age-related incidence and other epidemiological aspects of myelodysplastic syndromes

British journal of Huemutology. 1992 , 82, 358-367

Age-related incidence and other epidemiological aspects of myelodysplastic syndromes

C. Aur., N. GATTERMANX A N D W. SCHNEIDER Department of Internal Medicine, Haematology and Oncology Division, Heinrich Heine University, Diisseldorf

Received 10 December 199 1: accepted for publication 26 May 1992

Summary. Although most haematologists perceive a rising prevalence and incidence of myelodysplastic syndromes (MDS), reliable epidemiological data on these disorders are largely lacking. The bone marrow register of the University of Diisseldorf allowed us to assess among other epidemiological features the incidence of MDS. which was compared to that of acute myeloid leukaemia (AML). Among a total of 18 416 different patients registered between 1975 and 1990, 584 cases of MDS ( 3 . 2 % ) and 506 cases of AML (2.8%) were identified. Over the study period. the percentage of newly diagnosed MDS rose from 1.3% to 4.50/,, while there was no upward trend for AML. Among all patients undergoing bone marrow biopsy, the proportion of those over 60 years of age increasedfrom41,9%in 1975 to 54.1Xin 1990. Wefounda strong correlation between the proportion of elderly patients and the relative frequency of MDS diagnoses. Thirty-one patients ( 5 . 3 % ) were classified as a secondary MDS because of previous treatment with cytotoxic chemotherapy and/or irradiation for a variety of malignancies. Twelve patients

were identified in whom occupational exposure to organic solvents could not be ruled out.

For calculating age-specific incidence rates, the analysis was confined to the town district of Dusseldorf (575 000 inhabitants). because exact demographical data were available for this population. In the last quinquennium of the study period ( 1986-90), myelodysplastic syndromes were more frequent than AMI, in the age group 50-70 years (4 .9 v 1~8/100000/year) . In patients over 70, the incidence of MDS was more than 3 times that of AML (22.8 v 6 .7 / 100 000). In this group, men had a higher incidence of MDS (33.9/100000) than women (18/100000) . Crude annual incidence (all age groups) was also higher for MDS (4.1/ 1 0 0 0 0 0 ) than for AML (2.1/100000) in recent years.

We conclude that MDS are relatively common haematological neoplasias. The rising incidence in recent years is probably not due to changes in aetiological factors, but may reflect increased awareness on the part of physicians and extended use of diagnostic procedures in elderly patients.

Despite an increasing number of investigations into the myelodysplastic syndromes. there is still a lack of reliable epidemiological data. In particular. only rough estimates are usually made of the incidence of these disorders. Early reports suggested that MDS were rare. For example Koath ~t nl (1964) failed to identify any preleukaemic phase in 580 leukaemia patients at Manchester Royal Infirmary in the early sixties. Meanwhile. the picture had changed. The French Registry of Acute Leukaemia and Myelodysplastic Syndromes, which covers 3 7 university centres. identified 579 new MDS patients in 198 3 in France (Groupe Franqais de Morphologie Hematologique, 1987). In the United States. Linman & Bagby ( 1 978) estitnated that about 1500 cases of MDS occur annually. Although these and other studies

Correspondence: Dr C. A d . Department of Internal Medlcine. Haematology and Oncology Division. Heinrich Heine University. Moorenstrasse 5 , 4000 Diisseldorf 1. Germany.

(Verwilghen & Boogaerts, 1987: Keizenstein & Dabrowski. 1991 ) indicate that MDS is more common than previously assumed. they have not yielded exact incidence rates.

Large-scale epidemiological studies have been impeded by incongruent or even lacking definitions and classifications of MDS (Galton. 1986). As part of these difficulties, official morbidity and mortality statistics are inadequate tools for assessing the magnitude of the MDS problem. For instance, MUS is not listed in the ninth revision of the widely used International Classification of Disease (TCD) (World Health Organization. 1977). Instead, cases have to be assigned to various other diagnoses which are not always well defined. However. even if MDS were included in a revised version of the ICD code, this would not necessarily lead to a more reliable estimate of their frequency. In view of the well- known difficulties in making the correct diagnosis. particu- larly during the early phases of disease, it cannot be expected that MDS patients are reliably identifed on a large scale. At

3 58

Epidemiology of MDS 3 59

present, accuracy of diagnosis and completeness of case registration seem to be confined to specialized registers such as regional cancer surveys or hospital-based statistics. Pro- vided they can draw on a reference population that is demographically well defined, these registers can yield valuable epidemiological data, including age-specific disease incidences. In this paper we present the epidemiology of MDS as reflected by the bone marrow register of the University of Dusseldorf.

