Ann Hematol (2015) 94(Suppl 2):S241–S247 DOI 10.1007/s00277-015-2314-2
REVIEW ARTICLE
Epidemiology of chronic myeloid leukaemia: an update Martin Höglund & Fredrik Sandin & Bengt Simonsson
Received: 18 July 2014 / Accepted: 23 October 2014 # Springer-Verlag Berlin Heidelberg 2015
Abstract National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. Chronic myeloid leukaemia (CML) registries with more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several European CML registries consistently show a crude annual incidence of 0.7–1.0/100,000, a median age at diagnosis of 57–60 years and a male/female ratio of 1.2–1.7. The incidence of CML has been stable over time. Worldwide, variations in the reported incidence of CML may be due to methodological issues, but a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. The prevalence of CML is not well known but has been estimated to be 10–12/100,000 inhabitants with a steady increase due to the dramatic improvement in survival of these patients. In recent population-based studies, CML patients have an overall survival that is comparable to that shown in large clinical trials, though relative survival in patients >70 years is still decreased. The importance of socio-economic factors and health-care setting for outcome and the possible increased risk of secondary cancer in CML are areas of ongoing research. Keywords Epidemiology . Chronic myeloid leukaemia (CML) . Incidence . Prevalence . Population-based registries M. Höglund : B. Simonsson Department of Medical Science, Uppsala University Hospital, Uppsala, Sweden F. Sandin Regional Cancer Centre, Uppsala-Örebro, Sweden M. Höglund (*) : B. Simonsson Division of Hematology (50C), Uppsala University Hospital, 751 85 Uppsala, Sweden e-mail: [email protected]
Population-based registries Important data on cancer epidemiology (i.e. incidence, mortality, age and sex distribution, overall survival) are obtained from cancer registries covering either the entire population of a nation [1, 2] or selected regions with well-characterised populations [3]. The National Cancer Registry in Sweden was formed already in 1958. All pathologists, cytologists and clinicians are obliged by law to report each occurrence of cancer that they diagnose or treat to this centralised, nationwide registry [4]. The Surveillance, Epidemiology, and End Results (SEER) registry collects data on all newly diagnosed cancers from US hospitals, including patient demographics form 17 tumour registries covering approximately 25 % of the US population [5]. More recently, population-based registries aiming to collect more detailed data on demographics, baseline patient characteristics as well as treatment and outcome in chronic myeloid leukaemia (CML) or other haematological cancers have been initiated at the regional or national levels [6–9]. Examples are the British Haematological Malignancy Research Network (HMRN), established in 2004 and operating across 14 hospitals using a single haematopathology laboratory [3], and the national Swedish CML Registry, founded in 2002 and covering >95 % of all newly diagnosed cases of CML [8]. At the international level, the European Treatment and Outcome Study (EUTOS) for CML has collected detailed populationbased data on patients with CML diagnosed in 2008–2012, in 27 European countries [10]. Reliability of data from registries claiming to be population based presupposes complete reporting, diagnostic accuracy, correct coding classification and a well-characterised background population of the registry catchment area(s). Results from more detailed population-based registries with full coverage of the target population are not only useful sources for epidemiological studies. By reducing the impact of
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selection on outcome, they may also provide important complementary data on treatment outcome to those obtained from clinical trials [11]. In addition, further information could be obtained by cross-linking to other population-based databases [12, 13]. Using real-time data from more detailed diseasespecific registries may also be helpful in evaluating adherence to guidelines and in improving the quality of care, including routines for diagnostics and follow-up [14]. However, delayed reporting, less stringent monitoring (as compared to clinical trials) and no detailed information on treatments are obvious limitations of population-based registries.
