European Journal of Haematology 92 (289–297)
ORIGINAL ARTICLE
Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union Odile Moulard1, Jyotsna Mehta2, Jon Fryzek3, Robert Olivares1, Usman Iqbal2, Ruben A. Mesa4 1
Oncology-Global Evidence and Value Development, Medical Affairs, Chilly-Mazarin, France; 2Oncology-Global Evidence and Value Development, Medical Affairs, Sanofi, Cambridge, MA; 3EpidStat Institute, Ann Arbor, MI; 4Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ, USA
Abstract Background: Primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV) are BCR ABL-negative myeloproliferative neoplasms (MPN). Published epidemiology data are scarce, and multiple sources are needed to assess the disease burden. Methods: We assembled the most recent information available on the incidence and prevalence of myelofibrosis (MF), ET, and PV by conducting a structured and exhaustive literature review of the published peer-reviewed literature in EMBASE and by reviewing online documentation from disease registries and relevant health registries in European countries. The search was restricted to human studies written in English or French and published between January 1, 2000, and December 6, 2012. Results: Eleven articles identified from EMBASE, three online hematology or oncology registries, and two Web-based databases or reports were used to summarize epidemiological estimates for MF, PV, and ET. The incidence rate of MF ranged from 0.1 per 100 000 per year to 1 per 100 000 per year. Among the various registries, the incidence of PV ranged from 0.4 per 100 000 per year to 2.8 per 100 000 per year, while the literature estimated the range of PV incidence to be 0.68 per 100 000 to 2.6 per 100 000 per year. The estimated incidence of ET was between 0.38 per 100 000 per year and 1.7 per 100 000 per year. While a few studies reported on the MPNs’ prevalences, it is difficult to compare them as various types of prevalence were calculated (point prevalence vs. period prevalence) and standardization was made according to different populations (e.g., the world population and the European population). Conclusion: There is a wide variation in both prevalence and incidence estimates observed across European data sources. Carefully designed studies, with standardized definitions of MPNs and complete ascertainment of patients including both primary and secondary MFs, should be conducted so that estimates of the population aimed to receive novel treatments for these neoplasms are better understood assist public health planning and provide valuable information about the burden of illness to policy makers, funding agencies, resource planners, healthcare insurers, and pharmaceutical manufacturers. Key words epidemiology; myelofibrosis; essential thrombocythemia; polycythemia vera; Europe Correspondence Ruben Mesa, MD, FACP, Mayo Clinic Cancer Center, 13400 E. Shea BLVD, Scottsdale, AZ 85259, USA. Tel: +1 480 301 8335; Fax: +1 480 301 4675; e-mail: [email protected] Accepted for publication 16 December 2013
Myeloproliferative neoplasms (MPNs) are relatively uncommon clonal diseases of the bone marrow and are classified based on chromosomal abnormalities (1). The three classic Philadelphia-chromosome-negative disorders (CMPNs) include primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV) (1). In PMF, stem cells in the bone marrow do not mature and fibers inside the
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12256
bone marrow become thick, resulting in the formation of fewer cells. ET results in an abnormal increase in platelets in the blood and bone marrow, while PV results in an abnormal increase in red blood cells in the blood and bone marrow and occasionally an increase in white blood cells and platelets (2). In 2008, the World Health Organization proposed specific clinical criteria for the diagnosis of MPNs (Fig. 1) (3).
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MyleoproliferaƟve neoplasms
Philadelphia chromosome negaƟve
Other
Primary myelofibrosis
Polycythemia vera
EssenƟal thrombocythemia
Philadelphia chromosome posiƟve
Chronic myelogenous leukemia
2008 WHO Diagnostic Criteria PV* Major criteria
1 Hgb >18.5 g/dL (men) >16.5 g/dL (women) or Hgb >17 g/dL (men), or >15 g/dL (women) if associated with a sustained increase of ≥ 2 g/dL from baseline that can not be attributed to correction of iron deficiency or§ 2 Presence of JAK2V617F or similar mutation
Minor criteria
* † ‡ § ‖
ET†
PMF‡
1 Platelet count ≥450 × 109/L
1 Megakaryocyte proliferation and atypia‖ accompanied by either reticulin and/or collagen fibrosis, or In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased bone marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (ie, prefibrotic PMF). Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm 2 Megakaryocyte 2 Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm proliferation with large and mature morphology. No or little granulocyte or erythroid proliferation 3 Not meeting 3 Demonstration of JAK2V617F or other clonal marker or no evidence of WHO criteria reactive bone marrow fibrosis for CML, PV, PMF, MDS or other myeloid neoplasm 4 Demonstration of JAK2V617F or other clonal marker or no evidence of reactive thrombocytosis 1 BM trilineage myeloproliferation 1 Leukoerythroblastosis 2 Subnormal serum Epo level 2 Increased serum LDH 3 EEC growth 3 Anemia 4 Palpable splenomegaly WHO indicates World Health Organization; PV, polycythemia vera; ET, essential thrombocythemia; PMF, primary myelofibrosis; Hgb, hemoglobin; CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; BM, bone marrow; Epo, erythropoietin; LDH, lactate dehydrogenase; EEC, endogenous erythroid colony. The diagnosis of PV requires meeting either both major criteria and 1 minor criterion or the first major criterion and 2 minor criteria. The diagnosis of ET requires meeting all 4 major criteria. The diagnosis of PMF requires meeting all 3 major criteria and 2 minor criteria. Or Hgb or hematocrit greater than the 99th percentile of reference range for age, sex, or altitude of residence or red cell mass >25% above the mean normal predicted. ‖Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering.
Figure 1 Classification of myeloproliferative neoplasms (MPNs) based on 2008 WHO diagnostic criteria. Other = chronic neutrophilic leukemia; chronic eosinophilic leukemia, not otherwise categorized; mastocytosis; and MPNs, unclassifiable. Adapted from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for MPNs: order out of chaos. Cancer 2009;115:3842–3847.
Most patients with these disorders are older than 60 yr at initial diagnosis, with shortened survival for those with more advanced disease (4). The median survival for myelofibrosis (MF) is 2–5 yr (5–7) once the patient becomes diagnosed and is symptomatic, while the median survival for PV (7–10) and ET (7, 9, 11) is much longer (median survival estimated at 8–10 yr or longer). In PMF, the median survival varies greatly according to risk groups. The International Working Group for Myelofibrosis Research and Treatment reported median survival of approximately 11 and
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2 yr for low- and high-risk patient groups, whereas median survivals of patients in the two intermediate-risk disease categories were 8 and 4 yr (5). In a large European study of patients with a median follow-up of 9.5 yr, it has been observed that the life expectancy of patients with PV, especially in patients younger than 50 yr old, is reduced when compared to the general population. On the contrary, life expectancy of patients with ET is not markedly affected by the disease, reflecting the more indolent nature of the proliferation (11).
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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Myelofibrosis, ET, and PV patients suffer substantial morbidity and mortality from thrombotic complications, progressive bone marrow functional decline, and leukemic transformation. PV and ET may lead to secondary myelofibrosis (SMF). MF is a relatively rare disease occurring de novo (PMF) or from a precursor MPN such as PV (post-PV MF) or ET (post-ET MF). The term MF is used throughout this paper as an umbrella term that includes PMF, post-PV MF, and post-ET MF if the accuracy is not reported. Clinically, patients with MF may develop splenomegaly, anemia, peripheral blasts, and various constitutional symptoms, including fatigue (12), which dramatically impact their quality of life. Patients with PV and ET may also suffer from splenomegaly and disease-associated symptoms such as pruritus, night sweats, fatigue, and bone pain [although this spectrum of symptoms is frequent to a lesser extent than seen in MF (13)]. While available therapies may provide relief from symptoms, they do not stop or reverse bone marrow fibrosis or address the underlying cause of disease. As information on MF, ET, and PV is not routinely collected in disease registries in the European Union (EU), multiple sources are needed understand the descriptive epidemiology of these disorders. To this end, we conducted an exhaustive literature review as well as a review of various disease registries and online databases summarize the incidence and prevalence of MF, PV, and ET in the EU. An evidence-based synthesis of MPN epidemiology data in European countries can inform population healthcare planning, resource allocation, and disease management decision making for these disorders.
