Curr Hematol Malig Rep (2014) 9:340–349 DOI 10.1007/s11899-014-0228-z


Epidemiology of MPN: What Do We Know? L. A. Anderson & M. F. McMullin

Published online: 17 August 2014 # Springer Science+Business Media New York 2014

Abstract The myeloproliferative neoplasms, are characterised by overproduction of myeloid cells. Chronic myeloid leukaemia, polycythaemia vera, essential thrombocythaemia, myelofibrosis and the very rare disorders chronic neutrophilic leukaemia, chronic eosinophilic leukaemia not otherwise specified and mastocytosis are all included in the group. Incidence and prevalence rates reported in the worldwide literature are presented in this review. Survival data on each condition is described. Information on the aetiology of the disorders is discussed including body mass index, diet, smoking and alcohol, allergies, associated medical conditions, occupation and environmental exposures with focus on recent new studies. The aetiology of the myeloproliferative neoplasms remains unknown, and this review of the current state of knowledge highlights the need for further comprehensive research. Keywords Epidemiology . Myeloproliferative neoplasms . Survival . Body mass index . Diet . Benzene

Introduction Myeloproliferative neoplasms (MPNs) comprise a heterogeneous group of neoplasms characterised by over-proliferative of immature and mature cells of the myeloid lineage. While these conditions have undergone numerous classification L. A. Anderson Centre for Public Health, Queen’s University Belfast, Grosvenor Road, Belfast BT12 6BJ, Northern Ireland e-mail: [email protected] M. F. McMullin (*) Centre for Cancer Research and Cell Biology, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7AE, Northern Ireland e-mail: [email protected]

modifications, the World Health Organisation (WHO) termed them MPNs in 2008, recognising the presence of defined acquired clones in these disorders [1]. According to the WHO, the classical MPNs including polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are classified along with chronic myelogenous leukaemia (CML) BCR-ABL1-positive, chronic neutrophilic leukaemia (CNL), chronic eosinophilic leukaemia not otherwise specified (CEL-NOS) and mastocytosis [1]. MPNs can be differentiated into Philadelphia (Ph) chromosome-positive and Ph chromosome-negative cases based on the presence or absence of a reciprocal translocation between chromosomes 9 and 22, designated (t9;22)(q34;q11.2). The BCR-ABL gene fusion results in a BCR-ABL fusion protein in CML cases and distinguishes them as a distinct clinical entity [1]. The discovery of the Janus kinase (JAK)2V617F mutation in the classic MPNs in 2005 identified an acquired clone in MPNs [2]. The JAK2V617F mutation is present in almost all PV cases, around 50 % of ET and PMF cases [2] and has been reported in some CNL cases [3]. JAK2 exon 12 mutations also occur in patients with PV and are associated with a younger age at presentation [4]. A number of other specific acquired genetic lesions have been identified in other MPNs. Mutations in the thrombopoietin receptor (MPL W515L/K) have been reported in ET [5, 6] and PMF [5, 6] patients. Other mutations such as the casitas B-linkage lymphoma proto-oncogene (CBL) [7] and ten 11 translocation oncogene family member (TET2) [8] have also been reported in the classic MPNs. In 2013, calreticulin (CALR) mutation was identified in patients with JAK2/MPL-negative MPNs, but absent in JAK2-positive cases [9••]. A CALR mutation was identified in one CNL case [10], and most CNL cases have a mutation in colony-stimulating factor 3 receptor (CSF3R) [11]. Most patients with systematic mastocytosis have a somatic D816V mutation in the KIT gene [12].

Curr Hematol Malig Rep (2014) 9:340–349

New insights into the epidemiology of these conditions published in recent years are reviewed including the incidence, prevalence and trends in diagnosis of these neoplasms, survival and associated aetiologic factors.


Foundation) per 100 000, respectively. Similar incidence and prevalence rates were reported by Moulard et al. in a review of European studies [30•]. CNL