PATIENTS AND METHODS

Catchment area. The Dusseldorf bone marrow register draws on a population of approximately 1 200 000. In order to obtain meaningful data on disease incidence, the catchment area must be recognized as having two different dimensions. On the one hand, there is the town district of Dusseldorf, a clearly defined area for which exact demographical data are available from the Statistical Office of the Land North Rhine-Westphalia. Some 575 000 inhabitants live in this region. As far as MDS incidence is concerned, we can state with confidence that hardly any patient from this area will be given a diagnosis of MDS without his bone marrow smear being seen in our laboratory. This is ensured by very close cooperation with all the hospitals in town. The few private physicians who perform bone marrow biopsies in their practice also avail themselves of our services. The town district of Diisseldorf constituted the reference population for which age-specific incidence rates of MDS and AML were calculated.

The total catchment area, on the other hand, is much bigger than the town district. Among 43 hospitals in this area, the university medical centre has the only specialized haematology department and receives bone smears from virtually all cases of suspected haematological malignancy for cytological evaluation. Unfortunately, we are not able to define this wider area of patient recruitment in terms of administrative regions. This precludes the employment of demographical data and hence the calculation of incidence rates in this larger population.

Patient recruitment and diagnostic criteria. The study covers a 16-year period from 1975 to 1990. Since 1983 our laboratory has used the French-American-British (FAB) classification of myelodysplastic syndromes (Bennett et aI, 1982). Retrieval of MDS cases before 1983 included the diagnoses of panmyelopathy with hypercellular marrow, sideroblastic anaemia, chronic myelomonocytic leukaemia (CMML) and smouldering leukaemia. MDS cases are entirely comparable over the study period of 16 years. This was achieved by re- evaluation of all MDS bone marrow specimens from 1975 to 1990, with uniformity of morphological criteria applied. Subclassification of MDS was made according to FAB criteria. Pure sideroblastic anaemia (PSA), which we recently characterized as a separate entity (Gattermann et aI, 1990). was included in the RARS category for the purpose of this study. Although PSA is perhaps not preleukaemia, its inclusion is in keeping with the FAB classification of MDS.

Our minimal haematological criteria for the diagnosis of MDS were: (1) in the peripheral blood: single or multiple

cytopenias or just macrocytosis without anaemia: and (2) in the bone marrow: clear morphological evidence of dysplasia in one or more cell lines (this criterion being fulfilled by one or more of the following: micromegakaryocytes, mega- karyocytes with multiple separate nuclei, percentage of myeloblasts between 5% and 30%, hypogranulation of promyelocytes and myelocytes, pseudo-Pelger cells, abnormal monocyte precursors, dyserythropoiesis. ring sideroblasts). We excluded patients with hypocellular bone marrow smears, because hypoplastic bone marrow is rare in MDS (Yoshida et al, 1988) and distinction between hypocellular MDS, hypocellular AML, and aplastic anaemia can be very difficult. We did not always have a histological specimen available to rule out aplastic anaemia. Furthermore, if hypocellular smears are due to marrow fibrosis, interpreta- tion of myelodysplasia is complicated by cytological distor- tion of cells that may be due to the fibrosis itself (Ost & Reizenstein, 1992).

The patients’ records were traced in the University clinic and other hospitals, and reviewed for several clinical and laboratory features. In particular, we looked for exclusion criteria for primary MDS, such as vitamin Bl2 and folic acid deficiency, alcoholism, hypersplenism, antibody-mediated cytopenia, paroxysmal nocturnal haemoglobinuria. solid tumours, chronic inflammatory diseases, severe metabolic disorders, and acute toxicity from myelotoxic substances or ionizing radiation. Analysis of the charts led to exclusion of 12% of patients whose cytological specimens had suggested a diagnosis of MDS. We tried to differentiate between primary and secondary MDS. Myelodysplastic disorders occurring as late complication after antineoplastic chemotherapy and/or radiation therapy were considered ‘secondary’ MDS, whereas all other cases in which such exogenous noxae could not be established were classified as ‘primary’ MDS.

