Key words

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Epidemiology of Myelodysplastic Syndromes

Epidemiologia zespołów mielodysplastycznych

Department of Hematology, Oncology, and Internal Diseases, Medical University of Warsaw, Poland

Adv Clin Exp Med 2009, 18, 5, 415–424 ISSN 1230−025X

© Copyright by Wroclaw Medical University

Abstract

The pathobiology, diagnosis, and novel therapeutic approaches of myelodysplastic syndromes (MDS) have attract− ed increasing interest during the last decade. The crude annual incidence of MDS is 3.2–12.4/100,000. An inci− dence of 24.5/100,000 was estimated among those older than 70 years. At that age, MDS is probably the most fre− quent hematological malignant disease. In contrast to earlier expectations, there was no increase in MDS incidence in 1991–2001. The main reason for the rise in incidence in previous years was the increasing frequency of bone marrow examinations in elderly patients. There are some epidemiological and clinical differences between Asian and Western myelodysplastic syndrome cases. Cigarette smoking, chemotherapy, radiotherapy, and exposure to benzene, solvents, and other toxic factors have been linked with increased risk of MDS. Familial MDS is scarce. Large multi−institutional studies are necessary to assess the incidence and risk factors for MDS (Adv Clin Exp Med 2009, 18, 5, 415–424).

Key words:myelodysplastic syndromes, epidemiology, incidence, risk factors.

Streszczenie

W ostatnich latach zwiększa się zainteresowanie patogenezą, rozpoznaniem oraz nowymi możliwościami terapeu− tycznymi zespołów mielodysplastycznych (m.d.s.). Zapadalność na zespoły mielodysplastyczne wynosi 3,2–12,4/ /100 000/rok. Po 70 r. ż. zapadalność wynosi 24,5/100 000/rok. W tej grupie wiekowej m.d.s. są jedną z najczęst− szych, o ile nie najczęstszą chorobą rozrostową układu krwiotwórczego. W latach 1991–2001 nie obserwowano zwiększenia zapadalności na m.d.s., wcześniejszy wzrost zapadalności należy wiązać z częstszymi badaniami szpiku wykonywanymi u pacjentów w wieku podeszłym. Istnieją różnice epidemiologiczne i kliniczne między chorymi na m.d.s. mieszkańcami Azji a mieszkańcami Europy i Ameryki Północnej. Wykazano związek między paleniem papierosów, chemioterapią, radioterapią, narażeniem na benzen, rozpuszczalniki i inne czynniki toksy− czne a zwiększonym ryzykiem m.d.s. Rodzinne występowanie m.d.s. należy do rzadkości. Potrzebne są zakrojone na szeroką skalę badania na temat występowania i czynników etiologicznych m.d.s. (Adv Clin Exp Med 2009, 18, 5, 415–424).

Słowa kluczowe: zespół mielodysplastyczny, epidemiologia, zapadalność, czynniki ryzyka.

Myelodysplastic syndromes (MDS) are a het− erogeneous group of clonal bone marrow disorders characterized by cytopenia, dysplastic features of one or more hematopoietic lines, and an increased risk of transformation into acute myeloid leukemia (AML). In recent years there has been growing interest in MDS epidemiology, etiology, prognos− tic factors, and, first and foremost, new therapeu− tic agents. Until 1973 there were only 143 MDS cases reported worldwide [1]. Recently, some hematological centers are able to collect similar

Incidence

In Europe and the United States the crude inci− dence of MDS was 3.2–12.6/100,000/year (Table 1). The first MDS incidence rates were published in 1992. Based on data from 26 counties in the United Kingdom, an incidence of 3.6/100,000 was esti− mated among patients younger than 80 [7]. The results of one of the most important registries, the Düsseldorf registry (covering the city district of Düsseldorf), were published in the same year. The incidence during 1975–1990 (584 cases) was 3.2/100,000 [8]. In 2004 the results of the 1991–2001 study period were published (1302 cases) in which the incidence was 4.9/100,000 [3]. The highest incidence was found in the Bournemouth registry (12.6/100,000/year) [9]. A very large number of patients was collected in the last years in American registries. Since 2001, patients of 17 US regions have been registered in the SEER (Surveillance, Epidemiology, and End Results) Program. During 2001–2003, 10,300 patients were registered and the incidence rate was 3.4/100,000/year [10]. Similar results (3.2/ /100,000/year) were obtained by both the SEER and the North American Association of Cancer Registries (NAACCR) based on 24,798 MDS patients [11]. Shimizu et al. reported a lower inci− dence rate in Asian; in 1991 MDS incidence in Japan was 1/100,000/year [15]. The SEER registry confirmed a higher incidence rate in whites (3.5/100,000/year) than in Asians (2.6/100,000/ /year) in the US population [10]. A crude incidence rate of 9.7/100,000/year was calculated among Nagasaki atomic−bomb survivors. The increased MDS rate should be connected with atomic bomb radiation and not with Asian race [16].