Epidemiology of MPN in Europe
Table 1 EMBASE search results conducted on December 6, 2012 Query
Search string
#1
‘myelofibrosis’ OR ‘myelofibrosis’/exp OR myelofibrosis OR ‘primary myelofibrosis’/exp OR ‘primary myelofibrosis’ OR ‘chronic idiopathic myelofibrosis’ OR ‘agnogenic myeloid metaplasia’/exp OR ‘agnogenic myeloid metaplasia’ OR ‘myeloid metaplasia’/exp OR ‘myeloid metaplasia’ OR ‘idiopathic myelofibrosis’/exp OR ’idiopathic myelofibrosis’ OR ‘ myeloproliferative neoplasm’:ab, ti OR ‘myeloproliferative neoplasms’:ab,ti OR ‘myeloproliferative disorder’:ab,ti OR ‘myeloproliferative disorders’:ab,ti OR mpn OR ‘polycythemia rubra vera’/exp OR ‘polycythemia rubra vera’ OR ‘polycythaemia rubra vera’ OR ‘polycythemia vera’/exp OR ‘polycythemia vera’ OR ’polycythaemia vera’/exp OR ‘polycythaemia vera’ OR ‘thrombocythemia’/exp OR ’thrombocythemia’ OR ‘thrombocythaemia’/exp OR ‘thrombocythaemia’ OR ‘essential thrombocythemia’/exp OR ‘essential thrombocythemia’ OR ‘essential thrombocythaemia’ OR ‘essential thrombocytemia’ inciden*:ti OR prevalen*:ti OR mortal*:ti OR survival:ti OR epidemiol*:ti OR ‘new cases’:ti OR recurren*:ti OR registr*:ti AND [2000–2013]/py #1 AND #2
#2
Methods
We synthesized the most recent information available on the incidence and prevalence of MF, ET, and PV by conducting a structured and exhaustive literature review of the published peer-reviewed literature in EMBASE and by reviewing online documentation from disease registries and relevant health registries. The material identified in the EMBASE search and online data were compared. The goal was to identify the most recent estimates of the incidence and prevalence of MF, ET, and PV. If relevant data were reported by more than one source for the same condition and geography, the source with the most recent data and/or the most relevant data was used. Various search strings were used to identify relevant articles (Table 1) via EMBASE. The search was restricted to human studies written in English or French and published between January 1, 2000, and December 6, 2012. References from this time period reported data over a period of 20 yr. Older data are not of interest due to the change in classification and diagnostic criteria and do not allow us to establish trends over time. Four hundred and eighty-four citations were retrieved, and the titles and abstracts of these publications
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
#3
Results 24 284
327 333
484
were reviewed by one of the authors (OM). Studies that seemed to report descriptive statistics on one of the malignancies of interest were included. Relevant full-text articles were retrieved and reviewed for inclusion. References of the articles retrieved through EMBASE were searched, and key relevant articles added to the review. This identified an additional four relevant articles prior to the year 2000, which were included in the review. Pertinent information from articles that reported on the incidence and/or prevalence of PMF, ET, or PV was abstracted. Additional information was abstracted from online hematology or oncology registries or Web-based databases or reports. Registries and relevant sources were identified from previous experience, online research into the structure of public health in each country, and involvement in organizations such as the International Association of Cancer Registries (14) and the European Network of Cancer Registries (15). Registries identified as having information on MPNs
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include the Croatian National Cancer Registry (16), the Finnish Cancer Registry (17), the Swedish Cancer Registry (18), and one regional registry in France [Gironde (19)]. In addition, two online databases or reports were also identified as having information on MPNs. The Orphanet (20) (the European portal for rare diseases and orphan drugs) report series are based on a systematic survey of the literature using several data sources such as Web sites, Medline, medical books, gray literature, and reports from experts. The RARECARE (21) project based on data provided by 65 population-based cancer registries in 18 European countries estimated the incidence and prevalence of rare conditions in the EU between 1978 and 2002. Information extracted from each data source includes the source of the data, region, country or countries, malignancy type, including any available information on International Classification of Diseases (ICD) codes, time period, median age, and data relevant to incidence and prevalence. Data
were collected by gender and methods for age standardization, and any age restrictions were noted. Results
Of the 484 articles identified in EMBASE, 453 were excluded because they were not in scope, did not have any European data, were in a language other than English or French, or were animal studies. Thirty-one full-text articles were retrieved and reviewed. Eleven articles had information on the incidence and/or prevalence of MF, PV, and/or ET in the EU. Forty-eight European hematology or oncology registries and two Web-based databases or reports were searched for additional information on the incidence and prevalence of MPNs. Only three online registries and two Web-based databases or reports had information on at least one of the MPNs of interest. Thus, the eleven articles identified from EMBASE, three hematology or oncology online registries,
Table 2 Summary of incidence estimates for MF in Europe Incidence rate per 100 0001 Source
Country
Online registries Studies before 2005 or aggregated periods Orphanet (20) Europe RARECARE (21) Europe, 18 countries Study after 2005 National Cancer Sweden Registry (18) Literature Studies before 2005 or aggregated periods Regional Registry, France Basse-Normandie (26) Regional Registry, France Cote d’Or (22) Regional Registry, France Gironde (28) Southwest Germany, Germany Hospitals (24) Goteborg, 2 Hospitals (23) Sweden Haematological Malignancy Research Network (25) Thames Cancer Registry (6)
UK UK
Definition of MF
Time period
Median age
Males
Females
All
MF2: ICD-10: D47.4 MF2: ICD-O3: 9961
NR 1995–2002
NR NR
NR NR
NR NR
1.03 0.1
MF2: ICD-7: 209
2010
NR
0.94
0.74
NR
PMF: ICD-O3 and ADICAP5 PMF: ICD-O3: 9961
1997–2004
NR
0.44
0.24
0.34
1980–2007
70
0.8
0.2
0.5
PMF: ICD-03
2002–2006
NR
0.7
0.2
0.4
PMF: WHO diagnostic criteria PMF: Study-defined diagnostic criteria6 PMF: ICD-O3: 9961
1998–2000
71
0.33
0.23
0.33
1983–1999
NR
NR
0.3
2004–2009
76 (M) 75 (F) 73
0.5
0.2
0.3
PMF: Established diagnostic criteria
1999–2000
69
0.4
0.3
0.4
NR, not reported; ICD, International Classification of Diseases; PMF, primary myelofibrosis; MF, myelofibrosis. Incidence rates are age-standardized to the European population unless otherwise noted. 2 Not specified if PMF or all MF. 3 Not age-standardized. 4 Age-standardized to world population. 5 veloppement de l’Informatique en Cytologie et en Anatomie PathologiADICAP = French classification proposed by the Association pour le De ques. 6 Bone marrow fibrosis of unexplained origin together with splenomegaly and leukoerythroblastic cell reaction in the peripheral blood and who did not fulfill criteria for polycythemia vera, essential thrombocythemia, leukemic disease or myelodysplasia. 1
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and two Web-based databases or reports were used to summarize epidemiological estimates for MF, PV, and ET. Incidence
The incidence rate of MF from the various online registries ranged from 0.1 per 100 000 per year [RARECARE (21)] to 1 per 100 000 per year [Orphanet (20)]. However, these registries did not indicate whether the data were for PMF only or PMF and SMF combined. The literature (6, 22–26) reviewed estimated a PMF incidence rate of around 0.3 per 100 000 per year. All of the estimates showed a higher incidence for males (range = 0.32 per 100 000 per year to 0.9 per 100 000 per year) than for females (range = 0.2 per 100 000 per year to 0.7 per 100 000 per year). The median age of diagnosis was between 69 yr [UK, Thames Cancer Registry (6)] and 76 yr [Sweden, Goteborg, 2 Hospitals (23)] (Table 2).