Besides MDS patients, all cases of acute myeloid leukaemia diagnosed between 19 75 and 1990 were retrieved from the database and reviewed. The AML patients were chosen as a reference group for comparison, because the epidemiology of AML is much better defined than that ofMDS (Linet & Devesa, 1990).

RESULTS

MDS and AML cases in the register Among a total of 18 41 6 different patients entered into the register between 1975 and 1990, 584 cases of MDS (3 .2%) and 506 cases of AML (2.8%) were identified (Table I). Case registration over the study period differed considerably between MDS and AML (Fig 1). As regards AML, there was no consistent increase or decline in newly diagnosed cases, which varied between 16 and 50 per year. On the other hand, MDS was diagnosed with increasing frequency. This increase was most pronounced during the last 8 years of study, with annual case numbers rising from 1 7 to 79. As the annual number of bone marrow specimens examined in our cytology laboratory has grown continuously, we looked whether the increase in MDS was simply due to an expansion of diagnostic services. This was not the case. As shown in Table 11, the proportion of MDS cases rose almost constantly from 1’3%

360 C. Aul, N . Gattermatin and W . Srhneider

80

70

60

c 50 v1 * 5 40 .- - &J 30

20

10

0

50

2 40

Z 30 - E

2 20

e" 10

0

Fig 1 . Ani

'75 '76 '77 '78 '79 '80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90

AML

'75 '76 '77 '78 '79 '80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90

ial case numbers of neuly diagnosed \IDS and r\\lL in the Dusseldorf bone marrow register ( 1 975-90).

50 C n - z 40

k .- .d

30

20

10

0 '75 '76 '77 '78 '79 '80 '81 '82 '83 '84 '85 '86 '87 '811 '89 '90

Fig 2. Distribution of MDS cases among FAB types over the study period.

during the first year of the survey to 4.5% in 1990, which clearly indicates that the increase in MDS surpassed the increase in study material. A similar trend was not seen in the AMl. group.

MIX subtypes One hundred and twenty-three MDS patients had refractory anaemia (RA) ( 2 1 . lx), 142 had RA with ringed sideroblasts (KAKS) (24.3%), 1 3 3 had KA with excess of blasts (RAER)

Epidemiology of MDS 3 6 1

Table I. Numbers and FAB type distribution of MDS and AML cases in the Dusseldorf bone marrow register (1975-90).

No. of cases

Diagnosis FAB type Total Wider catchment Diisseldorf

Myelodysplastic syndromes RA RARS RAEB RAEB/T CMML

Acute myeloid leukaemia M1 M2 M3 M4 M5 M6 M7 Not specified

584 364 123 74 142 88 133 80 91 57 95 65

506 303 128 79 189 111

1 9 12 101 65

35 19 16 9

7 2 11 6

220 49 54 53 34 3 0

203 49 78

7 36 16

7 5 5

Abbreviations: FAB, French-American-British Cooperative Group: RA, refractory anaemia: RARS, RA with ring sideroblasts: RAEB, RA with excess of myeloblasts: RAEB/T, RAEB in transformation: CMML, chronic myelomonocytic leukaernia: M1, acute myeloblastic leukaemia without maturation: M2, acute myeloblastic leukaemia with maturation: M3. acute promyelocytic leukaemia: M4, acute myelomonocytic leukaemia: M5, acute monocytic leukaemia: M6. acute erythroleukaernia: M7, acute megakaryoblastic leukaemia.

Table 11. Relative frequencies of MDS and AML in the Diisseldorf bone marrow register (1 975-90).