Reizenstein and Dabrowski conducted an international opinion poll in 1991 on the epi−

demiology of MDS among 41 hematologists, and 91% of them stated that during the previous 10–20 years the incidence of MDS had increased by at least 100% [17]. Increased exposure to leukemogenic agents at the workplace or during medical treatment were considered the main causative factors of the rise in the incidence of MDS. Improvements in diagnostics and demo− graphic changes had not influenced the increase in MDS, in their opinion. In the Düsseldorf reg− istry conducted between 1975 and 1990, the crude incidence of MDS showed a marked increase, from 1.3 to 4.1/100,000/year [8]. The age composition of the total population remained constant during that period. There was no upward trend for AML observed over the study period and the incidence of AML was almost constant at about 2.2/100,000/year. The annual number of bone marrow examinations had grown continuously; however, the increase in MDS surpassed the increase in study material. The percentage of patients over 60 years old among the newly registered cases on the bone marrow register of the University of Düsseldorf increased from 41.9% in 1975 to 54.1% in 1990. Over the same period, the percentage of over 70− −year−old patients climbed from 16.9% to 29.2%. These data suggest that the rising incidence of MDS can be due to the higher proportion of elderly patients who underwent bone marrow biopsies in 1990. There was no significant increase in frequency during the study period regarding occupational exposure to leuke− mogenic agents and the incidence of therapy− −related MDS. There was no further rise in MDS incidence in the Düsseldorf registry in 1991–2001 [3]. The incidence of MDS increased slightly in the American SEER and NAACCR in 2001–2004 (from 3.1 to 3.8/100,000/year).

Table 1.Incidence of MDS – review of literature

Tabela 1. Zapadalność na zespoły mielodysplastyczne – przegląd piśmiennictwa

Country – region Period No. of patients Incidence – Author – reference (Kraj – region) (Okres) (Liczba pacjentów) 1/100,000/year (Autor – piśmiennictwo)

(Zapadalność – 1/100 000/rok)

USA (SEER) 2001–2003 10,300 3.4 Ma 2007 [10]

USA (SEER+NAACCR) 2001–2003 24,798 3.2 Rollison 2008 [11]

Germany (Dusseldorf) 1991–2001 1302 4.9 Germing 2004 [3]

Germany (Dusseldorf) 1975–1991 584 3.2 Aul 1992 [8]

North Spain 1998 96 8.1 Giralt 1999 [12]

South−West. France 1993–1996 90 7.7 Bauduer 1997 [13]

Sweden (Jonkoping) 1978–1992 120 3.5 Radlund 1995 [14]

England (Bournemouth) 1981–1990 12.6 Williamson 1994 [9]

Japan 1991 1 Shimizu 1995 [15]|

Carli et al. confirmed that MDS appears to be more frequent in urban than in rural areas. This was especially true for men (3.1 vs. 1.5/100,000/ /year) [19]. The median MDS patient age in Europe and the United States is 68–76 years [3, 10, 20]. In a large unique database assessing the impact of karyotype on the natural course of MDS in Austria and Germany, the median age was

65 [21]. The lower age at this group could result cytogenetic examinations being more frequently done in younger patients due to costs. MDS patients under 50 years of age made up 6% of all MDS patients. Most of the patients were older than 60 (83–87%). The percentage of patients over 80 years old was 30–36% [3, 8, 11]. The crude annual incidence of MDS in patients younger than Tabela 2. Zapadalność na MDS w zależności od wieku i płci

