Current opinion and consensus statement regarding the diagnosis, prognosis, and treatment of patients with essential thrombocythemia: a survey of the Spanish Group of Ph-negative Myeloproliferative Neoplasms (GEMFIN) using the Delphi method
The current consensus on the diagnosis, prognosis, and treatment of essential thrombocythemia (ET) is based on experts’ recommendations. However, several aspects of the diagnosis of, prognosis of, and therapy for ET are still controversial. The Delphi method was employed with an expert panel of members of the Spanish Group of Ph-negative Myeloproliferative Neoplasms in order to identify the degree of agreement on the diagnosis, prognosis, and treatment of ET. Nine leading experts selected a total of 41 clinical hematologists with well-known expertise in ET. An electronic questionnaire was used to collect the questions rated in a four-step scale. The questions were grouped into four blocks: diagnosis, risk stratification, goals of therapy, and treatment strategy. After the first round consisting of 80 questions, a second round including 14 additional questions focused on the recommendations advocated by experts of the European LeukemiaNet in 2011 was analyzed. The median and mean values for the first and second rounds were calculated. A summary of the conclusions considered as the most representative of each block of questions is presented. The Delphi method is a powerful instrument to address the current approaches and controversies surrounding ET.
KeywordsEssential thrombocythemia Delphi Consensus statement Survey questionnaire
Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by persistent thrombocytosis, a tendency to develop vascular complications, and a risk of transformation into myelofibrosis and acute leukemia. ET is the commonest BCR-ABL1 MPN and also the one with the best prognosis, since patients with this condition have a near normal life expectancy.
According to the current World Health Organization (WHO) criteria, the diagnosis of ET requires the finding of a persistent thrombocytosis (>450 × 109/L) together with hyperplasia of mature megakaryocytes in the bone marrow with absent or minimal fibrosis, demonstration of a clonal marker, exclusion of other WHO-defined myeloid malignancies with accompanying thrombocytosis, and lack of evidence of reactive thrombocytosis . Recently, a proposal has been made to incorporate the mutations of the CALR and MPL genes within the category of clonal markers for the revised WHO diagnostic criteria .
In 2011 an expert panel of the European LeukemiaNet (ELN) proposed a set of recommendations on the assessment of vascular risk, the goals of therapy, and the treatment strategy to be used in patients with ET and other MPNs . The purpose of these proposals was to offer clinicians a framework of recommendations based on the results of randomized clinical trials, the expertise of leading authorities on MPN, and also the strategies adopted in real-life clinical practice. Despite this, several aspects of the diagnosis and management of ET patients are still controversial . Moreover, new data on the molecular pathogenesis of ET have recently been produced [5, 6]. Thus, it is now recognized that a significant proportion of ET patients carry mutations in the CALR gene, with these patients having a lower risk of thrombotic events than those with the JAK2V617F mutation [7, 8]. With regard to treatment, there is also novel information on the rational use of low-dose aspirin in low- and high-risk patients, the ability of pegylated interferon in modulating the mutational JAK2V617F allele load, new data coming from the ANAHYDRET trial, and the proposal of new prognostic scores, among several topics [9, 10, 11, 12, 13, 14]. However, the degree of incorporation of these and other advances in the routine clinical practice of hematologists managing ET patients is unknown.
The aim of this study is double: (1) to analyze the state of opinion and the degree of consensus on the current approaches regarding the diagnosis, prognosis, and treatment of ET patients using the Delphi technique and (2) to ascertain how the 2011 ELN recommendations concerning ET are perceived by Spanish hematologists with well-known expertise on MPN.
Material and methods
The Delphi technique is a widely used and accepted method aimed to develop consensus building by using a series of questionnaires to collect data from a panel of selected individuals. Through anonymous structured rounds of questions, participants are asked to answer particular enquiries regarding specific topics. The Delphi rounds allow participants to re-assess their own answers according to the information provided in the previous rounds. This technique identifies the degree of agreement but does not force consensus, allowing weighing up the opinions depending on the number of participants and the gradation of their answers. In terms of responses, two parameters are measured: the mean and the degree of agreement. The mean represents the average value of all the responses, and the degree of agreement is based on the median and the mode. One of the main advantages of the Delphi technique is subject anonymity, which can reduce the effects of dominant individuals, which often is a concern when using group-based processes to collect and synthesize information [15, 16].