No. of bone marrow MDS AML Year specimens (%I (%I

1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990

557 (612*) 756 (819) 657 (728) 694 (792) 730 (780)

983 (1083) 966 (1253) 920 (1351)

1326 (1650) 1642 (1883) 1735 (2007) 1611 (2009) 1698 (2041) 1703 (2109) 1651 (2258)

787 (937)

1975-90 18416 (22312)

1.3 3.6 1.5 2.3 1.8 4 .0 1.6 4.2 2.7 2.3 2.2 2 .0 2.8 2.8 2.4 3.5 1.9 4.1 2.9 2 .4 2.5 2.5 3.1 2.4 4.7 3.1 4.5 2.4 4.6 1.9 4 .5 2.7

3.2 2.8

* Repeat bone marrow aspirates included.

(22.8%), 91 had RAEB in transformation (RAEB/T) (1 5.6%) and 95 had CMML (1 6.3%). All FAB types contributed to the rise in annual case numbers (Fig 2). Of interest, most of our CMML patients were diagnosed after 1982. Table 111 shows the FAB type distribution in younger MDS patients as compared to population groups over 50, RAEB/T seems to be over-represented in younger patients, but this impression is not supported by statistical analysis.

The sex ratio (men/women) was almost balanced within morphological subgroups (RA 1.02, RARS 1 .00, RAEB 0.87, and RAEB/T 1.12). However, CMML was characterized by a high male-to-female ratio of 1.57. The series as a whole yielded a sex ratio of 1.06.

Follow-up At present, follow-up data are available for 452 MDS patients. Median follow-up is 20 months (range 0-165 months). 131 patients (29%) are still alive, whereas 321 patients (71%) have died. Causes of death were infection in 73 (22.7%), haemorrhagein 46 (14.3%) and transformation to AML in 84 patients (26.2%). 83 patients (25.9%) died of causes unrelated to MDS, and in 35 patients (10.9%) the precise cause of death could not be ascertained. In none of the cases was spontaneous recovery from a myelodysplastic

362 C. Aul, N. Gatterrnann and W. Schneider I40 1' I

Age (years)

1

Age (years)

Fig 3 . Age distribution of hlDS and AML patients.

0

VIJ X H 0 ,8' o o x v

0 R O

0 76

0 79

0 RZ

O Z 77

0 78

8 R4

XI

0 R <

14 . - . - ' ,

40 42 44 46 48 50 52 S4 56 58 I

Percentage of patients over 60 yr

Fig 4. Correlation between the proportion of patients over 6 0 among new entries to the bone marrow register and the percentage of new MDS cases among other diagnoses (relative frequency). Each dot represents the respective percentages for a particular year (1 9 75- 90). The correlation coefficient is r = 0 . 9 (P=O.OOOI 1.

syndrome observed. These results are comparable to other studies looking at the clinical course of MDS (Weber et nl. 1980; Coiffier c't ( 1 1 , 1983). More detailed follow-up data on

1 3 5 consecutive MDS patients from our register have recently been published (Aul et al, 1992) .

Age Whereas AML was encountered in all age groups, our MDS patients showed the well-known preponderance of the elderly (Fig 3 ) . The median age of MDS patients was 72 years at diagnosis and did not differ significantly between FAB groups. Only 39 patients (6.7%) were younger than 50, whereas 4 9 0 cases (83.9%) occurred after the age of 60.

Keferring to the register as a whole (not just MDS and AML cases). we noticed a change in the age distribution ofpatients undergoing bone marrow biopsy. The percentage of over 60- year-old patients among newly registered cases increased from41,90/,in 1975 to 54.1%in 1990.Overthesametime period, the percentage of over 70-year-old patients climbed from 16.9% to 29.2%. Fig 4 shows a strong correlation between the proportion of elderly patients and the relative frequency of MDS cases diagnosed. These data suggest that the rising incidence of MDS is a t least partly due to the fact that a higher proportion of elderly patients underwent bone marrow biopsies in recent years.

lncrdencr rates Considering the characteristic age distribution of MDS. it is appropriate to determine age-specific incidence rates rather than crude incidences. Only age-specific rates make compari- sons between different populations meaningful, because crude rates are greatly influenced by the age structure of each given population.