Incidence and Prevalence Historically, the incidence of MPNs reported in the literature combined all or certain MPN subtypes. The reported crude annual incidence rates of MPNs range from 1.15 [13] to 4.99 [14] per 100,000 [15••]. In 2013, in Germany, incidence of Ph MPNs was reported at 1.53 per 100,000 [16]. The individual incidence rates reported in the literature for each MPN subgroup are summarized in the following paragraphs and summarized in Table 1. CML CML results in an over proliferation of a mature granulocytes. Annual CML incidence in the USA is reported as 1.75 per 100,000 persons [17]. Incidence rates remained stable from 1975 to 2009 [17] but increase with advancing age [17, 18]. The HemaCare group published a European CML incidence rate of 1.10 per 100,000 persons for 2000–2002 [19], while incidence in Germany was recently reported at 0.89 per 100,000 [16]. Male incidence rates of CML are higher than those of females in the USA, and diagnosis often occurs at a younger age [20]. CML prevalence has been estimated at 70,000 cases in the USA and is anticipated to increase due to therapeutic advancements [21]. Classic MPNs PV results in an increased number of erythrocytes, while ET is characterised by an increased platelet count. Patients may also present as PMF with bone marrow fibrosis. Titmarsh et al. have undertaken an extensive systematic review of the literature pertaining to the incidence and prevalence of the classic MPNs worldwide [15••]. Incidence rates ranged from 0.01 to 2.61, 0.21 to 2.27 and 0.22 to 0.99 per 100 000 for PV, ET and PMF, respectively, with combined annual incidence rates of 0.84, 1.03 and 0.47 per 100 000, respectively. The review highlighted the heterogeneity of the incidence of these disorders worldwide possibly as a result of disease classification changes, misdiagnosis and cancer registration limitations or due to differing aetiologic exposures. The lowest incidence rates were reported in Japan [22], Israel [23] and the USA [24] and the highest in Sweden [14], England [25] and the USA [26] for PV, ET and PMF, respectively. Prevalence of PV, ET and PMF ranged from 0.49 [27] to 46.88 (MPN Research Foundation), from 11.00 [28] to 42.51 (MPN Research Foundation) and from 1.76 [29] to 4.05 (MPN Research

CNL is a rare MPN characterised by persistent neutrophilia. It is only very recently that specific associated molecular lesions have been described, making diagnosis easier [5]. In 2005, approximately 150 cases had been reported in the literature [31], but specific incidence figures for CNL have not been reported. In Germany, only six cases were reported between 2001 and 2010 in a sample of approximately 25 % of the population [16]. CEL-NOS CEL is a very rare disorder resulting in an over proliferation of eosinophils. The incidence of CEL-NOS remains to be elucidated with only nine cases reported from 2001 to 2010 in Germany from cancer registries, representing 25 % of the population [16]. Mastocytosis Mastocytosis is characterised by a neoplastic proliferation of mast cells which accumulate in one or more organ system. A national study from Denmark recently described an incidence of all types of mastocytosis of 0.89 per 100,000 per year and a prevalence of 9.59 per 100,000 [32]. A total of 58 cases were reported from 2001 to 2010 in the recent German study [16]. Prevalence has been estimated in Middle Europe at 0.5–1 cases per 10,000 population [33].

Survival Information on survival is available from some populations. New and improving treatments have also changed survival patterns in some MPNs in recent years. CML In Europe, CML 5-year relative survival was 44.9 % (42.6– 47.3 %) over the period 1995–2002 [34] and has increased from 32.3 % in 1996–1998 to 54.4 % in 2005–2007 [35]. Survival was highest in Northern and lowest in Eastern European countries [34, 35]. In the USA, 5-year relative survival was reported at 56.7 % in 2004 [36]. In the UK, regional based study survival was much higher at 88.6 % (81–93.3 %) during the period 2004–2011 [37].


Curr Hematol Malig Rep (2014) 9:340–349

Table 1 Summary of incidence, prevalence and 5-year survival figures for myeloproliferative neoplasms Overall MPN





CNL Mastocytosis

Incidence 1.15–4.99/100,000 0.89–1.75/100,000 0.01–2.61/100,000 0.21–2.27/100,000 0.22–0.99/100,000 Prevalence 0.49–46.88/100,000 11.00–42.51/100,000 1.76–4.05/100,000 5-year survival (%) 56.7 (USA) 84.8 89.9 39 (Sweden) 28 88.6 (UK)