Incidence Incidence of CML in the total adult population Published data on the annual incidence of CML varies from as low as 0.4/100,000 persons in some non-Western countries to 1.75/100,000 in the USA [7–9, 15–19]. As the incidence of CML increases by age, some of these variations are due to significant differences in the age distributions of the investigated populations (e.g. Western vs several non-Western countries). However, also figures on age-adjusted incidence vary considerably (0.7–1.8/100,000) between different studies (Table 1) [8, 20]. Methodological factors may, at least partly, explain these discrepancies. In particular, the inclusion of patients with BCR-ABL-negative myeloproliferative disorders may account for the higher incidence of CML in some registries, such as SEER reporting an incidence of 1.75/100,000, varying from 1.4 to 2.0 between different regions within the USA [17]. Moreover, incorrectly including referral patients in regional Bpopulation-based^ registries leads to an overestimation of the incidence. On the other hand, incomplete reporting of Table 1
new CML cases will result in too low figures. Several CML registries have therefore made considerable efforts to pick up all newly diagnosed cases of CML including those diagnosed at smaller hospitals [8, 9]. Notably, reports from the CML registries in UK, Germany and Sweden consistently show an age-adjusted incidence of 0.7–1.0/100,000 [8, 9, 20, 21]. Although we hypothesise that the divergence in CML incidence reported so far is mainly due to methodological issues, a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. Indeed, such differences have been shown in other haematological cancers such as chronic lymphocytic leukaemia and acute promyelocytic leukaemia [22, 23]. In CML, several reports suggest that the incidence of CML is lower in some Asian countries [16, 24]. Thus, Chen et al., analysing the incidence of CML in different ethnical subgroups within the USA, showed a lower incidence of CML in Asians as compared to Caucasians [17]. Of interest, a recent preliminary report from the EUTOS registry, based on population-based epidemiological data from 2956 patients in 20 countries with cytogenetically confirmed CML diagnosed in 2008–2012, showed that the raw incidence of CML varied from 0.76 (UK) to 1.96 (Finland) per 100,000 persons [25]. These surprisingly large differences cannot be explained solely by differences in the age distributions of the participating countries and need to be further analysed before making any firm conclusions about possible variations in CML incidence within Europe.
Age and sex differences The incidence in CML increases by age, at least up to 75– 80 years (Fig. 1). In Europe, the median age at diagnosis of CML, as estimated from population-based registries, is 57– 60 years (Table 1) [9, 20]. Importantly, this is about 10 years above the median age typically seen in clinical trials [19]. In
CML incidence of eight different population-based registries or surveys
Registry
Time of observation
No. of patients
Median age
Crude incidence
Age-standardised incidence
Reference
US (SEERS)
1975–2009
13,869
66
–
1.75a
Chen et al. [17]
NW France
1985–2006
906
56
–
0.8
Corm et al. [29]
Europe (RARECARE project)
1995–2002
1047
n.d.
1.2
–
Visser et al. [21]
Taiwan
1997–2007
2672
n.d.
0.7
–
Chang et al. [16]
SW Germany
1998–2000
218
57
0.62
–
Rohrbacher et al. [19]
Sw. CML registry
2002–2010
779
60
0.9
–
Höglund et al. [8]
UK (HMRN)
2004–2011
242
59
0.97
0.7b
Smith et al. [9]
EUTOS
2008–2012
2956
57
1.0
–
Hoffman et al. [25]
n.d. no data a
American-standardised population
b
World-standardised population
b
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Fig. 1 Annual incidence per 100,000 inhabitants in different age groups of CML patients (n= 1039) diagnosed in 2002–2012 (adjusted to the World Standard Population, WSP). Data are obtained from the Swedish Cancer Registry (www. socialstyrelsen.se/register/ halsodataregister/cancerregistret/ inenglish)
children, CML is a very rare disease with an incidence of 0.6– 1.2 million children/year [26]. CML is more common in males than in females with maleto-female ratio varying between 1.2 and 1.7 in different studies [8, 20, 27]. The gender difference in incidence is less prominent in younger age groups (Fig. 1).
specialised units and the introduction of cytogenetics, make it very difficult to compare present figures on incidence with data from the mid 1980s and earlier.
Has the incidence of CML increased over time?
Reliable data on the exact prevalence of CML are still scarce. Based on results from the Surveillance of Rare Cancer in Europe (RARECARE) project, Visser et al. estimated the prevalence of CML in 2008 to 5.6/100,000 [21]. In an epidemiological survey from northern France, Corm et al. reported a prevalence for 1998, 2003 and 2007, respectively, of 5.8, 6.8 and 7.3 per 100,000 inhabitants [29]. Due to the dramatic improvement in survival, following the introduction of imatinib and other tyrosine kinase inhibitors, as well as the increasing life expectancy in the general population, one may anticipate that the prevalence continues to increase. Thus, based on an excess annual mortality in CML of 1.53, and an annual incidence of approximately 1/100,000, Huang et al. estimated that the prevalence of CML in USA will increase from approximately 70, 000 in 2010 (corresponding to a prevalence of approximately 11.6/100,000) to reach a near plateau 35 times the annual incidence in 2050 (Fig. 3) [30]. Obviously, this trend has profound pharmaco-economic consequences [31].