Age Incidence – 100,000/year (Wiek) (Zapadalność – 1/100 000/rok)

Düsseldorf (1991–2001) USA – SEER (2001–2003)

women men women men

50–60 2.2 3.4 2.6 2.9

60–70 6.1 11.4 8.1 12.2

70–80 17.8 38.8 18 35.1

80–90 23.6 53.5 28 54

All ages 4.3 5.5

Tabela 3.Distributions of MDS subtypes according to FAB and WHO

Tabela 3. Podtypy MDS wg klasyfikacji FAB i WHO w poszczególnych rejestrach

MDS subtype Percentage of a given MDS subtype (Podtyp MDS) (% poszczególnych podtypów MDS)

FAB Dusseldorf Spain China Korea

(n = 1600) (n = 311) (n = 508) (n = 205)

RA 26 38 43.9 36.5

RARS 20 23.5 2.8 4.4

RAEB 22 20.5 27 31.2

RAEBt 17 6.4 21.1 18.5

CMML 15 11.3 5.2 6.2

WHO

RA 8.5 18.4

RCMD 24 20.3

RARS 11 21.5

RCMD−RS 15 6.6

RAEB 1 21 10.9

RAEB 2 18.5 14.1

5q− 2.2 0.8

FAB – French−American−British classification. RA – refractory anaemia.

RARS – refractory anemia with ringed sideroblasts. RCMD – refractory cytopenia with multilineage dysplasia.

RCMD−RS – refractory cytopenia with multilineage dysplasia with ringed sideroblasts. RAEB – refractory anaemia with excess of blasts.

RAEBt – refractory anaemia with aexcess of blasts in transformation. CMML – chronic mielomonocytic leukemia.

FAB – francusko−amerykańsko−brytyjska klasyfikacja. RA – niedokrwistość oporna na leczenie.

RARS – niedokrwistość oporna na leczenie z pierścieniowatymi syderoblastami. RCMD – cytopenia oporna na leczenie z wieloliniową dysplazją.

RCMD−RS – cytopenia oporna na leczenie z wieloliniową dysplazją z obecnością pierścieniowatych syderoblastów. RAEB – niedokrwistość oporna na leczenie z nadmiarem blastów.

40 and in 5th_{, 6}th_{, 7}th_{, 8}th_{. and 9}th _{decades of life}

amounted to 0.36, 1.29, 2.83, 8.68, 24.5, and 31.3/100,000, respectively [3]. Compared with Western countries, the median MDS patient age in Asian countries was about 10–15 years lower. The median age in China was 49, in Thailand 56, in Korea 57, and in Japan 60 [22–25]. A similarly low median MDS age of 57 was found in African patients [26]. There was a preponderance of males among MDS patients in most available studies. The male/female ratio is 1.44. One can observe the highest sex differences in patients older than 70 (Table 2) [3, 10]. Only in the Düsseldorf registry before 1990 and in the Bauduer et al. study were the sex proportions comparable.

MDS Subtypes

MDS are divided in two groups, de novo and therapy−related (t−MDS), based on the absence or presence of previous cytotoxic therapy. t−MDS accounts for 3–6% of all MDS cases [28]. The per− centages of MDS reported in several registries are presented in Table 3. Most registries used the FAB classification because the WHO classification was published in 1999. The American SEER and NAACCR were not analyzed because 50% of the patients had no subtype specified [11]. Higher fre− quencies of RA and lower RARS and CMML were found in Asian countries than in Western countries [22, 23, 26, 29]. Matsuda et al. compared FAB−RA features in Japanese and German patients. Table 4.MDS risk factors in selected case−control studies

Tabela 4. Czynniki ryzyka MDS wybranych kontrolowanych porównawczych serii kohortowych

Toxic agent Number of exposed Relative risk p−value Reference

(Czynnik toksyczny) cases/number of (Iloraz szans) (Piśmiennictwo)

exposed controls – OR OR (Liczba osób chorych i narażonych/liczba osób narażonych z grupy kontrolnej)

Hair dye – women 29/21 2.5 38

(Farby do włosów)

Org. solvents 8/2 3.5 38

(Rozpuszczalniki org.)