Epidemiology of MDS 363

700000 1- 600000

500000

400000

300000

200000

1OOOOO

n " '75 '76 '77 '78 '79 '80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90

Fig 5. Population figures and age structure in the town district of Dusseldorf (1975-90)

MDS

'76 '78 '80 '82 '84 '86 '88 '90

AML

'76 '78 '80 '82 '84 '86 '88 '90

1 0 80-100 yr 70-80 yr 60-70yr w 50-60yr 0-50yr I Fig 6. Age-specific incidences (per 100 000 population) of MDS and AML in the town district of Diisseldorf. For reasons of readability, only even- numbered years are shown. The columns consist of segments, each representing the disease incidence in a particular age group.

As explained in the Methods section, the calculation of incidence rates had to be restricted to a demographically well- defined population. Our reference population is represented in Fig 5, which shows that the population figures and the age structure in the town district of Dusseldorf did not undergo drastic changes over the study period. The calculation of incidence rates was based on the 38% of MDS cases in our registry belonging to this population. Given the basically

unchanged demography of the reference population, the steady increase in newly diagnosed MDS cases produced a considerable rise in age-related incidences (Fig 6). Regarding the age group which was mainly affected, namely the 70-80- year-old, incidence rates have climbed to approximately 2 5 per 100000 population per year. The respective rates of AML. also based on the town district of Dusseldorf, are shown for comparison in Fig 6.

364 C. A i d N. Gatterinariri and M'. Schneidrr Table 111. FAB type distribution of hlDS cases in different age groups.

Age groups

5 4 9 yr 50-69 yr 2 70 yr (11-39) Ir1=181) (r1=364J

Abbreviations: KA. refractory anaemia: RAKS. RA with ring sideroblasts: RAEB. K A with excess of myeloblasts: RAEB T. RAEB in transformation: ChlhlL. chronic myelomonocytic Icukaeniia.

To compensate for annual variation. we calculated the incidence of MUS and AML by %year calendar periods, using average annual case numbers (Table IV) . Besides age-related incidences, Table I\; also includes crude incidences of MDS and AMI,. For Ahll,. these remained almost constant over the study period (about 2 .2 per 100000 inhabitants per year). This is in good agreement with data from the literature showing age-adjusted AML incidences between 1 and 3 per l00000 per year (Linet & Devesa. 1990) . Concerning our age-specific incidences of AML. other workers also found an increase at older ages. with incidence rates of patients over 6 0 being somewhat higher than in our series (Young & Pollack, 1982: Barnovsky & Myers. 1986 ). The crude incidence of MDS showed a marked increase from 1 3 in the first to 4.1 per tO0OOO per year in the last 5-year period. thereby surpass- ing the incidence of AML. In the last quinquennium ( 1986- 90). myelodysplastic syndromes were about 3 times as frequent as AMLinpatientsover X ( 2 2 . 8 v6.7/100000). In

this age group, men had a higher incidence of MDS (33.9/ 100 000) than women ( 1 8/100 000). Annual crude incidences of MDS climbed constantly until 1989 (5.4/100 OOO), but showed no further increase in 1990 (4.7/100 000).

Occupational irlfluences The majority of patients (79.6%) were retired at the time of diagnosis of MDS or had never had a paid job (housewives). Even when earlier occupations were taken into account, the risk groups for the development of myeloid neoplasms, as specified by Mitelman et a1 (1978). were not encountered with a n above-random frequency in our patients. By review of medical records or direct questioning of our own patients, we found only 12 patients i- whom a n occupational exposure to organic solvents could not be ruled out (chemical workers. printers. painters, car prayers, filling station attend- ants). The remaining patients did not have occupations entailing contact with known myelotoxic substances.

