Abstract
Physicians from nine European countries were asked to complete a survey, which was conducted in two waves (Wave II, October 2009; Wave III, May 2010), based on their current treatment practices for essential thrombocythemia (ET). The aim of the study was to gain insight into physicians' criteria for treatment initiation and reasons for switching from one therapy option to another. The majority of patients receiving first-line cytoreductive therapy for ET were treated with hydroxycarbamide (HC; 63 and 71% in Waves II and III, respectively), while the majority of patients on second-line therapy received anagrelide (51 and 60% in Waves II and III, respectively). Efficacy was the main factor cited for switching therapies (cited by 47 and 58% of physicians in Waves II and III, respectively). Further studies are needed to determine whether current practices used by physicians for the treatment of ET are consistent with consensus guidelines.
Introduction
Essential thrombocythemia (ET) falls under the umbrella of myeloproliferative neoplasms (MPNs), which also include polycythemia vera (PV), chronic myelogenous leukemia (CML), and primary myelofibrosis.Citation1 ET is an acquired clonal disease that is characterized by sustained elevations in platelet number arising from an expansion of megakaryocytic lineage.Citation2 This overproduction of mature blood cells is the common underlying molecular pathology shared by most MPNs; however, ET (like PV and primary myelofibrosis) differs from CML in the absence of the Philadelphia chromosome abnormality. ET is one of the most common MPNs, with annual incidence estimated at 1.5 per 100 000 of the general population.Citation3 Although a diagnosis of ET is established at a median age of 65–70 years old, age of onset is wide ranging and patients are frequently diagnosed with the condition in their 30s or 40s.Citation2 Notably, ET occurs more often in females than in males (approximately two-fold higher) and, therefore, ET-associated pregnancies are commonly observed.Citation2
Among patients, the presentation of ET is clinically heterogeneous; while a proportion of patients (36%) are reported to be asymptomatic at diagnosis,Citation4 other patients experience characteristic vasomotor disturbances (including headaches, dizziness, visual disturbances, erythromelalgia) and the more serious complications of hemorrhages and vascular events, which represent dominant features of the condition.Citation2 The clinical course for patients with ET can also be complicated by events such as leukocytosis, splenomegaly, pruritus, arthropathy, and neurological impairment.Citation5 A retrospective analysis of 809 patients with ET revealed that 42% experienced thromboembolic events without bleeding, 1.4% experienced bleeding symptoms without thrombosis, and 15% experienced both bleeding and thrombosis.Citation4 Accordingly, major thromboses are associated with significant mortality and morbidity in patients with ET.Citation2 The recently updated World Health Organization (WHO) guidelines for the classification and diagnosis of MPNsCitation6 define the major criteria for ET as a platelet count ≥450 000/μl; megakaryocyte proliferation with large and mature morphology; no or little granulocyte or erythroid proliferation; not meeting the WHO criteria for any other MPNs; demonstration of JAK2V617F mutation or other clonal markers; and no evidence of reactive thrombocytosis. Since the introduction of these diagnostic criteria, a population-based study detected a significant increase in the incidence of ET, mainly owing to the use of JAK2 mutational screening and a lower platelet count threshold.Citation7 Moreover, in a recent survey of 250 European hematologists and hemato-oncologists, the treatment of ET was attributed to approximately 36% of physicians' MPN workload.Citation8
Lowering the risk of thrombosis constitutes a key goal in the treatment of ET, in addition to controlling disease-related symptoms and reducing primary and iatrogenic disease progression.Citation9 Risk stratification schemes have been proposed in efforts to elucidate thrombosis risk whereby the presence of one of the predisposing factors of age (above 60 years old), prior thrombosis, concurrent medical conditions associated with increased vascular risk, or elevated platelet count (>1500 × 109/l, but this may be an arbitrary value) is attributed to a high risk of thrombosis in a patient with ET.Citation10,Citation11 Hydroxycarbamide (HC), anagrelide, alkylating agents (such as busulphan), and interferon-alpha (IFN-α) represent cytoreductive strategies within the therapeutic armamentarium for ET. Of these existing strategies, HC is currently indicated for first-line use in the treatment of ET.Citation10,Citation12,Citation13 However, it has been shown that up to 10% of patients do not achieve the target platelet count or hematocrit reduction with HC at recommended doses.Citation9 Furthermore, owing to concern over a potential link between the use of HC and the development of leukemogenesis, guidelines recommend that subsequent therapies should exhibit no or minimal leukemogenic potential (anagrelide and interferon are such agents), particularly in younger patients.Citation10 Despite reported cytoreductive benefits and reduced potential for leukemogenicity with conventional and recombinant forms of IFN-α in ET,Citation9,Citation11,Citation12 the relative absence of confirmatory evidence (particularly in the prevention of thrombosis) from randomized controlled trials currently limits IFN-α to off-label use for the treatment of ET. Anagrelide, on the other hand, is indicated as second-line therapy for patients with ET who are resistant or intolerant to their first-line therapy. Anagrelide (Xagrid®/Agrylin®) is an oral imidazoquinazoline agent for which a significant body of evidence supported its approval in Europe (2004) and the USA (1997) for the reduction of elevated platelet counts in high-risk patients with ET.Citation14–Citation19
Few studies have examined the uptake of treatments for the management of ET in Europe.Citation8,Citation20 Therefore, we conducted a Europe-wide survey with the overall aim of examining treatment practices adopted by physicians responsible for treating patients with ET, and to gain insight into the factors driving the decision to start treatment and reasons to switch therapies.