Solvents 43/22 2.6 0.03 35

(Rozpuszczalniki)

Oils and greases 44/15 4.2 0.001 35

(Oleje i smary)

Pesticides 73/31 2.12 0.006 48

(Pestycydy)

Solvents 25/4 7.11 0.00005 48

(Rozpuszczalniki)

Org. solvents 33/9 1.66 < 0.05 39

(Rozpuszczalniki org.)

Hair dye 1.99 < 0.05 39

(Farby do włosów)

Hydrogen peroxide 20/9 2.38 49

(Woda utleniona)

Welding fumes 10/3 3.33 49

(Produkty uboczne spawania)

Explosives 13/6 2.46 50

(Materiały wybuchowe)

Coal tar 24/11 3.06 0.011 50

(Pył węglowy)

Exhaust gases 23/12 2.19 > 0.05 50

(Gazy spalinowe)

Pesticides, herbicides, 24/5 6.33 2

insecticides

(Pestycydy, herbicydy, insektycydy)

Solvents 41/23 2.74 2

57 vs. 71), had lower hemoglobin concentrations, lower platelet counts, and significantly lower fre− quency of cytogenetic abnormalities (29% vs. 53%) compared with the German patients [30]. Japanese FAB−RA patients had significantly less 5q deletion and complex karyotype than did German patients. After reclassification of the FAB−RA patients, the frequency of WHO−RA in the Japanese patients was significantly higher (73%) than in the German (24%, p < 0.001). The male−to−female ratio is higher especially in the RAEB and CMML subtypes. The sex ratio is bal− anced in the RARS subgroup. On the other hand, 5q−syndrome is found two times more frequently in women than in men [31, 32].

Myelodysplastic

Syndrome Etiology

There are a few studies involving the etiologi− cal factors of MDS, such as occurrence of MDS after chemotherapy, radiation therapy, and ben− zene exposure. At present, no studies have evalu− ated the role of dietary factors in MDS.

Smoking

In most studies, an association between tobac− co smoking and MDS is confirmed. Cigarette smoking represents a major source of non−occupa− tional benzene exposure, with smokers exposed to a 10−fold increase in benzene inhalation compared with nonsmokers [33]. Cigarettes also contain other human carcinogens. In several studies an excess of smokers or ex−smokers was found in MDS patients compared with control groups. The differences were statistically significant [2, 34– 36]. Smoking status and intensity were usually associ− ated with MDS risk. Strom et al. showed that increased MDS risk becomes statistically insignif− icant in those who had quit smoking longer than 15 years prior to diagnosis [2]. Earlier Bjork et al. suggested that only a 5−year period is required for MDS risk reduction [34]. MDS patients who had chromosomal abnormalities were more likely to be ever smokers than those with normal karyotypes (73 vs. 59%, OR = 1.92, 95%CI: 1.22–3.03) [2]. A positive association between smoking and MDS with chromosome 7 aberration was also reported [34]. Smoking and agricultural chemical exposure had a joint effect on increased MDS risk [2]. Fernandez−Ferrero et al. analyzed dyshemopoietic bone marrow features in healthy subjects. Smokers (statistically insignificant) and people aged over 50 (statistically significant) had higher

sumption had no association with dyshemopoiesis in that study.

Alcohol

Several studies analyzing the association of alcohol consumption with MDS risk gave conflict− ing results. Dalamaga et al. reported a rise in MDS risk (not significant) with alcohol drinking (one or more glasses per day vs. others) [36]. Alcohol intake and tobacco smoking jointly increased the risk of MDS significantly, whereas each of these factors alone had limited effect [36]. Ido et al. found a positive association (statistically signifi− cant) between alcohol drinking (at least 100 ml of ethanol per week) and increase MDS risk [38]. However, Nagata et al. and Strom et al. did not find elevated risk of MDS for drinkers [2, 39]. Strom et al. showed even that moderate consump− tion of wine (one glass/day or less) was associated with a significantly decreased risk of MDS [2]. These results support suggestions of an anticancer action of the antioxidant resveratrol found in the skin of red grapes [40].