Table 3 shows the incidence estimates for PV. Among the various registries, the incidence of PV ranged from 0.4 per 100 000 per year [Croatian National Cancer Registry (16)] to 2.8 per 100 000 per year [Orphanet (20)], while the literature estimated the range of PV incidence to be 0.68 per 100 000 per year [Southwest Germany, Hospitals (24)] to 2.6 per 100 000 per year [Sweden, Malmo City (27)]. Of the fourteen estimates, eight were above 1 per 100 000 per year and four were 2 per 100 000 per year or greater. For all but one estimate [Sweden, Malmo City (27)], the incidence rates were slightly higher among men (range = 0.5 per 100 000 per year to 3.0 per 100 000 per year) than among women (range = 0.3 per 100 000 per year to 2.8 per 100 000 per year). Median age at diagnosis was between 65 yr [Southwest Germany, Hospitals (24)] and 74 yr [Sweden, Goteborg, 2 Hospitals (23)]. The estimated incidence of ET was between 0.38 per 100 000 per year [RARECARE (21)] and 1.7 per 100 000
Table 3 Summary of incidence estimates for PV in Europe Incidence rate per 100 0001 Source
Country
Online registries Studies before 2005 or aggregated periods Orphanet (20) Europe RARECARE (21) Europe, 18 countries Studies after 2005 National Cancer Registry (16) Croatia National Cancer Registry (17) Finland National Cancer Registry (18) Sweden Literature Studies before 2005 or aggregated periods Regional Registry, France Basse-Normandie (26) Regional Registry, Cote d’Or (22) France Regional Registry, Gironde (28) France Regional Registry, Ile-de-France France region, Hospitals (33) HAEMACARE (34) Europe, 20 countries Southwest Germany, Germany Hospitals (24) Malmo City (27) Sweden Goteborg, 2 Hospitals (23)
Sweden
Thames Cancer Registry (6)
UK
Definition of PV
Time period
Median age
Males
Females
All
ICD-10: D45 ICD-O3: 9950
NR 1995–2002
NR NR
NR NR
NR NR
1.0–2.82 0.5
ICD-10: D45 ICD-O3: 9950 ICD-7: 208
2010 2009 2010
NR NR NR
0.52 0.83 0.93
0.32 0.63 0.53
0.42 NR NR
ICD-O3 and ADICAP4 ICD-O3: 9950 ICD-O3 PVSG criteria
1997–2004
NR
0.93
0.63
0.73
1980–2007 2002–2006 1980–1997
69 NR NR
1.0 1.5 NR
0.8 0.9 NR
0.9 1.2 0.8–1.55
ICD-O3: 9950
2000–2002
NR
1.62
1.52
1.52
WHO diagnostic criteria NA
1998–2000
65.1
0.72
0.72
0.72
1970–1979 1980–1984 1983–1999
NR NR 69 (M) 74 (F) 72
3.0 2.5 NR
1.4 2.8 NR
2.2 2.6 2.0
1.1
1.0
1.1
PVSG criteria or Pearson and Messinezy (1996) Established diagnostic criteria
1999–2000
NR, not reported; PVSG, Polycythemia Vera Study Group; ICD, International Classification of Diseases; PV, polycythemia vera. Incidence rates are age-standardized to the European population unless otherwise noted. 2 Not age-standardized. 3 Age-standardized to world population. 4 veloppement de l’Informatique en Cytologie et en Anatomie PathologiADICAP = French classification proposed by the Association pour le De que. 5 Estimated annual incidence rate. 1
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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per year [France, Regional Registry, Gironde (28)] (Table 4). In contrast to MF and PV, the incidence of ET was higher among women (range = 0.64 per 100 000 per year to 2.00 per 100 000 per year) than among men (range = 0.40 per 100 00 per year to 2.00 per 100 000 per year). Five of the estimates were above 1.0 per 100 000 per year, while 3 were below. Average age at diagnosis was between 64.3 yr [Southwest Germany, Hospitals (24)] and 73 yr [UK, Thames Cancer Registry (6)]. Prevalence
A few resources reported on prevalence of MF, PV, or ET (Table 5). Orphanet (20) reported a prevalence for any MF of 2.7 per 100 000 (time period not specified), while RARECARE (21) reported a 15-yr period prevalence of only 0.51 per 100 000 on January 1, 2003, for any MF. For PV, Orphanet (20) estimated the prevalence to be 30 per 100 000 (time period not specified), while RARECARE (21) reported a 15-yr period prevalence of 4.96 per 100 000 on January 1, 2003. Malmo City in Sweden (27) reported an annual prevalence of 8.0 per 100 000 between 1950 and 1984 with a point prevalence of 29.2 per
100 000 in 1984. The Finnish National Cancer Registry (17) reported an annual total prevalence of 4 per 100 000 for men and 3 per 100 000 for women. Orphanet (20) reported the highest prevalence for ET of 24 per 100 000 (time period not specified), and RARECARE (21) reported the lowest (4.00 per 100 000 on January 1, 2003). One hospital in Spain (29) estimated the prevalence of ET as 6.8 per 100 000 in 2007 and 2008, which was similar to a study in Copenhagen county, Denmark (30), which estimated the prevalence of ET at 11 per 100 000 between 1977 and 1998. Discussion
In this review, we utilized information from the peerreviewed scientific literature and online registries to assemble data on the incidence and prevalence of MF, PV, and ET in the EU. A few publications and registries reported descriptive epidemiology statistics for MF (four online registries and six publications), PV (six online registries and eight publications), or ET (two online registries and seven publications) in European countries. In particular, prevalence data are very rare (only six data sources).
Table 4 Summary of incidence estimates for ET in Europe Incidence rate per 100 0001 Source
Country
Studies before 2005 or aggregated periods Online registries RARECARE (21) Europe, 18 countries Literature Copenhagen Denmark county (30) Regional Registry, France Basse-Normandie (26) Regional Registry, France Cote d’Or (22) Regional Registry, France Gironde (28) Southwest Germany, Germany Hospitals (24) Goteborg, 2 Sweden Hospitals (23) Thames Cancer UK Registry (6)
Definition of ET
Time period
Median age
Males
Females
All
ICD-O3: 9962
1995–2002
NA
NA
NA
0.4
Study-defined diagnostic criteria2 ICD-O3 and ADICAP3
1977–1998
67
0.4
0.6
0.5
1997–2004
NA
1.04
1.54
1.254
ICD-O3: 9962
1980–2007
NA
2
2
2
ICD-O3
2002–2006
NA
1.5
1.8
1.7
WHO diagnostic criteria
1998–2000
64.3
0.75
1.05
0.85
PVSG criteria or Pearson and Messinezy (1996) Medical Research Council, Primary Thrombocythemia Protocol
1983–1999
67 (M) 72 (F) 73
NA
NA
1.6
1.4
1.9
1.7
1999–2000
NA, not available; PVSG, Polycythemia Vera Study Group; ICD, International Classification of Diseases; ET, essential thrombocythemia. Incidence rates are age-standardized to the European population unless otherwise noted. 2 Elevated platelet count >600 9 109/L in more than one platelet count measurement, no evidence of iron deficiency or when these parameters were not available a normal mean red cell volume, no known cause of reactive thrombocytosis, hematocrit ≤45 or if above no increase in total red cell volume, lack of bone marrow collagen fibrosis, and no leukoerythroblastic peripheral blood picture. 3 veloppement de l’Informatique en Cytologie et en Anatomie PathologiADICAP = French classification proposed by the Association pour le De que. 4 Age-standardized to world population. 5 Not age-standardized. 1
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There is a wide variation in both prevalence and incidence estimates observed across European data sources that could limit informed application of epidemiological estimates on these MPN for healthcare decision process. While MF incidence estimates ranged from 0.1 to 1 per 100 000 per year, most of the estimates were at the lower end of this range at around 0.3 per 100 000 per year. This is similar to a recent study in the United States, which found that MF incidence was about 1 per 100 000 per year and MF prevalence was 4–6 per 100 000 per year (31) based on data from two large health plans. The studies of PV incidence reported higher incidences than those of MF. The PV incidence from cancer registries was consistently lower, most likely because of under-reporting of cases (6). The studies with the most reliable methodology, large sample sizes, and nearly complete case ascertainment were conducted in Sweden (18, 23) and had the highest incidences of PV (2–3 per 100 000 per year). The largest range in incidences was found for studies of ET (0.38–2 per 100 000 per year). The study with the most complete case ascertainment was conducted in France (22), with an ET incidence rate of 2.0 per 100 000 per year. Further evidence that under-reporting may occur for PV and ET is