S~coridary M D S Thirtp-one MDS patients ( 5 . 3 % ) in our series had formerly been treated with ionizing radiation and/or cytotoxic or immunosuppressive drugs. Details of previous cancer treatment as well as underlying diseases are summarized in Table IT. 81% of patients receiving chemotherapy had been given alkylating agents. most frequently cyclophosphamide (cumulative dose 4.8-298.5 g ) and melphalan (0.7-10.2 g). Plant alkaloids (24%). antimetabolites (24%), methylhydra- zine derivatives ( 19%) or cytotoxic antibiotics (5%) were much rarer and mainly administered in combination with alkylating agents. Three patients had not received alkylating drugs, but considerable doses of azathioprine (44-288 g) because of psoriatic and rheumatoid arthritis or kidney transplantation. Patients treated with ionizing radiation alone had usually been exposed to high-dose radiotherapy (30-60 Gy ) involving substantial volumes of haemopoietic marrow. In the radiotherapy group, three patients with thyroid cancer had received high doses of radioiodine

Table IV. Average annual crude incidences and age-specific incidences of MDS and AML by 5-year calendar periods (incidences per 100000 population of the town district of Dhsseldorf 1.

1976-80 198 1-8 5 1986-90

Total hlen \Yomen Total Men Women Total Men Women

Myelodysplastic syndromes All ages* 1.29 1 . 1 3 1.44 1 4 9 yr 0 . I 0 0 . 2 0 0 ~ 0 0

50-09 yr 1 . 1 5 0.64 1.56 2 70 yr 8.70 10.98 7.59

Acute myeloid leukaemia All ages* 2.03 2.33 1 .76

50-69 yr 2.58 3.19 2 .08 2 70 yr 6.30 8.24 5 . 3 6

- <49 yr 1.11 1.41 0.81

2.12 0.05 3.19

1 1 . 0 3

2.40 1.29 3.81 5.66

2.41 0.00 4.60

1 7.28

2.94 1.72 5.31 7.27

1.87 4.11 0 . 1 1 0 .22 2.14 4.88 8.21 22.81

1.94 2.11 0 . 8 6 1.34 2.67 1.81 4.93 6.73

3.93 0.22 4.58

33.88

2.19 1.57 2.14 7.74

4.27 0.22 5.14

18.02

2.04 1.12 7.54 6.28

* Children excluded

Epidemiology of MDS 365 Table V. Clinical characteristics and details of previous cancer treatment in 3 1 patients with therapy-related secondary MDS. Latent period denotes the time interval between completion of chemotherapy/irradiation and diagnosis of MDS.

Year of MDS type Pat. Sex/age diagnosis (FAB) Primary disease

Radiotherapy area (dose)

1 F/hO

2 MI41

3 F/55

4 MI54

5 Pi73

6 MI37

7 FJ77 8 F/71 9 F/75

10 F/75

11 Mi46

12 FJ63

1 3 MI67

14 MI69

1 5 F/73

16 F/4J

17 F/64

18 F/74 19 F/28

20 F/48

21 MI63

22 F/70

23 F/72 24 MI76

25 MI76 26 FJ36

27 F/60

28 MI63

29 F/6h

30 M/68 31 M/h9

1975

1976

1976

1977

1979 1980

1982

1984 1985 1985

1986

1986

1986

1986

1986

1987

1987 1987

1988

1988

1988

1988

1988 1988

1988 1989

1989

1989

1989

1989 1900

RAEB/T Breast cancer RARS HD

RAEB Ovarian cancer

RAF5/T Solitary plasmacytoma

CMML Breast cancer

RA NHL

RAEB Hypernephroma RAEB Rheumatoid arthritis

CMML MM RAEB NHI,

RAEB HD

CMML HD

RA MM

RARS Gunshot wound RAF5 Breast cancer

RAERiT Breast cancer

RA Cervical cancer RAEBiT Vulvar cancer

RA HD

RARS Breast cancer

RAEB/T NHI.

RAEB Thyroid cancer

RARS MM RAEB Thyroid cancer

RA Larynx cancer

RAEB Renal transplant RAEB Thyroid cancer

RA NHL

RAEB Psoriatic arthritis

RA MM RAEB MM

Relapse/ Latent persistence

Chemotherapy period of primary drugs (total dose) (months) malignancy

-

Axilla/supraclavicular area (60 Cy) Inverted field (20 Gy)

-

Right hemithorax (55 Gy) Abdomen (1 2 Gy)

Left kidney/lumbar column (60 Gy) -

Spine (30 Gy) ~

Mediastinum (45 Gy) Waldeyer (40 Gy) Mantle field (40 Gy)

Thorotrast (?)