A group of nine leading experts (panel) on MPN from the Spanish Group of Ph-negative Myeloproliferative Neoplasms (GEMFIN) formed the advisory panel. Topics and questions regarding diagnosis, prognosis, and treatment were formulated by the panel and separated into four blocks: diagnosis, risk stratification, goals of therapy, and treatment strategy. The panel preselected a total of 41 clinical hematologists with well-known expertise in the diagnosis and management of patients with MPN. Each of the 41 participants received an e-mail with a password to get connected to an online web page that was specifically developed for this project by BCNscience. Answers to all the questions formulated were rated in a four-step scale according to the following responses: 1 = no agreement, 2 = some agreement, 3 = quite agreement, and 4 = strong agreement. The web page automatically collected the data, and the mean, the mode, and the median were calculated for each question according to the number of responders. Anonymity was strictly guaranteed, and no participant was able to get access to the answers of other members. Participants were encouraged to provide comments and suggestions to those questions perceived as not well formulated, ambiguous, or not sufficiently clarified.
The first Delphi round consisted of 80 questions. After the first round, results with the scores (mean, mode, and median) to each one of the questions were sent to the participants and the panel revised any comments or suggestions raised by them. Some questions were clarified, but the wording of all questions remained unchanged. The panel agreed to incorporate to the second round 14 additional questions focused on the recommendations on the diagnosis, assessment of vascular risk, and treatment approaches advocated by experts of the ELN in 2011. In the second round, participants were encouraged to revise their previous answers in accordance to the replies of other participants. The final analysis was made after receiving the answers of the second round, and the differences observed between first and second rounds were analyzed. A strong agreement (score 4) by ≥75 % of the panelists was selected as the single rule to draw conclusive final recommendations. Negative consensus was defined as score 1 (no agreement) by ≥75 % of the participants.
Mean and median (level of agreement) values corresponding to first and second rounds
Mean and median (level of agreement) values corresponding to first and second rounds
Mean and median (level of agreement) values corresponding to first and second rounds
Mean and median (level of agreement) values corresponding to first and second rounds
Summary of recommendations based on grade 4 agreements with panelist consensus ≥ 75 %
1. Need for institutional and nation-based ET registries
2. Usefulness of an algorithm for the differential diagnosis of a thrombocytosis
3. Molecular genotyping for JAK2V617F, CALR, and MPL genes is essential
4. Importance of the recognition of the prefibrotic form of myelofibrosis
5. Diagnosis of bone marrow biopsy must be done by expert hematopathologists
6. Training of pathologists on bone marrow diagnosis is highly recommended
7. History of thrombosis is considered more important than age as a variable for risk stratification
8. Assessment of cardiovascular risk factors is essential
9. Appearance of cardiovascular risk factors during clinical follow-up should modify risk assessment
10. European LeukemiaNet-defined goals of therapy are appropriate
11. Cytoreduction is mandatory if platelet number > 1500 × 109/L
12. Choice of cytoreductive treatment must consider the patient’s age, quality of life, and life expectancy
13. Anagrelide is considered the second-line treatment of choice after resistance/intolerance to hydroxyurea
14. Need to perform an ECG or an echocardiogram before starting treatment with anagrelide
15. Necessity to switch therapy after serious mucocutaneous side effects of hydroxyurea
16. Consensus to inform the patient about the side effects of treatment and the risk of transformation to myelofibrosis and acute leukemia
17. Need to evaluate periodically the adherence, efficacy, and side effects of therapy
18. Appearance of thrombosis during clinical evolution is a strong criterion to start cytoreductive therapy
The results of this survey using the Delphi technique provide a detailed insight into the current thinking of Spanish hematologists concerning the main topics on the diagnosis, prognosis, and clinical management of ET patients. The available information regarding the practice patterns of experts in the management of MPN is limited. To this respect, Streiff et al.  performed a similar survey among US hematologists and oncologists focusing on the physicians’ approach to patients with polycythemia vera (PV). The authors identified that a significant minority of physicians undertreated erythrocytosis and that little consensus existed concerning the treatment of thrombocytosis in this disease . In a study from the Italian Society of Hematology, the Delphi technique was adopted to develop practice guidelines for the treatment of ET patients . Similarly, the Delphi method has also been used by a group of pathologists and hematologists to obtain expert consensus during the elaboration of a standardized report to describe bone marrow histologic findings in myelofibrosis . The purpose of the present study was to ascertain a holistic view of ET by the Delphi method, integrating the main controversial aspects about the diagnosis, prognosis, and treatment of this disease.