1.5
1
0.5 Men Women * standardised according to the standard world population
Risk factors for developing CML 2010
2005
2000
1995
1990
1985
1980
1975
0 1970
Age−standardised* incidence per 100 000 inhabitants
In several countries, cancer statistics are available since the 1970s. Data from SEERS and the Swedish Cancer Registry (Fig. 2) give no clear evidence of a change in incidence of CML over time [17, 28]. However, changes in the classification system, as well as the development of more accurate diagnostics by the centralization of haematopathology to more
Prevalence
Fig. 2 Age-standardised annual incidence (adjusted to WSP) of CML diagnosed in 1970–2010 (n=4393). Data are obtained from the Swedish Cancer Registry (www.socialstyrelsen.se/register/halsodataregister/ cancerregistret/inenglish). Note that data from 1970s to 1980s may be imprecise due to decentralised haematopathology and no cytogenetics
The aetiology of CML is essentially unknown. Ionising radiation is the only established risk factor, having been linked to CML in atomic bomb survivors [32]. Results from a recent population-based case-control study suggested a weak association between smoking and CML, but this has not yet been
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Fig. 3 Estimated prevalence of chronic myeloid leukaemia in the USA by calendar year, from Huang et al. [30] (published by the permission of the authors)
confirmed by other studies [33]. In a study based on the Swedish Cancer Registry and Multigenerational Registry, Bjorkholm et al. found no significant familial aggregation of CML [13].
Survival rates and non-disease-related prognostic factors Overall and relative survival in the population-based setting Results from a number of population-based studies have confirmed the dramatic improvement in survival in patients with CML diagnosed since the introduction of tyrosine kinase inhibitors (TKIs) at the turn of the century [17, 28]. Furthermore, studying 832 consecutive patients in CCgR after 2 years of treatment with imatinib, Gambacorti-Passerini et al. reported that CML-related deaths were uncommon and survival was not significantly different from the general population [34]. Previous studies suggest that the survival rate in patients treated within clinical trials, or in large referral centres, was significantly better than that of all patients with CML [35]. However, results from at least two large population-based studies have shown almost equal figures on survival with that obtained from the more selected materials, with an estimated 5-year overall survival of 85 % for patients diagnosed in a chronic phase with no difference between males and females [8, 9]. Relative survival (RS), which might be a more relevant measure in an elderly population, was 90 % or higher in patients up to 75–80 years. Thus, in countries where TKIs are easily available, most patients with CML seem to have a life expectancy close to that of the normal population. Age and co-morbidity Apart from disease-related pretreatment factors (e.g. stage, Sokal, Hasford and EUTOS score, aberrant cytogenetics),
which are beyond the scope of this overview, several nondisease-related factors might have an impact on the prognosis of CML. A number of studies indicate that, even after the introduction of imatinib in 2001–2002, elderly CML patients (>60–70 years) have an inferior survival than younger ones [28, 36–38], although recent reports from UK and the German CML Study IV concluded that the relative survival was almost identical for patients under and over 60 (65)years [9, 39]. Possibly, the underuse of imatinib (or other TKIs) in the elderly CML patient populations during the first years after its introduction explains the inferior results in the very elderly population as reported in some population-based studies [8]. Do elderly patients respond differently to treatment with TKIs? Previous reports suggest that older patients respond equally well as younger to treatment with imatinib [40], although tolerance might be less good [41]. Nevertheless, Proetel et al. showed that older patients (≥65 years) responded more slowly to standard dose imatinib (400 mg/day) than younger, but equally well to a higher dose (800 mg/day). Grade 3 and 4 adverse events were similar in both age groups [39]. Clinical implications of these findings are unclear, although the authors suggest that the optimal dose of imatinib for older patients may be higher than 400 mg/day. In another publication based on patients participating in the German CML Study IV, co-morbidity, as measured using the Charlson index [42] and separated from age in the analysis, expectedly was associated with worse survival but had no negative impact on response to imatinib [43].