Right hemithorax (60 Gy) Right supraclavicular area (60 Gy)

Pelvis (50 Cyj

Pelvis (50 Cy) Mantle field (40 Gy)

Right hemithorax (51 Gy) Right supraclavicular area (45 Gy)

Abdomen (30 Gy) Iodine-131 (1150 mCi) IRft shoulder (60 Gy)

~

Iodine-131 (1400 mCij Pelvis (40 Gy) Larynxineck (50 Gy) -

Iodine-131 (1255 mCi) Neck (60 Cy)

CTX ( 12 3 000 mg) 57 CTX (8400 mg) 1 7

Trenimon ( 100 mg)

CTX (298 500 mg) ~

CTX (22400 mg) VCR (6 mg) VLB (15 mg) P (2800 mg) -

AZT (55000 mg)

MEL (?) P (i) MEL (10 200 mg) P (42 600 mg) CTX (26400 mg) VCR (66 mg) PCB (33 600 mg) P(13 440 mg)

CTX (4800 mg) VCR (8 mg) PCB (5600 mg) P(2240 mg) ADR (200 mg) BI, (80 mgj VLB (44 mg) DTIC (2800 mg)

MEL (2300 mg) P (20800 mg) -

-

67

54

3 72 10

73 24

60

96 40

3 0

67 528

1 50

CTX (7200 mg) MTX (480 mg) 5-FU (7200 mg)

21

~ 128 120

CTX(13260mgjVCR(24mg) 38 PCB (14280 mg) P (5880 mg) crX(25200mg)MTX(1440mg) 50 5-FU (21 600 mg)

CTX (?) VCR (i) PCB (?) P (?) 114

42

~

~

MEL (710 mg) P (3200 mg) 12 54 ~

185 19

147

-

AZT (43 500 mg) P (12420 mg) -

MEL (1515 mg) 36

AZT (288 250 mg) MTX (2 14 mg) 249

MEL (2300 mg) P (21 600 mg) 68

MEL (2006 mgj P (11 190 mgj 78

no no

no

no no no

no

yes

yes no

no

Yes

no

no

Yes no

110

no

no no

yes yes

no

yes

no

yes no

Abbreviations: HD, Hodgkin's disease: MM. multiple myeloma: NHL. non-Hodgkin's lymphoma: CTX. cyclophosphamide: VCR, vincristine: PCB. procarbazine: P, prednisone: ADR. adriamycin: BL. bleomycin: VLB. vinblastine: DTIC. dacarbazine: MEL. melphalan: MTX. methotrexate: 5-FU. 5-fluorouracil: AZT. azathioprine.

(?) =total dose not recorded.

(42.55-51.8 GBq) in addition to external bone irradiation. Our series also included one patient in whom MDS developed 44 years after diagnostic application of thorotrast (cerebral angiography).

The time interval from initial cytotoxic treatment to the

occurrence of secondary MDS was extremely variable, rang- ing from 10 to 528 months (median 60 months). The latency phase was considerably longer (median 13 7.5 months) in the group exposed to radiation only, as compared with patients who had been treated with cytostatic agents (5 7 months) or

366

combined radiochemotherapy ( 39 months). In eight patients. recurrence or persistence of the primary neoplasm was observed together with the manifestation of secondary MDS.

C. Aul, N. Gattermann and W. Schneider

DISCUSSION Several haematologists have observed a substantial increase in MDS in recent years. For example, Oscier (1987) , who examined the frequency of MDS in the Bournemouth area with a catchment population of about 200000. was able to recruit 137 new patients over a period of only 5 years. More than a third of his cases were diagnosed during the last year of study. Recently. Reizenstein & Dabrowski ( I99 1 ) conducted an international opinion poll in which 9 1% of 41 haematologists accepted a consensus statement that the prevalence and incidence of the myelodysplastic syndrome have increased by at least 100% during the past 10-20 years.

Principally, this observation may be attributed to several factors, including demographical changes, increased exposure to leukaemogenic agents. and improvements in geriatric medical care and diagnosis. In our study, changing demographics are unlikely to explain the rising frequency of MDS. because the age composition of the reference population remained rather constant.