Occupational

and Environmental

Risk Factors

zene metabolite benzoquinone, is associated with leukemia and chromosome 5 and 7 abnormalities [45]. Lv et al. distinguished three kinds of hema− tological abnormalities in people exposed to ben− zene: myelodysplastic syndrome, bone marrow dysplasia persisting after previous chronic expo− sure to benzene, and transient benzene poisoning. In 23 benzene−induced dysplasia workers, the fol− lowing features were distinguished: marked dyserythropoiesis, eosinophilic dysplasia, abnor− mal cytoplasmic granulation of neutrophilic pre− cursors, hemophagocytosis, and clonal T−cell ex− pansion. In this group of patients, TNF−α 238A polymorphism was found [46, 47].

Other MDS risk factors are not so well estab− lished. There are a few case−control studies assess− ing the relationship between occupational and environmental factors and MDS. In most of them, solvents were positively associated with MDS [35, 38, 39, 48] (Table 4). In a few studies, pesticides were linked with MDS [2, 48, 50]. In other stud− ies, hair dye, coal tar, ammonia fumes, exhaust gases, hydrogen peroxide, oils/greases, explo− sives, and welding gases were reported as MDS risk factors [35, 38, 39, 49, 51]. Still more difficult is to find association between MDS and occupa− tion, because many carcinogenic substances are not identified precisely and because several con− comitant or successive factors can play a role in leukemogenesis. Professions at risk of MDS were: health professionals, coal miners, textile operators, commercial sales representatives, machine opera− tors, agricultural workers, hairdressers, and cos− metologists [35, 39, 50].

Radiation Exposure

Besides Treatment

In most reports, no association between diag− nostic X−rays and MDS was found [2, 35, 49]. West et al. reported a significant association of MDS with exposure to dental X−rays and a possi− ble association with diagnostic X−rays of bones [49]. The same authors reported a weak associa− tion with MDS for those living near nuclear power station (< 8 km), but it did not approach statistical significance. Some studies showed higher MDS risk in occupational ionizing radiation exposure, but others did not confirm this [2, 49]. Non−ioniz− ing radiation, including high−voltage electromag− netic fields, radio transmission, and microwaves, showed some association with MDS (not statisti− cally significant) [49]. The leukemogenic effect of the atomic bomb was well established [52]. Radiation−induced MDS/AML associated with mutations in the AMLI gene in atomic−bomb sur− vivors was reported by Harada et al. [54]. After the

FAB classification was introduced, 12 of 190 cases of leukemia in atomic−bomb survivors were reclas− sified as MDS [53]. Among 647 MDS cases newly diagnosed in Nagasaki from 1980 to 2004, 204 (32%) were identified as atomic−bomb survivors. An inverse relationship was observed between the incidence of MDS and the distance from the hypocenter. The relationship was more noticeable in survivors exposed at 0–9 years of age [16].

Therapy−Related

Myelodysplastic Syndrome

Therapy−related MDS (t−MDS) accounts for about 3–6% all MDS cases [3, 55]. Patients with t−MDS are usually younger than de novo MDS patients, have more severe cytopenia, reduced cel− lularity, or marrow fibrosis, and unfavorable clini− cal course. The most potent therapeutic inducers of MDS/AML are alkylating agents (85% of the patients who developed t−MDS/AML had received alkylator 5–7 years earlier), topoisomerase II inhibitors (with a latency period of 2 years), and radiotherapy [56]. Some investigators found sig− nificantly increased MDS/AML in patients who had had splenectomy; however, some reports also state that splenectomy does not pose a significant risk for the development of MDS/AML [57, 58]. t−MDS is seen in patients who have received chemotherapy for Hodgkin’s and non−Hodgkin’s lymphoma, multiple myeloma, or breast, testicu− lar, or ovarian cancer and those who have been treated with radiotherapy for lymphomas, Ewing’s sarcoma, and breast or uterine cancer. The incidence of MDS in patients who underwent autologous transplantation due to Hodgkin’s or non−Hodgkin’s lymphoma is 4–7% [59, 60]. Both pretransplant therapy and myeloablative prepara− tive regimen are causes of t−MDS/AML. On cyto− genetic analysis, 80–90% of t−MDS cases and 40–50% of primary MDS cases had cytogenetic abnormalities. Among patients receiving alkylat− ing agents, chromosome 7 abnormalities were observed in 30%, chromosome 5 abnormalities in 18%, and both chromosome 5 and 7 abnormalities in 22% of t−MDS cases [44]. Deletions or loss of 7q or monosomy 7 result in mutations of the RAS gene and methylation of the p15 gene promoter. Previous treatment with topoisomerase I inhibitors has been linked with balanced translocations involving 11q23(61). For radiation, abnormalities were mostly in chromosome 8 [43].