Socio-economy and health-care setting Even in economically more developed countries, socioeconomic factors may have an impact on the prognosis in patients with haematological cancers [15]. In CML, in a recent population-based study from the UK (HMRN), the
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investigators found that patients living in more deprived areas had poorer outcome in terms of relative survival as well as a lower chance to obtain MMR despite treatment with a TKI [9]. Although, the mechanism(s) behind these findings remains to be elucidated, the authors speculate that nonadherence to TKI therapy may be the most important factor. Further studies on this subject are warranted. Previous publications suggested that centralised care of patients with CML is important for achieving results comparable with those of clinical trials [35, 44]. More recently, Lauseker et al., analysing the outcome of 1491 patients included in the German CML Study IV, observed a survival advantage for patients treated initially at a teaching hospital compared to those treated in municipal hospitals and by officebased physicians, respectively [45]. The difference remained when adjusted for age, performance status and EUTOS score. On the other hand, a report from the Swedish CML Registry, based on 779 patients, was not able to find any difference in survival between patients living in university versus nonuniversity catchment areas [8]. Apart from methodological issues, it may well be that the relative importance of centralised care in CML differs between countries due to differences in their health-care resources and organisation.
Do CML patients have an increased risk to develop other cancers? Studies on the risk of developing subsequent malignancies (other than MDS or acute leukaemia) after the diagnosis of CML have yielded somewhat conflicting results. Thus, in a study based on 1026 patients with CML, diagnosed in 1977–2008 and identified in the Danish Cancer Registry, Fredriksen et al. observed a 1.6-fold increased risk of developing a secondary malignancy as compared to the expected rate in the background population [46]. In a recent study from the Swedish CML Registry, based on a cohort of 868 patients with CML CP diagnosed in 2002–2011, Gunnarsson et al. reported that CML patients had a 1.5-fold increased risk of developing a secondary cancer as compared to the background population (matched by age, sex, health-care region and calendar year at diagnosis) [47]. Other investigators, analysing different kinds of study populations, have found that patients with CML have only a slight or borderline increase of secondary cancers [48, 49]. Notably, Verma et al., analysing a large cohort of CML patients treated between 1998 and 2010 at MD Anderson Cancer Center, concluded that the number of patients developing invasive malignancies were indeed smaller than expected [50]. Differences in patient numbers, selection, follow-up time and definition of Bsecondary cancer^ might explain these contradictory findings. Clearly, the question whether CML patients, nowadays mostly living an almost normal lifespan, have an increased risk of developing other cancers needs to be further investigated.
S245 Acknowledgments The authors appreciate the work of all clinicians reporting all newly diagnosed cases of CML to the Swedish CML Registry. Conflict of interest Nothing to disclose
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subanalysis of the randomized CML-Study IV. Ann Hematol 93(7): 1167–1176. doi:10.1007/s00277-014-2041-0 Gugliotta G, Castagnetti F, Palandri F, Breccia M, Intermesoli T, Capucci A, Martino B, Pregno P, Rupoli S, Ferrero D, Gherlinzoni F, Montefusco E, Bocchia M, Tiribelli M, Pierri I, Grifoni F, Marzocchi G, Amabile M, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M, Rosti G (2011) Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party. Blood 117(21): 5591–5599. doi:10.1182/blood-2010-12-324228 Breccia M, Alimena G (2013) The role of comorbidities in chronic myeloid leukemia. Leuk Res 37(7):729–730. doi:10.1016/j.leukres. 2013.04.001 Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40(5):373–383 Krauss MP, Lauseker M, Hehlmann R, Proetel U, Schreiber A, Kalmanti L, Hanfstein B, Einsele H, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Baerlocher GM, Heim D, Krause SW, Hofmann WK, Hasford J, Hochhaus A, Pfirrmann M, Müller MC (2013) Comorbidity, measured by the Charlson index, has no negative impact on remission in patients with chronic myeloid leukemia: results of the randomized CML-Study IV, vol 122. vol 21. Faber E, Muzik J, Koza V, Demeckova E, Voglova J, Demitrovicova L, Chudej J, Markuljak I, Cmunt E, Kozak T, Tothova E, Jarosova M, Dusek L, Indrak K (2011) Treatment of consecutive patients with chronic myeloid leukaemia in the cooperating centres from the Czech Republic and the whole of Slovakia after 2000—a report from the population-based CAMELIA Registry. Eur J Haematol 87(2): 157–168. doi:10.1111/j.1600-0609.2011.01637.x