Improvements in survival were apparent from the period 1999–2001 in Europe [35] and 2000 in the USA [36] which corresponds with the introduction of tyrosine kinase inhibitor (TKI) therapy. CML survival rates in these population-based settings [34–36, 38] are much lower than those observed in recent TKI therapy clinical trials which report overall 5-year survival rates of up to 96 % [39]. These differences are explained by access to TKIs which were licenced in 2001. These drugs completely change the survival pattern in CML, and depending on access to these drugs has dictated the change in survival. In the UK, TKI therapy is provided free of charge to patients and was given to 96.7 % of CML cases, perhaps explaining the much higher reported survival rates [37]. This disorder can affect all age groups, and the age of those with the disorder would be predicted to have an effect on survival where older individuals with the disorder have confounding issues with increasing age. This is reflected in survival figures. Five-year relative survival was higher in Europe in those aged 15–49 years (66.6 %) compared to those aged 70 years and over (22.5 %) [34]. In the USA during the period 2003–2005, 5-year relative survival was highest in those aged 15–44 years (87.1 %) compared to those aged 75–84 years (47.3 %) [36]. Similarly in the UK, survival was poorer in those aged 60 years and over (87.2 %) compared to younger patients (89.9 %) and was poorer in less affluent areas [37]. Improvements in survival in the USA have been most apparent in those aged up to 65 years [36], but most improvements have also been noted in those aged 75–84 years [36]. Young (70 years), leucocytosis and thrombosis at the time of PV diagnosis to adversely affect prognosis [43]. The 10-year relative survival ranged from 26 to 84 %, depending on the number of these prognostic risk factors [43]. ET European 5-year relative survival was 89.9 % (86.2–92.7 %) from 1995 to 2002 [34]. Relative survival declined to 85.8 % in those aged 70 years and over [34], while prior malignancy has been shown to have no influence on overall survival [41]. In Sweden, 1-, 5-, 10-, 15- and 20-year relative survival estimates were 92, 80, 68, 52 and 44 %, respectively, between 1993 and 2008 with improvements over time [40]. Overall survival at 10 years was 89.9 % in a study of 1,144 ET patients diagnosed from 1979 to 2010 with advancing age, anaemia, male gender, antecedent thrombotic events and high white blood cell counts, all adversely affect overall survival [44]. In a study from the International Working Group on Myelofibrosis Research and Treatment, older age, higher platelet and white cell counts and thrombosis also were associated with poorer survival [45]. The newly discovered CALR mutations have been reported to have no impact on survival [46]. PMF In Sweden, 1-, 5-, 10-, 15- and 20-year relative survival estimates were 76, 39, 21, 11 and 6 %, respectively, between 1993 and 2008 [40]. Survival that improved over time with an 8-year relative survival for PMF in the most recent time period (2001–2008) was 48 % [40]. Median survival for PMF patients from 1980 to 1995 was reported at 4.6 years in four European countries which increased to 6.5 years in the period 1996–2007 [47]. Increased plasma immunoglobulin free light chain concentration [48] and C-reactive protein [49], but not JAK2V617F [50] or JAK2 46/1 [51] status, are associated with poorer survival in PMF patients. In European and Mayo clinic cohorts of PMF patients with ASXL1, EZH2, SRSF2 and IDH mutations, respectively, were associated with reduced survival

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[52], as did CALR−ASXL1+ mutational status [53]. Survival is adversely affected by the presence of co-morbidities and higher-grade bone marrow fibrosis [54]. In a recently published review article of ruxolitinib therapy, a survival advantage is shown in treated PMF patients [55] as evidenced by recent trial data [56]. CNL Population-based data on the survival rates of CNL patients is lacking. The median survival time for CNL patients has been reported as 16 months [57], 23.5 months [58] and 30 months [59]. Five-year relative survival has been reported at 28 % [59]. Mastocytosis Mastocytosis is classified into the following subtypes: cutaneous mastocytosis, indolent systemic mastocytosis (ISM), systemic mastocytosis with associated clonal haematological non-mast cell lineage disease (SM-AHNMD), aggressive systemic mastocytosis (ASM), mast cell leukaemia (MCL), mast cell sarcoma and extracutaneous mastocytoma. In the Danish national study, survival varied greatly across subgroups of mastocytosis; however, median survival for ASM was 6.7 years, SM-AHNMD 4.4 years and MCL 0.8 years [32]. Overall survival in SM-AHNMD patients is reported as 85.2 months [60]. Survival was worse in those with ASXL1 mutations [60]. In patients with ISM, older (>60 years) age at diagnosis, increased serum alkaline phosphatase and development of AHNMD were predictive of shortened survival. In ISM, a 5-year cumulative probability of death of 2.2 % was described [61].