found in a recent, large US study based on two health plans (31). This study reported the prevalence of PV as 44–57 per 100 000 and ET as 38–57 per 100 000, while our European review found that the prevalence of PV was between 5 and 30 per 100 000 and ET was between 4 and 24 per 100 000. However, it must be noted that only a few of the EU studies reported on the MPNs’ prevalences. Further, it is difficult to compare them as various types of prevalence were calculated (point prevalence vs. period prevalence) and standardization was made according to different populations (e.g., the world population and the European population). The differences in the epidemiological estimates of these MPNs stem from a change in diagnosis and classifications of them over time, limitations inherent to registry data including potential sources of bias such as missing data or under-reporting, and statistical variance due to the small number of cases of these three rare diseases. In addition, the online registries (Orphanet, RARECARE, and Swedish National Cancer Registry) did not distinguish between PMF and SMF. As noted above, the variation in incidence is largest for ET. This could be due to the problems diagnosing ET. In the recent past, there was not a single clinical or
Table 5 Summary of prevalence estimates for MF, PV, and ET in Europe Prevalence rate per 100 0001 Source
Definition of MF, PV, and ET
Time period
Males
Females
ICD-10: D47.4 ICD-O3: 9961
NA 1988–2002
NR NR
NR NR
ICD-10: D45 ICD-O3: 9950 NA
NA 1988–2002 1950–1984 1984
NR NR 7.75 24.83
NR NR 8.35 33.23
Finland
ICD-O3: 9950
2009–2010
45,6
35,6
periods Europe Europe, nine countries Denmark
ICD-10: D47.3 ICD-O3: 9962 Study-defined diagnostic criteria7
NA 1988–2002 1999
NR NR NR
NR NR NR
242,3 4.004 113
Spain
WHO diagnostic criteria
2007–2008
NR
NR
6.83
Country
Any myelofibrosis Studies before 2005 or aggregated periods Orphanet (20) Europe RARECARE (21) Europe, nine countries PV Studies before 2005 or aggregated periods Orphanet (20) Europe RARECARE (21) Europe, nine countries Malmo City (27) Sweden Studies after 2005 National Cancer Registry (17) ET Studies before 2005 or aggregated Orphanet (20) RARECARE (21) Copenhagen county (30) Studies after 2005 Villareal, one hospital (29)
All
2.72,3 0.514
302,3 4.964 8.05 29.23 NR
NR, not reported; ICD, International Classification of Diseases; MF, myelofibrosis; PV, polycythemia vera; ET, essential thrombocythemia. 1 Prevalences are age-standardized to the European population unless otherwise noted. 2 Not standardized. 3 Point prevalence. 4 15-yr period prevalence on January 1, 2003. 5 Annual prevalence over >10-yr period. 6 Standardized to world population. 7 Elevated platelet count >600 9 109/L in more than one platelet count measurement, no evidence of iron deficiency or when these parameters were not available a normal mean red cell volume, no known cause of reactive thrombocytosis, hematocrit ≤45 or if above no increase in total red cell volume, lack of bone marrow collagen fibrosis, and no leukoerythroblastic peripheral blood picture.
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laboratory finding that would confirm the presence of ET. ET was a diagnosis of exclusion. In 2005, the discovery of the Janus kinase 2 (JAK2) mutation greatly improved the understanding of MPNs and proved to be a useful aid in the diagnosis of these neoplasms (32). The newly revised WHO 2008 criteria (3) for diagnosing ET include some important modifications from the 2001 version. The threshold for platelet values was lowered from 600 9 109 L to 450 9 109 L and included the use of the clonal marker JAK2-V617F. As the WHO criteria were just updated in 2008, very little epidemiologic data are available using the new criteria. From the data available, it appears that ET incidence is increasing, which most likely results from the less stringent platelet values (22). It is expected that the WHO classification of 2008 will also change the estimates of PV and MF as the current estimates are based on older classification and methods, leading to diagnosis. However, to date, a few studies have been published on the incidence or prevalence of MPNs and it is not possible to estimate the impact of the new classification on trends in epidemiology data. Specifically, only one study on the incidence of MF, three studies on the incidence of PV, one study on the prevalence of PV, and one study on the prevalence of ET have been published since 2005. All other studies are older, or present data aggregated over a long period of time. Estimates of the population aimed to receive novel treatments, such as the JAK2 inhibitors, should be better understood assist public health planning and provide valuable information about the burden of illness to policy makers, funding agencies, resource planners, healthcare insurers, and pharmaceutical manufacturers. Therefore, it is important to have a clearer picture of the descriptive epidemiology of the MPNs in the EU. Large observational research leveraging patient-level databases and/or comprehensive registries should be designed to target the complete ascertainment of the MPNs as much as possible. Further, standardized definitions or coding across appropriate real-world databases and hematological malignancy registries is needed to add precision to or substantiate the estimates across geographies. Regardless of the limitations of the registries and studies reported here, the prevalence of ET and PV is considerable and warrant prioritized attention toward the development of novel agents that can change the underlying course of the disease as well as allocation of resources for improved screening, diagnosis, and disease management. References 1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2008. 2. National Cancer Institute. Myeloproliferative disorders. http:// www.cancer.gov/cancertopics/types/myeloproliferative (Accessed 25 March 2013).
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3. Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer 2009;115:3842–7. 4. Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood 2005;105:973–7. 5. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009;113:2895–901. 6. Phekoo KJ, Richards MA, Moller H, Schey SA. The incidence and outcome of myeloid malignancies in 2,112 adult patients in southeast England. Haematologica 2006;91:1400–4. 7. Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy. Am J Hematol 2008;83:491–7. 8. Ania BJ, Suman VJ, Sobell JL, et al. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935–1989. Am J Hematol 1994;47:89–93. 9. Buhr T, Georgii A, Choritz H. Myelofibrosis in chronic myeloproliferative disorders: incidence among subtypes according to the Hannover Classification. Pathol Res Pract 1993;189:121–32. 10. Prochazka AV, Markowe HL. The epidemiology of polycythaemia rubra vera in England and Wales 1968–1982. Br J Cancer 1986;53:59. 11. Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med 2004;117:755–61. 12. Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res 2009;33:1199–203. 13. Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood 2011;118:401–8. 14. International Association of Cancer Registries. www.iacr.com. fr (Accessed 30 November 2012). 15. European Network of Cancer Registries, International Association of Cancer Registries, World Health Organization. www. encr.com.fr (Accessed 30 November 2012). 16. Croatian National Institute of Public Health. Croatian National Cancer Registry. http://www.hzjz.hr/cancer/ (Accessed 30 November 2012). 17. Cancer Statistics. Finnish Cancer Registry. http://www.cancer. fi/syoparekisteri/en/ (Accessed 30 November 2012). 18. Official Statistics of Sweden. Swedish Cancer Registry. http:// www.socialstyrelsen.se/register/halsodataregister/cancerregist ret/inenglish (Accessed 11 December 2012). 19. Registre des hemopathies malignes de la Gironde. Quelques donnees issues des 5 premieres annees de recueil (periode 2002– 2006). etudes.isped.u-bordeaux2.fr/REGISTRES-CANCERSAQUITAINE/ (Accessed 15 December 2012).