Methods
Physicians involved in the treatment of ET across nine European countries were selected to complete a 45-minute internet-based survey regarding their current treatment practices based on the criteria described in . Surveys were performed in two different waves such that Wave II was conducted during a 1-month period from 14 September to 16 October 2009, while Wave III was undertaken from 2 April to 11 May 2010. The results of the Wave I survey (conducted in early 2009) are not presented here.
Table 1. Sample screening criteria for physicians participating in the study
The survey comprised specific questions and was conducted in two parts. The first part was designed to examine current practices (physicians' perceptions of ET and current treatments, and prescription patterns) and the second was designed to assess information related to the individual records of patients with ET (patient chart studies).
Survey design
Wave II
Hematologists from public, private, and mixed clinical settings who were involved in the treatment and management of ET, and currently treating at least four patients with ET were eligible to participate in the survey. In addition, all respondents were required to currently prescribe cytoreductive treatments for patients with ET and to spend at least 75% of their time in clinical practice. All participants were directors/heads of department/consultants or senior grade staff with at least 4 years (but less than 35 years) of practice experience. In this wave, hematologists from France, Germany, Italy, the UK, Spain, Portugal, Belgium, the Netherlands, and Ireland completed the 45-minute internet-based survey. Overall, physician perception and patient chart data were obtained from 311 hematologists and 1253 patients with ET, respectively.
Wave III
Wave III employed an identical design to Wave II, with the exception of a few methodological differences. In addition to the selection criteria for Wave II, hematologists, hemato-oncologists, and physicians in internal medicine were included in this wave. Furthermore, physicians were required to have initiated treatment in at least two patients within the last 12 months (currently in first- or second-line therapy). In Wave III, physician perception data were obtained from 307 physicians and patient chart data from 948 patients with ET.
Results
Survey population
In Wave II, a total of 311 hematologists from France, Germany, Italy, the UK, Spain, Portugal, Belgium, the Netherlands, and Ireland participated in the survey and patient charts were available from 1253 patients (see for country breakdown). In Wave III, 219 hematologists, 87 hemato-oncologists, and one physician in internal medicine participated in the survey, from France, Germany, Italy, the UK, Spain, Portugal, Belgium, the Netherlands, and Ireland (see for country breakdown). Across countries, physicians provided patient charts for a total of 948 patients.
Table 2. Country breakdown of participants in the survey by role and the patient charts available for analysis
ET epidemiology
According to physician's perspectives on their current treatment practice, in a typical year, the average number of patients diagnosed with ET was similar across waves (10.8 and 9.3 in Waves II and III, respectively). Responses to questions regarding the management of patients with ET indicated that physicians in Europe treated on average 30 patients with ET, in Wave II, and 38 patients with ET, in Wave III. When examined by individual countries, more patients were treated in France (n = 39 and 50 in Wave II and III, respectively; P = 0.05) and the UK (n = 51 and 62, respectively; P = 0.01) in both waves. Physician respondents reported seeing a mean of 10.9 (Wave II) and 11.1 (Wave III) patients with ET in a typical month, which was generally consistent across the majority of countries (except for the UK, where physicians saw approximately 18 patients with ET per month). However, the results indicated that 70% of patients were seen on less than a monthly basis (Wave III). In general, patients visited physicians eight times in the first year of treatment, which declined to five visits annually in the second and subsequent years. Survey results also showed that both physicians and patients were largely in agreement in rating the severity of their condition as moderate (Wave II data only).