Regarding the diagnostic approach for ET, there was a strong accordance on the need to perform a rational step-based molecular analysis for mutations in the JAK2V617F, CALR, and MPL genes; that is, the genetic workflow analysis should search for mutations in JAK2V617F first, CALR second, and MPL third. The awareness of genotype-phenotype correlations and the prognostic significance of thrombotic risk of JAK2V617F and CALR mutations probably influenced the total agreement of responders about the need of a complete characterization of all ET patients from the molecular point of view. Second, the prognostic significance of the prefibrotic form of primary myelofibrosis, in terms of both the survival and the risk of myelofibrotic transformation, probably stands behind the generalized support to recognize this histological entity by a pathologist specifically trained in the field of MPN histology . Third, the panelists agreed about the necessity of institutional and nation-based ET registries. In this regard, the Spanish registry of PV patients demonstrates how the analysis of a particular issue in a large cohort of MPN patients may provide useful clinical information . Finally, it is worth noting that some techniques related to ET diagnosis such as isotopic red blood cell mass measurement and in vitro culture of hematopoietic progenitors were not considered as useful studies, although the degree of agreement was not so conclusive to consider them as negative recommendations. Experts on MPN argue that both tests are cumbersome, costly, and available only in research centers, limiting the practical application of these techniques for diagnostic purposes .
The results of the survey on risk stratification showed two main agreements: (1) the history of thrombosis is considered the most important clinical variable for thrombotic risk stratification and (2) the importance of assessing cardiovascular risk factors at diagnosis and during clinical evolution. Interestingly, 23 and 61 % of participants showed a strong (score 4) and a quite agreement (score 3), respectively, that is, a positive trend, to support the existence of an intermediate risk category that is not currently recognized as such by the ELN. Such intermediate group could include patients that do not belong to the high- or the low-risk categories but display one or more cardiovascular risk factors. The British Committee for Standards in Haematology defines this category as patients with age between 40 and 60 years but without cardiovascular risk factors . Although ELN recommendations on ET treatment advocate for a strict control of cardiovascular risk factors and cessation of smoking , the existence of this category of risk is still controversial, although in clinical practice this group of ET patients represents a real challenge.
In the present survey, the participants agreed with the general goals of treatment established by the ELN and that the choice of cytoreductive treatment must consider the patient’s age, quality of life, and life expectancy. In addition, majority of the panelists also agreed on the need to start cytoreduction in case of extreme thrombocytosis (>1500 × 109/L). However, in specific topics such as the target hematologic values of cytoreductive treatment, there was no strong agreement with respect to the ELN recommendations [24, 25]. Thus, participants showed a trend to agree that normalization of the platelet count was an appropriate target, but disagreed on the need to normalize the leukocyte count. To this respect, leukocytosis at diagnosis or persisting on cytoreductive treatment has been associated with an inferior thrombosis-free survival [26, 27, 28]. However, two reasons may explain in part the lack of agreement of most clinicians to initiate cytoreduction based on an increased leukocyte count. First, there are no prospective studies addressing this issue, and, second, leukocytosis is not a prominent feature of WHO-defined ET patients . In short, there are still no formal recommendations to initiate cytoreductive treatment based on this feature alone.
Some issues regarding the treatment strategy deserve to be mentioned. ELN states that hydroxyurea is the first-line cytoreductive therapy at any age, although in young patients (<40 years old), its use should be carefully considered . Responses to this recommendation were very heterogeneous; however, there was a tendency to favor anagrelide as a potential first-line treatment for high-risk young patients, despite the fact that this use is an off-label indication in Europe . Likely, ANAHYDRET trial results may have influenced this current view . On the other hand, anagrelide was considered the preferred second-line cytoreductive option for ET patients resistant to hydroxyurea. With regard to anagrelide, participants expressed a strong agreement about the need to perform an ECG or an echocardiogram before starting treatment with this drug.
Of note, survey responders strongly agreed that interferon is not an acceptable first-line therapy for young patients (score 4 negative agreement ≥ 75 %). Interferon has demonstrated clinical efficacy in phase II–III clinical studies, but its role needs to be clarified in randomized studies . The ongoing prospective trial of the MPD-Research Consortium comparing hydroxyurea with PEG-IFN-alpha-2a in high-risk ET and PV patients will certainly provide useful information about this issue . Busulfan was not viewed as a current therapeutic option in ET, although recent data have shown its usefulness in elderly ET patients resistant or intolerant to hydroxyurea .
Despite the lack of strong consensus, the use of antiplatelet therapy, specifically aspirin, warrants also some comment. Most participants expressed a favorable opinion to support the use of aspirin in all ET patients, irrespective of whether or not they receive cytoreductive therapy. This opinion was particularly favored in patients with microvascular disturbances or associated cardiovascular risk factors. However, JAK2V617F mutational status was not contemplated as a variable to be taken into account for the indication of aspirin .
Concerning assessment of response, the 2013 revised response criteria of the ELN propose normalization of bone marrow histology as a major criterion to define complete response. These criteria have been designed for clinical trials in order to facilitate the development of new therapeutic agents for ET patients . Evaluation of bone marrow in order to assess the efficacy of treatment was not contemplated by any of the participants. This is not surprising, given that ET is a chronic disease that has a near-normal life expectancy, is relatively easy to control clinically, and involves a large proportion of elderly people .