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20. Orphanet. The portal for rare diseases and orphan drugs. http://www.orpha.net/consor/cgi-bin/index.php (Accessed 1 December 2012). 21. RARECARE. Surveillance of rare cancers in Europe. www. rarecare.eu (Accessed 1 December 2012). 22. Girodon F, Bonicelli G, Schaeffer C, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: a populationbased study. Haematologica 2009;94:865–9. 23. Johansson P, Kutti J, Andreasson B, et al. Trends in the incidence of chronic Philadelphia chromosome negative myeloproliferative disorders in the city of Goteborg, Sweden, during 1983–99. J Int Med 2004;256:161–5. 24. Rohrbacher M, Berger U, Hochhaus A, et al. Clinical trials underestimate the age of chronic myeloid leukemia (CML) patients. Incidence and median age of Ph/BCR-ABL-positive CML and other chronic myeloproliferative disorders in a representative area in Germany. Leukemia 2008;23: 602–4. 25. Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. BJC 2011;105:1684–92. 26. Troussard X, Duchenet V, Cornet E, Mouchel D, Malet M, Collignon A. Hematological malignancies: incidence in BasseNormandie, France, for 1997–2004. Rev Epidemiol Sante Publique 2009;57:e14–24.
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27. Berglund S, Zettervall O. Incidence of polycythemia vera in a defined population. Eur J Haematol 1992;48:20–6. 28. Le Guyader-Peyrou S, Gobert E, Menard E, Reiffers J, Monnereau A. Incidence et survie des cas incidents d’hemopathies malignes de la Gironde diagnostiques sur la periode 2002– 2006. Communication appears to 6th days Cancerop^ ole Southwest – Toulouse. October 2010. 29. Mena-Duran AV, Sanchis-Cervera J, Sanchis-Piqueras C. Prevalence of essential thrombocythemia in the JAK2V617F era: a population based study approach in a Spanish community hospital. Haematologica 2009;94(Suppl. 2):587 abs 1510. 30. Jensen MK, de Nully Brown P, Nielsen OJ, Hasselbalch HC. Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area. Eur J Haematol 2000;65:132–9. 31. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma 2013 [Epub ahead of print]. 32. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–8. 33. Najean Y, Rain JD, Billotey C. Epidemiological data in polycythaemia vera: a study of 842 cases. Hematol Cell Ther 1998;40:159. 34. Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010;116:3724–34.
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ORIGINAL ARTICLE
Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union Odile Moulard1, Jyotsna Mehta2, Jon Fryzek3, Robert Olivares1, Usman Iqbal2, Ruben A. Mesa4 1
Oncology-Global Evidence and Value Development, Medical Affairs, Chilly-Mazarin, France; 2Oncology-Global Evidence and Value Development, Medical Affairs, Sanofi, Cambridge, MA; 3EpidStat Institute, Ann Arbor, MI; 4Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ, USA
Abstract Background: Primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV) are BCR ABL-negative myeloproliferative neoplasms (MPN). Published epidemiology data are scarce, and multiple sources are needed to assess the disease burden. Methods: We assembled the most recent information available on the incidence and prevalence of myelofibrosis (MF), ET, and PV by conducting a structured and exhaustive literature review of the published peer-reviewed literature in EMBASE and by reviewing online documentation from disease registries and relevant health registries in European countries. The search was restricted to human studies written in English or French and published between January 1, 2000, and December 6, 2012. Results: Eleven articles identified from EMBASE, three online hematology or oncology registries, and two Web-based databases or reports were used to summarize epidemiological estimates for MF, PV, and ET. The incidence rate of MF ranged from 0.1 per 100 000 per year to 1 per 100 000 per year. Among the various registries, the incidence of PV ranged from 0.4 per 100 000 per year to 2.8 per 100 000 per year, while the literature estimated the range of PV incidence to be 0.68 per 100 000 to 2.6 per 100 000 per year. The estimated incidence of ET was between 0.38 per 100 000 per year and 1.7 per 100 000 per year. While a few studies reported on the MPNs’ prevalences, it is difficult to compare them as various types of prevalence were calculated (point prevalence vs. period prevalence) and standardization was made according to different populations (e.g., the world population and the European population). Conclusion: There is a wide variation in both prevalence and incidence estimates observed across European data sources. Carefully designed studies, with standardized definitions of MPNs and complete ascertainment of patients including both primary and secondary MFs, should be conducted so that estimates of the population aimed to receive novel treatments for these neoplasms are better understood assist public health planning and provide valuable information about the burden of illness to policy makers, funding agencies, resource planners, healthcare insurers, and pharmaceutical manufacturers. Key words epidemiology; myelofibrosis; essential thrombocythemia; polycythemia vera; Europe Correspondence Ruben Mesa, MD, FACP, Mayo Clinic Cancer Center, 13400 E. Shea BLVD, Scottsdale, AZ 85259, USA. Tel: +1 480 301 8335; Fax: +1 480 301 4675; e-mail: [email protected] Accepted for publication 16 December 2013
Myeloproliferative neoplasms (MPNs) are relatively uncommon clonal diseases of the bone marrow and are classified based on chromosomal abnormalities (1). The three classic Philadelphia-chromosome-negative disorders (CMPNs) include primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV) (1). In PMF, stem cells in the bone marrow do not mature and fibers inside the
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12256
bone marrow become thick, resulting in the formation of fewer cells. ET results in an abnormal increase in platelets in the blood and bone marrow, while PV results in an abnormal increase in red blood cells in the blood and bone marrow and occasionally an increase in white blood cells and platelets (2). In 2008, the World Health Organization proposed specific clinical criteria for the diagnosis of MPNs (Fig. 1) (3).
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MyleoproliferaƟve neoplasms
Philadelphia chromosome negaƟve
Other
Primary myelofibrosis
Polycythemia vera
EssenƟal thrombocythemia
Philadelphia chromosome posiƟve
Chronic myelogenous leukemia
2008 WHO Diagnostic Criteria PV* Major criteria
1 Hgb >18.5 g/dL (men) >16.5 g/dL (women) or Hgb >17 g/dL (men), or >15 g/dL (women) if associated with a sustained increase of ≥ 2 g/dL from baseline that can not be attributed to correction of iron deficiency or§ 2 Presence of JAK2V617F or similar mutation
Minor criteria
* † ‡ § ‖
ET†
PMF‡
1 Platelet count ≥450 × 109/L
1 Megakaryocyte proliferation and atypia‖ accompanied by either reticulin and/or collagen fibrosis, or In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased bone marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (ie, prefibrotic PMF). Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm 2 Megakaryocyte 2 Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm proliferation with large and mature morphology. No or little granulocyte or erythroid proliferation 3 Not meeting 3 Demonstration of JAK2V617F or other clonal marker or no evidence of WHO criteria reactive bone marrow fibrosis for CML, PV, PMF, MDS or other myeloid neoplasm 4 Demonstration of JAK2V617F or other clonal marker or no evidence of reactive thrombocytosis 1 BM trilineage myeloproliferation 1 Leukoerythroblastosis 2 Subnormal serum Epo level 2 Increased serum LDH 3 EEC growth 3 Anemia 4 Palpable splenomegaly WHO indicates World Health Organization; PV, polycythemia vera; ET, essential thrombocythemia; PMF, primary myelofibrosis; Hgb, hemoglobin; CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; BM, bone marrow; Epo, erythropoietin; LDH, lactate dehydrogenase; EEC, endogenous erythroid colony. The diagnosis of PV requires meeting either both major criteria and 1 minor criterion or the first major criterion and 2 minor criteria. The diagnosis of ET requires meeting all 4 major criteria. The diagnosis of PMF requires meeting all 3 major criteria and 2 minor criteria. Or Hgb or hematocrit greater than the 99th percentile of reference range for age, sex, or altitude of residence or red cell mass >25% above the mean normal predicted. ‖Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering.
Figure 1 Classification of myeloproliferative neoplasms (MPNs) based on 2008 WHO diagnostic criteria. Other = chronic neutrophilic leukemia; chronic eosinophilic leukemia, not otherwise categorized; mastocytosis; and MPNs, unclassifiable. Adapted from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for MPNs: order out of chaos. Cancer 2009;115:3842–3847.