S247 45. Lauseker M, Hasford J, Pfirrmann M, Hehlmann R, German CMLSG (2014) The impact of health care settings on survival time of patients with chronic myeloid leukemia. Blood 123(16):2494– 2496. doi:10.1182/blood-2013-11-539742 46. Frederiksen H, Farkas DK, Christiansen CF, Hasselbalch HC, Sorensen HT (2011) Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study. Blood 118(25):6515–6520. doi:10.1182/blood-2011-04348755 47. Gunnarsson N, Stenke L, Höglund M, Sandin F, Björkholm M, Dreimane A, Lambe M, Markevärn B, Olsson-Strömberg U, Richer J, Wadenvik H, Wallvik J, Själander A (2014) Second malignancies following treatment of chronic myeloid leukemia in the tyrosine kinase inhibitor era. ASH Annual Meeting Abstracts 2014, abstract no 154. Br. J. Haematol. doi:10.1111/bjh.13346 48. Rebora P, Czene K, Antolini L, Gambacorti Passerini C, Reilly M, Valsecchi MG (2010) Are chronic myeloid leukemia patients more at risk for second malignancies? A population-based study. Am J Epidemiol 172(9):1028–1033. doi:10.1093/aje/kwq262 49. Voglova J, Muzik J, Faber E, Zackova D, Klamova H, Steinerova K, Michalovicova Z, Demitrovicova L, Cmunt E, Novakova L, Tothova E, Belohlavkova P, Mayer J, Indrak K (2011) Incidence of second malignancies during treatment of chronic myeloid leukemia with tyrosine kinase inhibitors in the Czech Republic and Slovakia. Neoplasma 58(3):256–262 50. Verma D, Kantarjian H, Strom SS, Rios MB, Jabbour E, QuintasCardama A, Verstovsek S, Ravandi F, O’Brien S, Cortes J (2011) Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood 118(16):4353–4358. doi:10.1182/blood2011-06-362889
REVIEW ARTICLE
Epidemiology of chronic myeloid leukaemia: an update Martin Höglund & Fredrik Sandin & Bengt Simonsson
Received: 18 July 2014 / Accepted: 23 October 2014 # Springer-Verlag Berlin Heidelberg 2015
Abstract National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. Chronic myeloid leukaemia (CML) registries with more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several European CML registries consistently show a crude annual incidence of 0.7–1.0/100,000, a median age at diagnosis of 57–60 years and a male/female ratio of 1.2–1.7. The incidence of CML has been stable over time. Worldwide, variations in the reported incidence of CML may be due to methodological issues, but a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. The prevalence of CML is not well known but has been estimated to be 10–12/100,000 inhabitants with a steady increase due to the dramatic improvement in survival of these patients. In recent population-based studies, CML patients have an overall survival that is comparable to that shown in large clinical trials, though relative survival in patients >70 years is still decreased. The importance of socio-economic factors and health-care setting for outcome and the possible increased risk of secondary cancer in CML are areas of ongoing research. Keywords Epidemiology . Chronic myeloid leukaemia (CML) . Incidence . Prevalence . Population-based registries M. Höglund : B. Simonsson Department of Medical Science, Uppsala University Hospital, Uppsala, Sweden F. Sandin Regional Cancer Centre, Uppsala-Örebro, Sweden M. Höglund (*) : B. Simonsson Division of Hematology (50C), Uppsala University Hospital, 751 85 Uppsala, Sweden e-mail: [email protected]
Population-based registries Important data on cancer epidemiology (i.e. incidence, mortality, age and sex distribution, overall survival) are obtained from cancer registries covering either the entire population of a nation [1, 2] or selected regions with well-characterised populations [3]. The National Cancer Registry in Sweden was formed already in 1958. All pathologists, cytologists and clinicians are obliged by law to report each occurrence of cancer that they diagnose or treat to this centralised, nationwide registry [4]. The Surveillance, Epidemiology, and End Results (SEER) registry collects data on all newly diagnosed cancers from US hospitals, including patient demographics form 17 tumour registries covering approximately 25 % of the US population [5]. More recently, population-based registries aiming to collect more detailed data on demographics, baseline patient characteristics as well as treatment and outcome in chronic myeloid leukaemia (CML) or other haematological cancers have been initiated at the regional or national levels [6–9]. Examples are the British Haematological Malignancy Research Network (HMRN), established in 2004 and operating across 14 hospitals using a single haematopathology laboratory [3], and the national Swedish CML Registry, founded in 2002 and covering >95 % of all newly diagnosed cases of CML [8]. At the international level, the European Treatment and Outcome Study (EUTOS) for CML has collected detailed populationbased data on patients with CML diagnosed in 2008–2012, in 27 European countries [10]. Reliability of data from registries claiming to be population based presupposes complete reporting, diagnostic accuracy, correct coding classification and a well-characterised background population of the registry catchment area(s). Results from more detailed population-based registries with full coverage of the target population are not only useful sources for epidemiological studies. By reducing the impact of
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selection on outcome, they may also provide important complementary data on treatment outcome to those obtained from clinical trials [11]. In addition, further information could be obtained by cross-linking to other population-based databases [12, 13]. Using real-time data from more detailed diseasespecific registries may also be helpful in evaluating adherence to guidelines and in improving the quality of care, including routines for diagnostics and follow-up [14]. However, delayed reporting, less stringent monitoring (as compared to clinical trials) and no detailed information on treatments are obvious limitations of population-based registries.