Lastly, most responders acknowledged the convenience of informing the patient about the risk of myelofibrotic and/or acute transformation as part of the natural evolution of the disease or as a complication of therapy (e.g., sequential use of chemotherapy) [35, 36]. Similarly, all participants were of the opinion of the usefulness of evaluating periodically the adherence, efficacy, and side effects of therapy. With regard to the adverse consequences of treatment, most participants strongly agreed on the necessity to switch therapy after serious mucocutaneous side effects of hydroxyurea.
In conclusion, this survey provides extensive information on how experts on MPN appraise the academic and also the practical approach of the diagnosis, prognosis, and treatment of ET patients and how they perceive the recommendations made by the ELN on this disease. The results of this survey may help to increase the awareness of unmet needs in several aspects of ET and the need to optimize the care of these patients.
We are indebted to all members of GEMFIN who participated in this study.
This work was supported by grants PI13/00393, PI13/00557, and RD12/0036/0010 from the Instituto de Salud Carlos III; SGR 2014-567; and funding from Shire Pharmaceuticals Ibérica for the conduct of this study.
The authors are grateful to the physicians who kindly participated in the expert panel: Anna Angona, Hospital del Mar, Barcelona; Maria Luisa Antelo, Hospital de Navarra, Navarra; Elisa Arbelo, Hospital Virgen de Macarena, Sevilla; Ana Isabel Arribas, Hospital de la Axarquia, Málaga, and Inmaculada Ballesteros Hospital de la Axarquia, Málaga; Concepción Boqué, Hospital Universitario de Bellvitge, Barcelona; Gonzalo Caballero, Hospital Universitario Miguel Servet, Zaragoza; Dolores Fernandez, Hospital Clínico San Cecilio, Granada; Carlos Fernandez, Hospital Materno Infantil; Teresa Herrera, A Coruña; J. Valentín Garcia, Hospital Ramón y Cajal, Madrid; Montse Gómez, Hospital Quirón de Valencia, Valencia; Maria Teresa Gómez Casares, Hospital Dr. Negrín, Canarias; Jose Julio Hernandez, Hospital de San Eloy, Vizcaya; Juan Carlos Hernandez, Hospital Quirón Valencia, Valencia; Ana Jimenez, Hospital 12 de Octubre, Madrid; Ana Kerguelen, Hospital Universitario La Paz, Madrid; Elisa Luño, Hospital Universitario Central de Asturias, Asturias; Joaquín Martinez López, Hospital 12 de Octubre; María Isabel Mata, Hospital Costa del Sol, Málaga; Antonio Paz Coll, Hospital Puerto Real, Cádiz; Maria Jose Ramírez, Hospital de Jerez de la Frontera, Cádiz; Juan Nicolás Rodriguez, Hospital Juan Ramón Jimenez, Huelva; Adriana Simiele, Hospital Povisa, Pontevedra; Antonio Cervero, Hospital General Universitario de Valencia, Valencia; Jesús Maria Cesar, Hospital Ramón y Cajal, Madrid; Natalia de las Heras, Hospital Universitario de León; Margarita Fernandez de la Mata, Hospital Universitario Reina Sofía, Córdoba; Mar Hermosilla, Hospital San Pedro, Rioja; Esperanza Lavilla, Hospital Lucus Augusti, Lugo; Carmen Loureiro, Hospital do Meixoeiro, Pontevedra; Elena Magro, Hospital Príncipe de Asturias, Madrid; Sergio Ortegón, Hospital General de Llorena, Badajoz; Maria Antonia Peñalver, Hospital Universitario Severo Ochoa, Madrid; Maria Angeles Pérez, Hospital Fundación Jimenez Díaz, Madrid; and Maria del Carmen Santo, Hospital Central de Asturias, Asturias.
Carlos Besses designed the study, collected the data, analyzed and interpreted the results, and wrote the paper; Juan Carlos Hernández-Boluda collected the data, analyzed and interpreted the results, and wrote the paper; Manuel Pérez Encinas collected the data, analyzed and interpreted the results, and approved the final version; José María Raya collected the data, analyzed and interpreted the results, and approved the final version; Jesús María Hernández-Rivas collected the data, analyzed and interpreted the results, and approved the final version; Antonio Jiménez Velasco collected the data, analyzed and interpreted the results, and approved the final version; Joaquín Martínez López collected the data, analyzed and interpreted the results, and approved the final version; Vicente Vicente collected the data, analyzed and interpreted the results, and approved the final version; and Carmen Burgaleta designed the study, collected the data, analyzed and interpreted the results, and approved the final version.
Compliance with ethical standards
Conflict of interest
Carlos Besses, Vicente Vicente, and Carmen Burgaleta received honoraria from Shire for speaking at symposia.
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