Most patients with these disorders are older than 60 yr at initial diagnosis, with shortened survival for those with more advanced disease (4). The median survival for myelofibrosis (MF) is 2–5 yr (5–7) once the patient becomes diagnosed and is symptomatic, while the median survival for PV (7–10) and ET (7, 9, 11) is much longer (median survival estimated at 8–10 yr or longer). In PMF, the median survival varies greatly according to risk groups. The International Working Group for Myelofibrosis Research and Treatment reported median survival of approximately 11 and
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2 yr for low- and high-risk patient groups, whereas median survivals of patients in the two intermediate-risk disease categories were 8 and 4 yr (5). In a large European study of patients with a median follow-up of 9.5 yr, it has been observed that the life expectancy of patients with PV, especially in patients younger than 50 yr old, is reduced when compared to the general population. On the contrary, life expectancy of patients with ET is not markedly affected by the disease, reflecting the more indolent nature of the proliferation (11).
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Myelofibrosis, ET, and PV patients suffer substantial morbidity and mortality from thrombotic complications, progressive bone marrow functional decline, and leukemic transformation. PV and ET may lead to secondary myelofibrosis (SMF). MF is a relatively rare disease occurring de novo (PMF) or from a precursor MPN such as PV (post-PV MF) or ET (post-ET MF). The term MF is used throughout this paper as an umbrella term that includes PMF, post-PV MF, and post-ET MF if the accuracy is not reported. Clinically, patients with MF may develop splenomegaly, anemia, peripheral blasts, and various constitutional symptoms, including fatigue (12), which dramatically impact their quality of life. Patients with PV and ET may also suffer from splenomegaly and disease-associated symptoms such as pruritus, night sweats, fatigue, and bone pain [although this spectrum of symptoms is frequent to a lesser extent than seen in MF (13)]. While available therapies may provide relief from symptoms, they do not stop or reverse bone marrow fibrosis or address the underlying cause of disease. As information on MF, ET, and PV is not routinely collected in disease registries in the European Union (EU), multiple sources are needed understand the descriptive epidemiology of these disorders. To this end, we conducted an exhaustive literature review as well as a review of various disease registries and online databases summarize the incidence and prevalence of MF, PV, and ET in the EU. An evidence-based synthesis of MPN epidemiology data in European countries can inform population healthcare planning, resource allocation, and disease management decision making for these disorders.
Epidemiology of MPN in Europe
Table 1 EMBASE search results conducted on December 6, 2012 Query
Search string
#1
‘myelofibrosis’ OR ‘myelofibrosis’/exp OR myelofibrosis OR ‘primary myelofibrosis’/exp OR ‘primary myelofibrosis’ OR ‘chronic idiopathic myelofibrosis’ OR ‘agnogenic myeloid metaplasia’/exp OR ‘agnogenic myeloid metaplasia’ OR ‘myeloid metaplasia’/exp OR ‘myeloid metaplasia’ OR ‘idiopathic myelofibrosis’/exp OR ’idiopathic myelofibrosis’ OR ‘ myeloproliferative neoplasm’:ab, ti OR ‘myeloproliferative neoplasms’:ab,ti OR ‘myeloproliferative disorder’:ab,ti OR ‘myeloproliferative disorders’:ab,ti OR mpn OR ‘polycythemia rubra vera’/exp OR ‘polycythemia rubra vera’ OR ‘polycythaemia rubra vera’ OR ‘polycythemia vera’/exp OR ‘polycythemia vera’ OR ’polycythaemia vera’/exp OR ‘polycythaemia vera’ OR ‘thrombocythemia’/exp OR ’thrombocythemia’ OR ‘thrombocythaemia’/exp OR ‘thrombocythaemia’ OR ‘essential thrombocythemia’/exp OR ‘essential thrombocythemia’ OR ‘essential thrombocythaemia’ OR ‘essential thrombocytemia’ inciden*:ti OR prevalen*:ti OR mortal*:ti OR survival:ti OR epidemiol*:ti OR ‘new cases’:ti OR recurren*:ti OR registr*:ti AND [2000–2013]/py #1 AND #2
#2
Methods
We synthesized the most recent information available on the incidence and prevalence of MF, ET, and PV by conducting a structured and exhaustive literature review of the published peer-reviewed literature in EMBASE and by reviewing online documentation from disease registries and relevant health registries. The material identified in the EMBASE search and online data were compared. The goal was to identify the most recent estimates of the incidence and prevalence of MF, ET, and PV. If relevant data were reported by more than one source for the same condition and geography, the source with the most recent data and/or the most relevant data was used. Various search strings were used to identify relevant articles (Table 1) via EMBASE. The search was restricted to human studies written in English or French and published between January 1, 2000, and December 6, 2012. References from this time period reported data over a period of 20 yr. Older data are not of interest due to the change in classification and diagnostic criteria and do not allow us to establish trends over time. Four hundred and eighty-four citations were retrieved, and the titles and abstracts of these publications
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
#3
Results 24 284
327 333
484
were reviewed by one of the authors (OM). Studies that seemed to report descriptive statistics on one of the malignancies of interest were included. Relevant full-text articles were retrieved and reviewed for inclusion. References of the articles retrieved through EMBASE were searched, and key relevant articles added to the review. This identified an additional four relevant articles prior to the year 2000, which were included in the review. Pertinent information from articles that reported on the incidence and/or prevalence of PMF, ET, or PV was abstracted. Additional information was abstracted from online hematology or oncology registries or Web-based databases or reports. Registries and relevant sources were identified from previous experience, online research into the structure of public health in each country, and involvement in organizations such as the International Association of Cancer Registries (14) and the European Network of Cancer Registries (15). Registries identified as having information on MPNs
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include the Croatian National Cancer Registry (16), the Finnish Cancer Registry (17), the Swedish Cancer Registry (18), and one regional registry in France [Gironde (19)]. In addition, two online databases or reports were also identified as having information on MPNs. The Orphanet (20) (the European portal for rare diseases and orphan drugs) report series are based on a systematic survey of the literature using several data sources such as Web sites, Medline, medical books, gray literature, and reports from experts. The RARECARE (21) project based on data provided by 65 population-based cancer registries in 18 European countries estimated the incidence and prevalence of rare conditions in the EU between 1978 and 2002. Information extracted from each data source includes the source of the data, region, country or countries, malignancy type, including any available information on International Classification of Diseases (ICD) codes, time period, median age, and data relevant to incidence and prevalence. Data
were collected by gender and methods for age standardization, and any age restrictions were noted. Results
Of the 484 articles identified in EMBASE, 453 were excluded because they were not in scope, did not have any European data, were in a language other than English or French, or were animal studies. Thirty-one full-text articles were retrieved and reviewed. Eleven articles had information on the incidence and/or prevalence of MF, PV, and/or ET in the EU. Forty-eight European hematology or oncology registries and two Web-based databases or reports were searched for additional information on the incidence and prevalence of MPNs. Only three online registries and two Web-based databases or reports had information on at least one of the MPNs of interest. Thus, the eleven articles identified from EMBASE, three hematology or oncology online registries,
Table 2 Summary of incidence estimates for MF in Europe Incidence rate per 100 0001 Source
Country
Online registries Studies before 2005 or aggregated periods Orphanet (20) Europe RARECARE (21) Europe, 18 countries Study after 2005 National Cancer Sweden Registry (18) Literature Studies before 2005 or aggregated periods Regional Registry, France Basse-Normandie (26) Regional Registry, France Cote d’Or (22) Regional Registry, France Gironde (28) Southwest Germany, Germany Hospitals (24) Goteborg, 2 Hospitals (23) Sweden Haematological Malignancy Research Network (25) Thames Cancer Registry (6)
UK UK
Definition of MF
Time period
Median age
Males
Females
All
MF2: ICD-10: D47.4 MF2: ICD-O3: 9961
NR 1995–2002
NR NR
NR NR
NR NR
1.03 0.1
MF2: ICD-7: 209
2010
NR
0.94
0.74
NR
PMF: ICD-O3 and ADICAP5 PMF: ICD-O3: 9961
1997–2004
NR
0.44
0.24
0.34
1980–2007
70
0.8
0.2
0.5
PMF: ICD-03
2002–2006
NR
0.7
0.2
0.4
PMF: WHO diagnostic criteria PMF: Study-defined diagnostic criteria6 PMF: ICD-O3: 9961
1998–2000
71
0.33
0.23
0.33
1983–1999
NR
NR
0.3
2004–2009
76 (M) 75 (F) 73
0.5
0.2
0.3
PMF: Established diagnostic criteria
1999–2000
69
0.4
0.3
0.4
NR, not reported; ICD, International Classification of Diseases; PMF, primary myelofibrosis; MF, myelofibrosis. Incidence rates are age-standardized to the European population unless otherwise noted. 2 Not specified if PMF or all MF. 3 Not age-standardized. 4 Age-standardized to world population. 5 veloppement de l’Informatique en Cytologie et en Anatomie PathologiADICAP = French classification proposed by the Association pour le De ques. 6 Bone marrow fibrosis of unexplained origin together with splenomegaly and leukoerythroblastic cell reaction in the peripheral blood and who did not fulfill criteria for polycythemia vera, essential thrombocythemia, leukemic disease or myelodysplasia. 1
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Epidemiology of MPN in Europe
and two Web-based databases or reports were used to summarize epidemiological estimates for MF, PV, and ET. Incidence
The incidence rate of MF from the various online registries ranged from 0.1 per 100 000 per year [RARECARE (21)] to 1 per 100 000 per year [Orphanet (20)]. However, these registries did not indicate whether the data were for PMF only or PMF and SMF combined. The literature (6, 22–26) reviewed estimated a PMF incidence rate of around 0.3 per 100 000 per year. All of the estimates showed a higher incidence for males (range = 0.32 per 100 000 per year to 0.9 per 100 000 per year) than for females (range = 0.2 per 100 000 per year to 0.7 per 100 000 per year). The median age of diagnosis was between 69 yr [UK, Thames Cancer Registry (6)] and 76 yr [Sweden, Goteborg, 2 Hospitals (23)] (Table 2).
