet aggregation) and pregnancy outcome. The ‘outcome of pregnancy was not different between patients who received no specific therapy and those treated with ASA telpeuhwwn toda. comfcentenslpragnosis- anc realmer essential brombocythamiataicKoy |EMEY2F4t868lopsedTimeMs=ABsource=search f.. 9120271820'6 Prognosis and veximent of essental tembocybemia alone. Three pregnancies were carried to term, and resulted in deliveries of healthy babies, despite the use of 32P or busulfan around the time of conception, ‘The only significant predictor of spontaneous abortion was a previous history of miscarriages. On the other hand, patients who managed to sustain their pregnancy through the first trimester were able to carry their pregnancies to term without any thrombohemorthagic or obstetric complications. Complications during delivery were infrequent, even in the absence of prophylactic platelet apheresis. Others have reported that pregnancy in ET may be associated with premature delivery, stillbirth, intrauterine growth retardation, placental abruption, and preeclampsia [134,135]. These events were rarely encountered in our patient group. Uncontrolled studies have suggested the benefit of ASA, heparin, and interferon alpha in reducing the incidence of miscarriages or other pregnancy-related complications [136-139]. However, such reports suffer from an event and patient selection bias that makes it dificult to appreciate their putative antiabortive effect. Therefore, at present, it cannot be concluded that specific therapy influences the outcome of pregnancy in low- or intermediate-risk patients with ET. Our current practice is to observe these patients without specific therapy. In high-risk women with ET who are either pregnant or desire to become pregnant, specific therapy with a platelet/owering agent is indicated to protect the mother from recurrent thrombosis. Because antimetabolites are primarily implicated in fetal matformations associated with chemotherapy, the use of HU in the first trimester is often discouraged [140]. However, in a review of the literature on the use of HU in ET, AML, CML, and sickle cell disease, there were no reports of fetal malformations in nine patients exposed to HU in the first trimester [141]. Similarly, no il effects to the fetus were observed following second and third trimester exposures. ‘The theoretical risk of teratogenicity of interferon alpha is considered to be less than that of HU (91,134,135); there are numerous reports of successful pregnancies in patients with ET who were treated with this agent, As regards teratogenicity, anagrelide may also be safer than HU, but this agent is not currently recommended for use in pregnancy. Based on the above information, the current trend favors the use of interferon alpha during pregnancy [4,142]. However, we do not consider the inadvertent exposure to either anagrelide or HU as a reason to terminate pregnancy. Instead, such Patients should be reassured that inadvertent exposures to either of these agents have not resulted in adverse pregnancy ‘outcome [141], The use of anagrelide or HU should not be withheld from the high-risk pregnant woman who does not tolerate interferon alpha therapy, provided well-informed signed consent is obtained, Based on the above observations, it cannot be concluded that specific therapy influences pregnancy outcome in ET. Thus, we currently do not use drug therapy in low-risk patients. In case of recurrent abortions, the use of low-dose ASA or alpha- interferon is reasonable, but of unproven benefit [134.136.142]. The use of a platelet4owering agent may be necessary in high-risk women. Currently, both HU and anaarelide are contraindicated for use during pregnancy. On the other hand, several successful pregnancies have been reported in patients with ET receiving therapy with alpha interferon [134,138,143 144) CLINICAL TRIALS — Often, there is no better therapy to offer a patient than enrollment onto a well designed, scientifically valid, peer reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www. clinicaltrials.gov). ‘Agents under active investigation include combinations of agents already used in essential thrombocytosis, agents approved for other diseases, and other novel agents. As an example, imetelstat is an investigational antisense oligonucleotide directed against telomerase. In a pilot study, all 18 patients with essential thrombocytosis treated with imetelstat achieved a hematologic response and 16 achieved a complete hematologic response [145]. The most common toxicities were myelosuppression, and elevations in liver enzymes were usually reversible, SUMMARY AND RECOMMENDATIONS Indications for treatment ‘* Most patients with essential thrombocythemia (ET) are asymptomatic and can be observed for months or years after the diagnosis is established before requiring treatment. Treatment strategies are based primarily on the presence or absence of risk factors for thrombosis (lable 1) (see ‘Proanosis' above) ‘Treatment telpeuhwwn toda. comfcentenslpragnosis- anc realmer essential brombocythamiataicKoy |EMEN2Fat868lopsedTimeMs=ABsource=search... 1020zm0%6 Prognosis andtresiment of essential rembocythemia ‘* We suggest that low-risk patients not be treated with myelosuppressive or platelet-owering agents (Grade 2C). (See ‘Low risk patients’ above.) ‘¢ We recommend the use of platelet-lowering agents for high risk patients with ET (Grade 18), Our current initial regimen of choice is hydroxyurea in combination with low dose aspirin. (See ‘High risk patients’ above and ‘Hivdroxvurea! above and ‘Low dose aspirin’ above.) ‘© We suggest that myelosuppressive or platelet owering agents not be employed in low-risk or intermediate-isk Women who are either pregnant or are of childbearing age (Grade 2C), ‘If myelosuppressive or platelet lowering agents are indicated in a high-risk pregnant patient with ET, we suggest the Use of interferon over no treatment or treatment with anaorelide or hycroxvurea (Grade 2C). (See ‘Pregnant women or those who desire to become preanant’ above.) ‘© We suggest the use of low-dose aspirin (eg, 100 mg/day orally) in the presence of vasomotor symptoms or general indications for aspirin use (eg, presence of cardiovascular risk factors) and in the absence of acquired von Willebrand disease (Grade 2C). Patients with ET should be advised to discontinue smoking and control obesity and other cardiovascular risk factors, if present. 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