Incidence Incidence of CML in the total adult population Published data on the annual incidence of CML varies from as low as 0.4/100,000 persons in some non-Western countries to 1.75/100,000 in the USA [7–9, 15–19]. As the incidence of CML increases by age, some of these variations are due to significant differences in the age distributions of the investigated populations (e.g. Western vs several non-Western countries). However, also figures on age-adjusted incidence vary considerably (0.7–1.8/100,000) between different studies (Table 1) [8, 20]. Methodological factors may, at least partly, explain these discrepancies. In particular, the inclusion of patients with BCR-ABL-negative myeloproliferative disorders may account for the higher incidence of CML in some registries, such as SEER reporting an incidence of 1.75/100,000, varying from 1.4 to 2.0 between different regions within the USA [17]. Moreover, incorrectly including referral patients in regional Bpopulation-based^ registries leads to an overestimation of the incidence. On the other hand, incomplete reporting of Table 1
new CML cases will result in too low figures. Several CML registries have therefore made considerable efforts to pick up all newly diagnosed cases of CML including those diagnosed at smaller hospitals [8, 9]. Notably, reports from the CML registries in UK, Germany and Sweden consistently show an age-adjusted incidence of 0.7–1.0/100,000 [8, 9, 20, 21]. Although we hypothesise that the divergence in CML incidence reported so far is mainly due to methodological issues, a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. Indeed, such differences have been shown in other haematological cancers such as chronic lymphocytic leukaemia and acute promyelocytic leukaemia [22, 23]. In CML, several reports suggest that the incidence of CML is lower in some Asian countries [16, 24]. Thus, Chen et al., analysing the incidence of CML in different ethnical subgroups within the USA, showed a lower incidence of CML in Asians as compared to Caucasians [17]. Of interest, a recent preliminary report from the EUTOS registry, based on population-based epidemiological data from 2956 patients in 20 countries with cytogenetically confirmed CML diagnosed in 2008–2012, showed that the raw incidence of CML varied from 0.76 (UK) to 1.96 (Finland) per 100,000 persons [25]. These surprisingly large differences cannot be explained solely by differences in the age distributions of the participating countries and need to be further analysed before making any firm conclusions about possible variations in CML incidence within Europe.
Age and sex differences The incidence in CML increases by age, at least up to 75– 80 years (Fig. 1). In Europe, the median age at diagnosis of CML, as estimated from population-based registries, is 57– 60 years (Table 1) [9, 20]. Importantly, this is about 10 years above the median age typically seen in clinical trials [19]. In
CML incidence of eight different population-based registries or surveys
Registry
Time of observation
No. of patients
Median age
Crude incidence
Age-standardised incidence
Reference
US (SEERS)
1975–2009
13,869
66
–
1.75a
Chen et al. [17]
NW France
1985–2006
906
56
–
0.8
Corm et al. [29]
Europe (RARECARE project)
1995–2002
1047
n.d.
1.2
–
Visser et al. [21]
Taiwan
1997–2007
2672
n.d.