Table 3 shows the incidence estimates for PV. Among the various registries, the incidence of PV ranged from 0.4 per 100 000 per year [Croatian National Cancer Registry (16)] to 2.8 per 100 000 per year [Orphanet (20)], while the literature estimated the range of PV incidence to be 0.68 per 100 000 per year [Southwest Germany, Hospitals (24)] to 2.6 per 100 000 per year [Sweden, Malmo City (27)]. Of the fourteen estimates, eight were above 1 per 100 000 per year and four were 2 per 100 000 per year or greater. For all but one estimate [Sweden, Malmo City (27)], the incidence rates were slightly higher among men (range = 0.5 per 100 000 per year to 3.0 per 100 000 per year) than among women (range = 0.3 per 100 000 per year to 2.8 per 100 000 per year). Median age at diagnosis was between 65 yr [Southwest Germany, Hospitals (24)] and 74 yr [Sweden, Goteborg, 2 Hospitals (23)]. The estimated incidence of ET was between 0.38 per 100 000 per year [RARECARE (21)] and 1.7 per 100 000
Table 3 Summary of incidence estimates for PV in Europe Incidence rate per 100 0001 Source
Country
Online registries Studies before 2005 or aggregated periods Orphanet (20) Europe RARECARE (21) Europe, 18 countries Studies after 2005 National Cancer Registry (16) Croatia National Cancer Registry (17) Finland National Cancer Registry (18) Sweden Literature Studies before 2005 or aggregated periods Regional Registry, France Basse-Normandie (26) Regional Registry, Cote d’Or (22) France Regional Registry, Gironde (28) France Regional Registry, Ile-de-France France region, Hospitals (33) HAEMACARE (34) Europe, 20 countries Southwest Germany, Germany Hospitals (24) Malmo City (27) Sweden Goteborg, 2 Hospitals (23)
Sweden
Thames Cancer Registry (6)
UK
Definition of PV
Time period
Median age
Males
Females
All
ICD-10: D45 ICD-O3: 9950
NR 1995–2002
NR NR
NR NR
NR NR
1.0–2.82 0.5
ICD-10: D45 ICD-O3: 9950 ICD-7: 208
2010 2009 2010
NR NR NR
0.52 0.83 0.93
0.32 0.63 0.53
0.42 NR NR
ICD-O3 and ADICAP4 ICD-O3: 9950 ICD-O3 PVSG criteria
1997–2004
NR
0.93
0.63
0.73
1980–2007 2002–2006 1980–1997
69 NR NR
1.0 1.5 NR
0.8 0.9 NR
0.9 1.2 0.8–1.55
ICD-O3: 9950
2000–2002
NR
1.62
1.52
1.52
WHO diagnostic criteria NA
1998–2000
65.1
0.72
0.72
0.72
1970–1979 1980–1984 1983–1999
NR NR 69 (M) 74 (F) 72
3.0 2.5 NR
1.4 2.8 NR
2.2 2.6 2.0
1.1
1.0
1.1
PVSG criteria or Pearson and Messinezy (1996) Established diagnostic criteria
1999–2000
NR, not reported; PVSG, Polycythemia Vera Study Group; ICD, International Classification of Diseases; PV, polycythemia vera. Incidence rates are age-standardized to the European population unless otherwise noted. 2 Not age-standardized. 3 Age-standardized to world population. 4 veloppement de l’Informatique en Cytologie et en Anatomie PathologiADICAP = French classification proposed by the Association pour le De que. 5 Estimated annual incidence rate. 1
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per year [France, Regional Registry, Gironde (28)] (Table 4). In contrast to MF and PV, the incidence of ET was higher among women (range = 0.64 per 100 000 per year to 2.00 per 100 000 per year) than among men (range = 0.40 per 100 00 per year to 2.00 per 100 000 per year). Five of the estimates were above 1.0 per 100 000 per year, while 3 were below. Average age at diagnosis was between 64.3 yr [Southwest Germany, Hospitals (24)] and 73 yr [UK, Thames Cancer Registry (6)]. Prevalence
A few resources reported on prevalence of MF, PV, or ET (Table 5). Orphanet (20) reported a prevalence for any MF of 2.7 per 100 000 (time period not specified), while RARECARE (21) reported a 15-yr period prevalence of only 0.51 per 100 000 on January 1, 2003, for any MF. For PV, Orphanet (20) estimated the prevalence to be 30 per 100 000 (time period not specified), while RARECARE (21) reported a 15-yr period prevalence of 4.96 per 100 000 on January 1, 2003. Malmo City in Sweden (27) reported an annual prevalence of 8.0 per 100 000 between 1950 and 1984 with a point prevalence of 29.2 per
100 000 in 1984. The Finnish National Cancer Registry (17) reported an annual total prevalence of 4 per 100 000 for men and 3 per 100 000 for women. Orphanet (20) reported the highest prevalence for ET of 24 per 100 000 (time period not specified), and RARECARE (21) reported the lowest (4.00 per 100 000 on January 1, 2003). One hospital in Spain (29) estimated the prevalence of ET as 6.8 per 100 000 in 2007 and 2008, which was similar to a study in Copenhagen county, Denmark (30), which estimated the prevalence of ET at 11 per 100 000 between 1977 and 1998. Discussion
In this review, we utilized information from the peerreviewed scientific literature and online registries to assemble data on the incidence and prevalence of MF, PV, and ET in the EU. A few publications and registries reported descriptive epidemiology statistics for MF (four online registries and six publications), PV (six online registries and eight publications), or ET (two online registries and seven publications) in European countries. In particular, prevalence data are very rare (only six data sources).