Current treatment practice
Treatment lines
Physicians estimated that patients received first-line therapy for an average duration of 43 and 30 months in Waves II and III, respectively. Upon analysis of questions related to current treatment practice, results revealed the characteristics of the average patient with ET receiving first-line therapy (data from Wave III only) were: being aged 63 years old (67% >60 years old); being diagnosed at 61 years of age (61% diagnosed >60 years old); and being more likely to be female (52%). Similarly, the typical patient with ET receiving second-line therapy was (data from Wave III only): aged 63 years old (64% >60 years old); diagnosed at 59 years of age (58% diagnosed >60 years old); and more likely to be female (54%).
Based on physician perspectives on the proportion of patients receiving cytoreductive therapy, in Wave II (n = 311) physicians reported that 67% of patients were receiving first-line therapy followed by 23, 8, and 2% receiving second-, third- and fourth-line (or more) therapy, respectively. Questions posed to physicians in Wave III (n = 307) indicated that 62% of patients were receiving cytoreductive therapy (46% in combination with aspirin or another antiplatelet agent; 16% without another treatment), while 25% were receiving another form of therapy and 12% received no therapy at all. Similarly, patient chart data from Wave III indicated that 65% (n = 616) of patients were receiving first-line therapy while the remaining 35% (n = 332) were receiving second-line (or more) treatment.
Based on patient chart data, the majority of patients on first-line therapy received HC monotherapy (63 and 71% for Waves II and III, respectively; ). Of these patients, 88% received an additional antithrombotic/antiplatelet drug, which was most commonly aspirin (90%). When used as monotherapy, physicians administered HC at average doses of 1002 mg in Wave II or 802 mg in Wave III. Across waves, anagrelide monotherapy was most frequently used as second-line therapy (51 and 60% for Waves II and III, respectively; ). On average, anagrelide monotherapy was administered at a dose of 1.8 mg in Wave II and 1.4 mg in Wave III. Of the patients who received anagrelide, 51% were treated with an additional antithrombotic/antiplatelet drug (mainly aspirin, 92%). Efficacy in reducing platelet count and platelet selective action were the most frequently stated reasons for prescribing anagrelide (88 and 86% of physicians, respectively, in Wave II; 77 and 81%, respectively, in Wave III), and were cited as the most important reason by approximately one-third of these physicians.
Table 3. Current prescribing patterns for patients with ET receiving first- (n = 1451) and second-line (n = 455) therapy (patient chart data)
Treatment targets
In the European countries surveyed, data from responses to questions relating to physician's current treatment practice demonstrated that the average platelet count at which physicians initiated ET therapy was 954 000/μl (ranging between 801 000 and 1 400 000/μl across countries) and 939 000/μl (781 000 to 1 150 000/μl) in Waves II and III, respectively. Moreover, physicians aimed to achieve an average platelet count of 411 000/μl and 419 000/μl (in Waves II and III, respectively) with cytoreductive therapy, which was generally similar between countries.
Analyses of patient chart data revealed that the average physician-defined target platelet count was 455 000/μl (range 425 000–500 000/μl) while the mean current platelet count was 438 000/μl (range 388 000–504 000/μl).
Treatment initiation
When asked to rank factors driving the decision to start treatment, thromboembolic history, platelet count, and cardiovascular history were cited as the most important reasons driving treatment initiation by physicians in Waves II and III (), and was consistent between individual countries (with the exception of physicians in Ireland, who cited platelet count as the most important reason). Age ranked fourth as a driving factor determining decisions to start treatment in both waves. Specifically, the threshold at which age prompted physicians to initiate cytoreductive treatment was reported to be above 57 years old in Waves II and III.
Table 4. Factors driving the decision to start ET treatment (ranked from 1–10; 1 = not important, 10 = very important)
Switching patterns
Overall, 17% (Wave II; n = 310) and 18% (Wave III; n = 307) of patients were reported to switch treatments within 12 months of initiating cytoreductive therapy, based on physician's perceptions. In Wave II, the main reasons cited by physicians for switching from first- to second-line treatment were efficacy (47%), tolerability (38%), and safety (12%). In Wave III, efficacy also represented the predominant reason behind the decision to switch from first-line cytoreductive treatment (58% compared with 27% for tolerability and 14% for safety), but was cited by a higher proportion of physicians than in Wave II. Based on patient chart data, of the patients who switched from first-line HC therapy for ET, the majority (53%) received second-line treatment with anagrelide (; Wave III data only).