0.7
–
Chang et al. [16]
SW Germany
1998–2000
218
57
0.62
–
Rohrbacher et al. [19]
Sw. CML registry
2002–2010
779
60
0.9
–
Höglund et al. [8]
UK (HMRN)
2004–2011
242
59
0.97
0.7b
Smith et al. [9]
EUTOS
2008–2012
2956
57
1.0
–
Hoffman et al. [25]
n.d. no data a
American-standardised population
b
World-standardised population
b
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S243
Fig. 1 Annual incidence per 100,000 inhabitants in different age groups of CML patients (n= 1039) diagnosed in 2002–2012 (adjusted to the World Standard Population, WSP). Data are obtained from the Swedish Cancer Registry (www. socialstyrelsen.se/register/ halsodataregister/cancerregistret/ inenglish)
children, CML is a very rare disease with an incidence of 0.6– 1.2 million children/year [26]. CML is more common in males than in females with maleto-female ratio varying between 1.2 and 1.7 in different studies [8, 20, 27]. The gender difference in incidence is less prominent in younger age groups (Fig. 1).
specialised units and the introduction of cytogenetics, make it very difficult to compare present figures on incidence with data from the mid 1980s and earlier.
Has the incidence of CML increased over time?
Reliable data on the exact prevalence of CML are still scarce. Based on results from the Surveillance of Rare Cancer in Europe (RARECARE) project, Visser et al. estimated the prevalence of CML in 2008 to 5.6/100,000 [21]. In an epidemiological survey from northern France, Corm et al. reported a prevalence for 1998, 2003 and 2007, respectively, of 5.8, 6.8 and 7.3 per 100,000 inhabitants [29]. Due to the dramatic improvement in survival, following the introduction of imatinib and other tyrosine kinase inhibitors, as well as the increasing life expectancy in the general population, one may anticipate that the prevalence continues to increase. Thus, based on an excess annual mortality in CML of 1.53, and an annual incidence of approximately 1/100,000, Huang et al. estimated that the prevalence of CML in USA will increase from approximately 70, 000 in 2010 (corresponding to a prevalence of approximately 11.6/100,000) to reach a near plateau 35 times the annual incidence in 2050 (Fig. 3) [30]. Obviously, this trend has profound pharmaco-economic consequences [31].
1.5
1
0.5 Men Women * standardised according to the standard world population
Risk factors for developing CML 2010
2005
2000
1995
1990
1985
1980
1975
0 1970
Age−standardised* incidence per 100 000 inhabitants
In several countries, cancer statistics are available since the 1970s. Data from SEERS and the Swedish Cancer Registry (Fig. 2) give no clear evidence of a change in incidence of CML over time [17, 28]. However, changes in the classification system, as well as the development of more accurate diagnostics by the centralization of haematopathology to more
Prevalence
Fig. 2 Age-standardised annual incidence (adjusted to WSP) of CML diagnosed in 1970–2010 (n=4393). Data are obtained from the Swedish Cancer Registry (www.socialstyrelsen.se/register/halsodataregister/ cancerregistret/inenglish). Note that data from 1970s to 1980s may be imprecise due to decentralised haematopathology and no cytogenetics
The aetiology of CML is essentially unknown. Ionising radiation is the only established risk factor, having been linked to CML in atomic bomb survivors [32]. Results from a recent population-based case-control study suggested a weak association between smoking and CML, but this has not yet been
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Fig. 3 Estimated prevalence of chronic myeloid leukaemia in the USA by calendar year, from Huang et al. [30] (published by the permission of the authors)
confirmed by other studies [33]. In a study based on the Swedish Cancer Registry and Multigenerational Registry, Bjorkholm et al. found no significant familial aggregation of CML [13].