Aetiology Limited information is available pertaining to the aetiology of MPN subgroups with the majority of the published literature focusing on CML. Risk factors which have been investigated are outlined below, highlighting recent advances in the knowledge of the causes of MPNs where available. There have been several very large cohorts of individuals investigated extensively and followed for long periods of time. Various factors (see Table 2) which may be linked to the aetiology of haematological malignancy including MPNs have been explored in these groups, and significant findings are discussed. Body Mass Index A recent report from the Million Women Study demonstrated a 29–32 % increased risk of MPN/myelodysplasia with each

343 Table 2 Aetiological factors which have been considered in the myeloproliferative neoplasms Possible aetiological factors in myeloproliferative neoplasms Body mass Height Physical activity Diet Smoking Alcohol Allergies Previous medical conditions Concurrent medical conditions Benzene Occupation Radiation Residence Blood donation

10 kg/m2 increase body mass index [62••]. Height was not associated with excess risk in this myeloid subgroup [62••]. Using data from the National Institutes of Health-AARP Diet and Health Study, high body mass index (BMI) was associated with a non-significant increased risk of CML [odds ratio (OR) 1.46, 95 % confidence interval (CI) 0.95–2.23] [63]. No association between BMI, height or weight and CML was identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort [64•]. There was, however, a suggestion of an inverse association between waist/hip ratio and CML (highest vs. lowest quartile: relative risk (RR) 0.36, 95 % CI 0.12–1.09) in women [64•]. Conversely, a metaanalysis published in 2008 demonstrated a 26 % increased risk of CML in obese patients [65] despite only one of the included prospective studies showing a significant relative risk estimate (RR 1.65, 1.18–2.31) [66]. This may be due to the small number of cases identified in many of these studies, limiting their power to detect a significant association alone. High BMI has also been linked to an increased risk of CML in some case-control studies, but these studies are hampered by recall of BMI prior to disease onset [67, 68]. In the Iowa Women’s Health Study published in 2013, there was a suggestion of an increased risk of ET, but not PV, with increasing BMI (p trend 0.042) and weight (p trend 0.039) [69]. Physical Activity Using data from the National Institutes of Health-AARP Diet and Health Study, vigorous physical activity was associated with a 30 % reduced risk of CML [63] in keeping with previous findings from a Canadian case-control study (high vigorous activity versus none: OR 0.75, 95 % CI 0.57–0.99) [70]. In the Iowa Women’s Health Study, high intensity


physical activity was also inversely associated with ET (RR 0.66, 95 % CI 0.44–0.98), but not with PV (RR 1.20, 95 % CI 0.65–2.20) [69]. Diet Diet was found not to be associated to CML in the recently published National Institutes of Health-AARP Diet and Health Study [63] in keeping with prior reports from the National Enhanced Cancer Surveillance System in Canada [70]. Similarly, the EPIC cohort study, the largest cohort study to date to investigate diet and cancer outcomes, recently published findings, demonstrating no association between intake of meat, fish, fruit, vegetables, nuts/seeds or dairy products and CML [71•]. To our knowledge, no large cohort studies have investigated the role of dietary factors in the aetiology of other MPNs. Smoking/Alcohol In the NIH-AARP study, smoking more than 19 cigarettes per day was associated with a 53 % increased risk of CML (HR 1.53, 95 % CI 1.03–2.27) [63]. Musselman et al. also identified an increased risk of CML with increased smoking intensity with risk decreasing gradually upon quitting smoking [72]. However, previously published studies did not identify any association with smoking [70, 73, 74]. In the Million Women Study, smoking was associated with a 42 % increased risk of MPN/myelodysplastic disease compared to never smokers [75••]. Conversely, alcohol was not significantly associated with these disease entities in this study [75••]. The Iowa Women’s Health Study found the association with current smoking to be most pronounced in PV patients (RR 2.83, 95 % CI 1.44–5.57) with no significant association in ET patients (RR 1.32, 95 % CI 0.78–2.24) and no relation between alcohol consumption and PVor ET [69]. Similarly, in a small Italian case-control study of 39 ET cases, no association with smoking or alcohol was identified [76]. In a large population-based case-control study of leukaemia, CML risk was not significantly elevated for all levels of alcohol and wine intake [77]. For wine, the OR was 2.13 (95 % CI 1.01– 4.50) for the highest versus lowest quartile of intake [77]. Allergies The VITamins And Lifestyle cohort study was used to investigate the role of allergies in the development of haematological malignancies [78]. MPNs were grouped along with other myeloid malignancies based on the WHO classification system [1]. No significant associations between allergies and myeloid neoplasms were identified [78].