Other Risk Factors

nificantly higher and the number who had large families (three or more children) significantly lower than controls [49]. A question arises: is fam− ily size protective or is there a genetic association linking infertility and MDS or is MDS so long in its incubation that MDS affects fertility?

Currently there is no evidence for a viral etiol− ogy of MDS. In only one paper was increased inci− dence of hepatitis B virus infection found in an MDS group of patients compared with the normal population [22].

Autoimmune disorders such as polymyalgia rheumatic, Raynaud’s syndrome, inflammatory bowel disease, relapsing polychondritis, vasculitis, immunohemolytic anemia, and immune thrombo− cytopenia [36, 72]. A positive direct Coombs’ test, presence of autoantibodies, and effectiveness of immunosupressive treatment in some cases sug− gest an autoimmune character of MDS. The rela− tionship of MDS to abnormalities of the immune system also suggest decreased natural killer (NK) cell activity and decreased CD4+_/CD8+_{T−cell ratio}

and T−cell interleukin−2 (IL−2) receptors [73]. MDS cases were more likely to report having a parent, sibling, or child diagnosed with a hematopoietic cancer than controls [2, 49]. A higher incidence of MDS (41 cases) was observed in cases with a family history of hematopoietic cancer (lymphoma, leukemia, mul− tiple myeloma) among first−degree relatives com− pared with a control group (24 cases). It was sta− tistically significant [2].

Myelodysplastic Syndrome

Secondary to Inherited

and Acquired Bone Marrow

Failure Disorders

Myelodysplastic syndrome following inherit− ed bone marrow failure disorders are very rare among all MDS cases; they usually develop before

est probability of developing secondary MDS/AML, with a cumulative incidence of myeloid neoplasia at the age of 40 of 33% [62]. MDS/AML is reported in Shwachman−Diamond syndrome in 5–33% of cases, in Diamond Blackfan anemia in 1.5–23%, and in dyskeratosis congenita in 8% [63–65]. The Severe Congenital Neutropenia (SCN) International Registry report− ed an incidence of MDS/AML of 36% after 12 years on G−CSF therapy. The true risk of patients with SCN developing MDS/AML was not clearly defined because most patients with SCN died at a young age from infection in the pre− cytokine era. About 80% of SCN patients with MDS/AML have G−CSF receptor mutations. All MDS secondary to bone marrow failure disorders are characterized by chromosome 5 and/or 7 abnormalities [62, 65, 66]. Increased risk of MDS (especially juvenile myelomonocytic leukemia, JMML) is observed in neurofibromatosis type 1 patients. They have an NF1 gene mutation which modulates Ras protein [67]. MDS associated with Down’s syndrome has been reported to account for 20–25% of childhood MDS cases in the past; nowadays, the dysplastic prodrome of acute myeloid leukemia in Down’s syndrome is classi− fied within myeloid leukemia in Down’s syndrome and excluded from population−based studies of MDS [68]. Severe aplastic anemia (SAA) patients remain at risk for MDS/AML; the cumulative inci− dence of myeloid neoplasia is 10–16%. In contrast, MDS/AML after hematopoietic stem cell trans− plantation due to SAA is not observed [65].

Familial MDS

Data on familial MDS are rare, usually based on case reports. Most of these patients are under 40 years old. Cytogenetic analysis showed chro− mosome 5 and 7 abnormalities as the most com− mon. In the Polish literature, two familial cases were described; the patients were at 29–42 years old [70].

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Address for correspondence:

Krzysztof Mądry

Department of Hematology, Oncology, and Internal Diseases Medical University of Warsaw

Banacha 1a 02−097 Warszawa Poland

Tel.: 693 351 797

E−mail: [email protected]

Conflict of interest: None declared