Survival rates and non-disease-related prognostic factors Overall and relative survival in the population-based setting Results from a number of population-based studies have confirmed the dramatic improvement in survival in patients with CML diagnosed since the introduction of tyrosine kinase inhibitors (TKIs) at the turn of the century [17, 28]. Furthermore, studying 832 consecutive patients in CCgR after 2 years of treatment with imatinib, Gambacorti-Passerini et al. reported that CML-related deaths were uncommon and survival was not significantly different from the general population [34]. Previous studies suggest that the survival rate in patients treated within clinical trials, or in large referral centres, was significantly better than that of all patients with CML [35]. However, results from at least two large population-based studies have shown almost equal figures on survival with that obtained from the more selected materials, with an estimated 5-year overall survival of 85 % for patients diagnosed in a chronic phase with no difference between males and females [8, 9]. Relative survival (RS), which might be a more relevant measure in an elderly population, was 90 % or higher in patients up to 75–80 years. Thus, in countries where TKIs are easily available, most patients with CML seem to have a life expectancy close to that of the normal population. Age and co-morbidity Apart from disease-related pretreatment factors (e.g. stage, Sokal, Hasford and EUTOS score, aberrant cytogenetics),
which are beyond the scope of this overview, several nondisease-related factors might have an impact on the prognosis of CML. A number of studies indicate that, even after the introduction of imatinib in 2001–2002, elderly CML patients (>60–70 years) have an inferior survival than younger ones [28, 36–38], although recent reports from UK and the German CML Study IV concluded that the relative survival was almost identical for patients under and over 60 (65)years [9, 39]. Possibly, the underuse of imatinib (or other TKIs) in the elderly CML patient populations during the first years after its introduction explains the inferior results in the very elderly population as reported in some population-based studies [8]. Do elderly patients respond differently to treatment with TKIs? Previous reports suggest that older patients respond equally well as younger to treatment with imatinib [40], although tolerance might be less good [41]. Nevertheless, Proetel et al. showed that older patients (≥65 years) responded more slowly to standard dose imatinib (400 mg/day) than younger, but equally well to a higher dose (800 mg/day). Grade 3 and 4 adverse events were similar in both age groups [39]. Clinical implications of these findings are unclear, although the authors suggest that the optimal dose of imatinib for older patients may be higher than 400 mg/day. In another publication based on patients participating in the German CML Study IV, co-morbidity, as measured using the Charlson index [42] and separated from age in the analysis, expectedly was associated with worse survival but had no negative impact on response to imatinib [43].
Socio-economy and health-care setting Even in economically more developed countries, socioeconomic factors may have an impact on the prognosis in patients with haematological cancers [15]. In CML, in a recent population-based study from the UK (HMRN), the
Ann Hematol (2015) 94(Suppl 2):S241–S247
investigators found that patients living in more deprived areas had poorer outcome in terms of relative survival as well as a lower chance to obtain MMR despite treatment with a TKI [9]. Although, the mechanism(s) behind these findings remains to be elucidated, the authors speculate that nonadherence to TKI therapy may be the most important factor. Further studies on this subject are warranted. Previous publications suggested that centralised care of patients with CML is important for achieving results comparable with those of clinical trials [35, 44]. More recently, Lauseker et al., analysing the outcome of 1491 patients included in the German CML Study IV, observed a survival advantage for patients treated initially at a teaching hospital compared to those treated in municipal hospitals and by officebased physicians, respectively [45]. The difference remained when adjusted for age, performance status and EUTOS score. On the other hand, a report from the Swedish CML Registry, based on 779 patients, was not able to find any difference in survival between patients living in university versus nonuniversity catchment areas [8]. Apart from methodological issues, it may well be that the relative importance of centralised care in CML differs between countries due to differences in their health-care resources and organisation.
Do CML patients have an increased risk to develop other cancers? Studies on the risk of developing subsequent malignancies (other than MDS or acute leukaemia) after the diagnosis of CML have yielded somewhat conflicting results. Thus, in a study based on 1026 patients with CML, diagnosed in 1977–2008 and identified in the Danish Cancer Registry, Fredriksen et al. observed a 1.6-fold increased risk of developing a secondary malignancy as compared to the expected rate in the background population [46]. In a recent study from the Swedish CML Registry, based on a cohort of 868 patients with CML CP diagnosed in 2002–2011, Gunnarsson et al. reported that CML patients had a 1.5-fold increased risk of developing a secondary cancer as compared to the background population (matched by age, sex, health-care region and calendar year at diagnosis) [47]. Other investigators, analysing different kinds of study populations, have found that patients with CML have only a slight or borderline increase of secondary cancers [48, 49]. Notably, Verma et al., analysing a large cohort of CML patients treated between 1998 and 2010 at MD Anderson Cancer Center, concluded that the number of patients developing invasive malignancies were indeed smaller than expected [50]. Differences in patient numbers, selection, follow-up time and definition of Bsecondary cancer^ might explain these contradictory findings. Clearly, the question whether CML patients, nowadays mostly living an almost normal lifespan, have an increased risk of developing other cancers needs to be further investigated.
S245 Acknowledgments The authors appreciate the work of all clinicians reporting all newly diagnosed cases of CML to the Swedish CML Registry. Conflict of interest Nothing to disclose
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