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Other Medical Conditions Many patients with haematological malignancy have previous or concurrent medical conditions. The associations and influence on aetiology of previous medical conditions is of great interest. Studies which have investigated previous medical conditions are considered. Risk of CML was not significantly elevated in patients receiving solid organ transplants in the US SEER-Medicare database (RR 2.04, 95 % CI 0.81–5.15), but there was a strong association between organ transplantation and chronic myeloproliferative disease (RR 2.99, 95 % CI 1.28–6.99) [79]. CML risk was elevated within the same data set for those with end-stage renal disease (OR 1.74, 95 % CI 1.08–2.80) [80]. These findings could suggest that infectious agents may be implicated in the development of MPNs. Using data from the SEER-Medicare database, it was recently reported that respiratory tract infections (bronchitis, pneumonia and sinusitis) and cellulitis were more common at least 12 months antecedent to CML diagnosis compared to a control population [81•]. In the same study, only cellulitis was significantly associated with other MPNs (OR 1.43, 95 % CI 1.32–1.55) [81•]. Autoimmune conditions and hepatitis B and C virus overall were not associated with either CML or other MPNs using the same data set [82, 83]. CML was also not significantly associated with HCV in an Italian casecontrol study, but an elevated non-significant increased risk in those with HBV was suggested (odds ratio 2.70, 95 % CI 0.86–8.43) [84]. This study also found no association between CML and human T cell lymphotropic virus types I and II [84]. A Chinese case-control study of 79 CML cases did not report any strong associations between a range of prior medical conditions and risk of CML [85]. CML risk was elevated in those with peptic ulcer disease (OR 2.0, 95 % CI 1.1–3.8) and in patients with prior cancer history (OR 3.5, 95 % CI 2.0–5.8) even after restriction to those who had not received prior radiation/chemotherapy treatment in a case-control study of 186 CML cases published in 2012 [86]. CML risk is elevated in breast cancer survivors (EAR 2.06, 95 % CI 1.3–2.9) [87], but this may be demonstrated at link with therapies for the breast cancer such as radiotherapy. Recently, ET, but not PV, risk was elevated in patients with diabetes in the Iowa Women’s Health Study (RR 1.82, 95 % CI 1.16–2.84) but did not remain significant in a multivariate model [69]. Risk of PV was elevated in those with adenoma of the parathyroid gland in a previous cohort study, but the absolute number of cases developing PV was small [88]. Benzene Exposure to benzene, an aromatic hydrocarbon which is present in crude oil, has been shown to be a likely carcinogen in many haematological malignancies. There have been a

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number of investigations of benzene exposure and the aetiology of MPNs. A meta-analysis published in 2010 found no association between work-based benzene exposure and CML when all studies were included [89]. Similar findings were reported in a more recent meta-analysis [90]. However, benzene exposure was associated with an increased risk of CML in studies that commenced follow-up after 1970 (RR (meta-analysis) 1.67, 95 % CI 1.02–2.74) [90]. These findings are strengthened by the lack of heterogeneity and publication bias detected within the review [90]. In a recent nested casecontrol study of petroleum workers, Glass et al. found no evidence of an association between low-level benzene exposure and CML or myeloproliferative disorders, but sample sizes were limited (n=28 CML and n=30 myeloproliferative cases) [91]. Terreros reported a 46.6 times higher rate of myeloproliferative syndrome in those reporting exposure to benzene [92]. Many occupations highlighted in our recent review article point towards occupations where benzene exposure is a factor as a possible aetiological agent for the classic MPNs [93••]. A strong association with benzene exposure was observed in a case-control study of ET by Mele et al. in 1996 (OR 46.6, 95 % CI 2.02–2761) [76]. Occupation Assessment of occupation and the associated exposure risks is difficult as occupations need to be defined and individuals can participate in many different occupations, but there are now tools which can be used to assess occupations and the associated exposures. Information from the literature discussed below considers occupations including construction, metalworks and agricultural and electrical works. CML risk was elevated in male construction workers in a recent case-control study from California (OR 1.25, 95 % CI 1.09–1.44) [94]. Metalworkers had a higher risk of MPNs in an Australian case-control study (RR 3.0, 95 % CI 1.04–10.6) [95] identified in our systematic review [93••]. Male CML patients were more likely than controls to have been farmers or agricultural workers in a meta-analysis of seven studies (RR 1.38, 95 % CI 1.06–1.79) published in 2007, more common in male workers exposed to pesticides (RR 1.39, 95 % CI 1.03–1.88) [96]. However, findings from the studies were inconsistent and exposure to pesticides overall was not associated with an increased risk of CML [96] or with ET in a small Italian case-control study [76]. In our systematic review [93••], agricultural work/farming was also not associated with ET [76, 97] or myeloproliferative syndrome [92] in three small studies. However, an increased risk of PV and myelofibrosis cases was observed in males with rural sector jobs (RR 2.25, 95 % CI 1.21–3.8) and farmers (RR 5.17, p

Epidemiology of MPN: what do we know?

The myeloproliferative neoplasms, are characterised by overproduction of myeloid cells. Chronic myeloid leukaemia, polycythaemia vera, essential throm...
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