Table 4 Summary of incidence estimates for ET in Europe Incidence rate per 100 0001 Source
Country
Studies before 2005 or aggregated periods Online registries RARECARE (21) Europe, 18 countries Literature Copenhagen Denmark county (30) Regional Registry, France Basse-Normandie (26) Regional Registry, France Cote d’Or (22) Regional Registry, France Gironde (28) Southwest Germany, Germany Hospitals (24) Goteborg, 2 Sweden Hospitals (23) Thames Cancer UK Registry (6)
Definition of ET
Time period
Median age
Males
Females
All
ICD-O3: 9962
1995–2002
NA
NA
NA
0.4
Study-defined diagnostic criteria2 ICD-O3 and ADICAP3
1977–1998
67
0.4
0.6
0.5
1997–2004
NA
1.04
1.54
1.254
ICD-O3: 9962
1980–2007
NA
2
2
2
ICD-O3
2002–2006
NA
1.5
1.8
1.7
WHO diagnostic criteria
1998–2000
64.3
0.75
1.05
0.85
PVSG criteria or Pearson and Messinezy (1996) Medical Research Council, Primary Thrombocythemia Protocol
1983–1999
67 (M) 72 (F) 73
NA
NA
1.6
1.4
1.9
1.7
1999–2000
NA, not available; PVSG, Polycythemia Vera Study Group; ICD, International Classification of Diseases; ET, essential thrombocythemia. Incidence rates are age-standardized to the European population unless otherwise noted. 2 Elevated platelet count >600 9 109/L in more than one platelet count measurement, no evidence of iron deficiency or when these parameters were not available a normal mean red cell volume, no known cause of reactive thrombocytosis, hematocrit ≤45 or if above no increase in total red cell volume, lack of bone marrow collagen fibrosis, and no leukoerythroblastic peripheral blood picture. 3 veloppement de l’Informatique en Cytologie et en Anatomie PathologiADICAP = French classification proposed by the Association pour le De que. 4 Age-standardized to world population. 5 Not age-standardized. 1
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There is a wide variation in both prevalence and incidence estimates observed across European data sources that could limit informed application of epidemiological estimates on these MPN for healthcare decision process. While MF incidence estimates ranged from 0.1 to 1 per 100 000 per year, most of the estimates were at the lower end of this range at around 0.3 per 100 000 per year. This is similar to a recent study in the United States, which found that MF incidence was about 1 per 100 000 per year and MF prevalence was 4–6 per 100 000 per year (31) based on data from two large health plans. The studies of PV incidence reported higher incidences than those of MF. The PV incidence from cancer registries was consistently lower, most likely because of under-reporting of cases (6). The studies with the most reliable methodology, large sample sizes, and nearly complete case ascertainment were conducted in Sweden (18, 23) and had the highest incidences of PV (2–3 per 100 000 per year). The largest range in incidences was found for studies of ET (0.38–2 per 100 000 per year). The study with the most complete case ascertainment was conducted in France (22), with an ET incidence rate of 2.0 per 100 000 per year. Further evidence that under-reporting may occur for PV and ET is
found in a recent, large US study based on two health plans (31). This study reported the prevalence of PV as 44–57 per 100 000 and ET as 38–57 per 100 000, while our European review found that the prevalence of PV was between 5 and 30 per 100 000 and ET was between 4 and 24 per 100 000. However, it must be noted that only a few of the EU studies reported on the MPNs’ prevalences. Further, it is difficult to compare them as various types of prevalence were calculated (point prevalence vs. period prevalence) and standardization was made according to different populations (e.g., the world population and the European population). The differences in the epidemiological estimates of these MPNs stem from a change in diagnosis and classifications of them over time, limitations inherent to registry data including potential sources of bias such as missing data or under-reporting, and statistical variance due to the small number of cases of these three rare diseases. In addition, the online registries (Orphanet, RARECARE, and Swedish National Cancer Registry) did not distinguish between PMF and SMF. As noted above, the variation in incidence is largest for ET. This could be due to the problems diagnosing ET. In the recent past, there was not a single clinical or
Table 5 Summary of prevalence estimates for MF, PV, and ET in Europe Prevalence rate per 100 0001 Source
Definition of MF, PV, and ET
Time period
Males
Females
ICD-10: D47.4 ICD-O3: 9961
NA 1988–2002
NR NR
NR NR
ICD-10: D45 ICD-O3: 9950 NA
NA 1988–2002 1950–1984 1984
NR NR 7.75 24.83
NR NR 8.35 33.23
Finland
ICD-O3: 9950
2009–2010
45,6
35,6
periods Europe Europe, nine countries Denmark
ICD-10: D47.3 ICD-O3: 9962 Study-defined diagnostic criteria7
NA 1988–2002 1999
NR NR NR
NR NR NR
242,3 4.004 113
Spain
WHO diagnostic criteria
2007–2008
NR
NR
6.83
Country
Any myelofibrosis Studies before 2005 or aggregated periods Orphanet (20) Europe RARECARE (21) Europe, nine countries PV Studies before 2005 or aggregated periods Orphanet (20) Europe RARECARE (21) Europe, nine countries Malmo City (27) Sweden Studies after 2005 National Cancer Registry (17) ET Studies before 2005 or aggregated Orphanet (20) RARECARE (21) Copenhagen county (30) Studies after 2005 Villareal, one hospital (29)
All
2.72,3 0.514
302,3 4.964 8.05 29.23 NR
NR, not reported; ICD, International Classification of Diseases; MF, myelofibrosis; PV, polycythemia vera; ET, essential thrombocythemia. 1 Prevalences are age-standardized to the European population unless otherwise noted. 2 Not standardized. 3 Point prevalence. 4 15-yr period prevalence on January 1, 2003. 5 Annual prevalence over >10-yr period. 6 Standardized to world population. 7 Elevated platelet count >600 9 109/L in more than one platelet count measurement, no evidence of iron deficiency or when these parameters were not available a normal mean red cell volume, no known cause of reactive thrombocytosis, hematocrit ≤45 or if above no increase in total red cell volume, lack of bone marrow collagen fibrosis, and no leukoerythroblastic peripheral blood picture.
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Epidemiology of MPN in Europe
laboratory finding that would confirm the presence of ET. ET was a diagnosis of exclusion. In 2005, the discovery of the Janus kinase 2 (JAK2) mutation greatly improved the understanding of MPNs and proved to be a useful aid in the diagnosis of these neoplasms (32). The newly revised WHO 2008 criteria (3) for diagnosing ET include some important modifications from the 2001 version. The threshold for platelet values was lowered from 600 9 109 L to 450 9 109 L and included the use of the clonal marker JAK2-V617F. As the WHO criteria were just updated in 2008, very little epidemiologic data are available using the new criteria. From the data available, it appears that ET incidence is increasing, which most likely results from the less stringent platelet values (22). It is expected that the WHO classification of 2008 will also change the estimates of PV and MF as the current estimates are based on older classification and methods, leading to diagnosis. However, to date, a few studies have been published on the incidence or prevalence of MPNs and it is not possible to estimate the impact of the new classification on trends in epidemiology data. Specifically, only one study on the incidence of MF, three studies on the incidence of PV, one study on the prevalence of PV, and one study on the prevalence of ET have been published since 2005. All other studies are older, or present data aggregated over a long period of time. Estimates of the population aimed to receive novel treatments, such as the JAK2 inhibitors, should be better understood assist public health planning and provide valuable information about the burden of illness to policy makers, funding agencies, resource planners, healthcare insurers, and pharmaceutical manufacturers. Therefore, it is important to have a clearer picture of the descriptive epidemiology of the MPNs in the EU. Large observational research leveraging patient-level databases and/or comprehensive registries should be designed to target the complete ascertainment of the MPNs as much as possible. Further, standardized definitions or coding across appropriate real-world databases and hematological malignancy registries is needed to add precision to or substantiate the estimates across geographies. Regardless of the limitations of the registries and studies reported here, the prevalence of ET and PV is considerable and warrant prioritized attention toward the development of novel agents that can change the underlying course of the disease as well as allocation of resources for improved screening, diagnosis, and disease management. References 1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2008. 2. National Cancer Institute. Myeloproliferative disorders. http:// www.cancer.gov/cancertopics/types/myeloproliferative (Accessed 25 March 2013).
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