Table 5. Prescribing pattern in patients with ET currently in their second-line or more of therapy (patient chart data)
Discussion
This Europe-wide internet-based survey examined current practices and perceptions of more than 600 physicians treating patients with ET. The survey was conducted in two 1-month waves over a period between September 2009 and May 2010, and there were no significant changes between Waves II and III for most parameters. When interpreting data from both waves, it should be noted that these findings represent responses from selected European physicians and may not be generalizable to clinical practice in Europe as a whole. However, given the dearth of survey-based studies in this area, these data enable us to gain an understanding of current clinical experience with regard to the treatment of ET. As data were obtained both from patient charts and from questions posed to physicians directly, the results of this survey also allow us to examine how physician perceptions compare with their clinical practice based on patient charts. Overall, for parameters where both physician perception and patient chart data were available, such as for target platelet counts and the proportion of patients receiving first-line therapy, physician opinion tended to match the data obtained from patient charts.
Reducing the risk of thrombosis is a key treatment goal, and, to this end, risk stratification schemes have been proposed to aid ET management. Patients above 60 years of age are proposed to be at high risk of thrombosis,Citation10 which generally corresponds to the threshold age at which physician respondents to this survey were reported to initiate cytoreductive treatment (above 57 years old). According to the current survey results, HC was the predominant first-line treatment of choice among physicians, which agrees with ET treatment guidelines.Citation10,Citation13 As second-line therapy, anagrelide is the only agent to have received European Medicines Agency approval for use in patients with ET, and in the current survey, anagrelide appeared to be the treatment of choice for second-line ET therapy, suggesting that physicians are utilizing anagrelide within its European licence. Target platelet counts cited by physicians in our survey were 411 000/μl and 419 000/μl in Waves II and III, respectively. This is in line with the most recent guidelines for response criteria, which define a complete response to ET treatment as achieving platelet counts <400 000/μl in addition to no disease-related symptoms, a normal spleen size and white blood cell counts <10 000/μl.Citation12,Citation21 Treatment targets and reasons cited for switching therapies were fairly consistent across countries and between the survey waves, suggesting that physicians may be adopting consensus guidelines in a unified manner.
Results from a similar survey published in 2009,Citation8 which examined the management of ET with a focus on the uptake of anagrelide treatment among 250 hematologists and oncologists in Europe (France, Germany, Italy, Spain, and the UK), may allow comparisons with findings presented in our study. When compared with this previous survey, patients in the present study appeared to achieve a lower platelet count with their current ET therapy (mean platelet counts of 438 000/μl [range 388 000–504 000/μl] versus 566 000/μl [range 100 000–2 200 000/μl]). Moreover, a significant proportion of patients did not achieve their target platelet count in the previous survey (64.3%), while in the current study the mean platelet count achieved was lower than the average target platelet count of 455 000/μl. The proportion of patients receiving first-line therapy (65%) appeared to be lower in the current survey than in the previous survey (73.3% of patients), and more patients in the present study received first-line therapy with anagrelide alone or in combination with other therapies (22–26% compared with 14.9% in the previous study). As previously reported by Reilly,Citation8 35.7% of patients with ET receiving second-line therapy were treated with anagrelide, which is somewhat lower than the 69% reported to be receiving second-line anagrelide (alone or in combination) in our current survey.
It may be considered that the above-mentioned differences reflect the changes in treatment practices since the previous survey was conducted. Physicians may be more inclined to switch therapies if the existing treatment regimen does not result in an adequate reduction of platelets. Indeed, when questioned, the majority of physicians cited lack of efficacy as the most important reason for switching therapies (more physicians in Wave III cited efficacy as the main reason to switch to another treatment regimen than in Wave II). With relevance to changes in practice, timelines for data collection in the previous survey (2006) preceded new consensus guidelines that were developed with the aim of identifying a universal definition of clinical resistance/intolerance to HC.Citation22 Specifically, these were defined as a platelet count greater than 600 000/μl after 3 months of treatment with at least 2.0 mg HC/day (2.5 mg/day in patients with a body weight >80 kg), or a platelet count greater than 400 000/μl (with a white blood cell count less than 2500/μl or hemoglobin levels lower than 10 g/dl) at any dose of HC. One benefit expected to arise from the introduction of these guidelines was greater consistency in the management of patients with ET.Citation23 However, there is currently limited evidence to support these criteria as major determinants for the decision to switch treatments in clinical practice. Such inconsistencies highlight the need for future studies to determine at what point physicians make the decision to switch from first-line to an alternative line of therapy, and whether these reasons are consistent with consensus guidelines.
Author contributions
Concept/design: JR; Data interpretation: JR; Drafting article: JR; Critical revision of article: JR; Approval of article: JR.
Disclosures
John T. Reilly has attended advisory boards for Shire and has no financial conflicts of interest to declare.
Acknowledgements
Medical writing support for this article was provided by Farah Dalwai, PhD, Medicus International, and funded by an unrestricted educational grant from Shire.
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