Considering the possibility of increased leukaemogenic exposure, we looked for known risk factors for the development of MDS. Reports in the literature have ascribed a n aetiological role to cytostatic treatment, ionizing radiation and prolonged occupational exposure to organic solvents or pesticides (Rieche. 1984: Aksoy et d, 1987: Kinsky. 1987: Philip & Pedersen-Bjergaard. 1988: Farrow et al. 1989: Crane & Keating. 1991; k v i n e & Bloomfield. 1992) . 31 patients were identified in our series in whom a diagnosis of therapy-related secondary MDS could be made. Although there was a slight increase in frequency over the study period (Table V), it is clear that this patient group cannot account for the substantial rise in the overall incidence of MDS.

We also screened our FADS population for occupational contact with myelotoxic substances. However. only 12 cases were found in which significant exposure to organic solvents could not be ruled out. A more meaningful analyis of occupational/environmental exposure and MDS ~ ~ o u l d require a case control study of patients and age. sex and area of residence matched controls. Patients and controls must be able to provide detailed information on their job history. hobbies history and exposure to particular chemical and radiation hazards. Optimally, exposure histories should be verified by an occupational hygienist. Our retrospective study cannot provide data for such a detailed analysis. Records were often incomplete with respect to occupational exposure. and in many instances supplementary data could not be gathered because patients were no longer alive. Although we failed to provide evidence of an involvement of environmental noxae. our finding that the incidence of MDS in the elderly (over 7 0 ) was considerably higher in males than females (Table IV) might point to a potential role of occupational exposure in the pathogenesis of MDS.

However, instead of invoking a change in aetiological factors. we would rather ascribe the recent development to

certain aspects of geriatric medical care. MDS is a difficult diagnosis which may be masked in geriatric patients by multiple concurrent illnesses (Aul et al, 1984). In addition, it seems that there has been a natural reluctance to perform bone marrow aspirates in elderly people. In recent years, however, physicians have become acquainted with the disease entity of MDS as well as its diagnostic criteria. This has been facilitated by the introduction of a practicable morphological classification proposed by the FAB group in 1982 (Bennett et a]. 1982). It is our impression that improved knowledge of MDS coincided with an increasing willingness on the part of physicians to perform bone marrow biopsies in elderly persons in order to arrive at a plausible explanation for abnormal haematological findings. This impression is supported by our data base showing a marked increase in the proportion of bone marrow specimens from elderly patients. This development, which cannot be explained by changes in the age structure of the reference population, was strongly correlated with the increase in the relative frequency of MDS. We would therefore suggest that the rise in MDS is at least partly due to increased physician awareness and extended use of diagnostic procedures in the elderly.

An increased level of suspicion must be coupled with diagnostic accuracy to make case ascertainment as complete as possible. In this context, it is interesting to look at the subtype distribution of our MDS patients over time (Fig 2.). Most patients with chronic myelomonocytic leukaemia were diagnosed after 1982. that is when the FAB group had provided useful diagnostic criteria for this disorder. We do not believe that CMML cases were really lacking from our study population before 1983. At least some of them must have been misdiagnosed as chronic myeloid leukaemia or reactive monocytosis. Thus, diagnostic accuracy seems to be a factor contributing to the increase in MDS.

The ascending curve of annual MDS cases in our register apparently levels off after 1987. which might be interpreted as indicating that case finding has become almost complete. This would also suggest that our incidence figures come close to reality. However. more years of observation are needed to see whether a clear plateau has been reached. Furthermore, because of the paucity of symptoms in early stages of MDS, there will always be a number of unknown cases. A reliable estimate of the true incidence of MDS appears difficult to obtain. It would require screening for abnormal blood counts in a sizeable population and performing bone marrow biopsies in all cases of unexplained cytopenia. However, as long as therapeutic options are lacking ( A d & Gattermann, 1992 I. invasive diagnostic procedures are not easily justifi- able.

Finally. one should be aware of a phenomenon which has been described as the 'greying' of the population. In developed countries, the percentage of people over age 65 is expected almost to double over the next four decades, from now 12% to 23% by the year 2030 (Frank-Stromberg, 199 1 ). These profound changes in the age composition of our population will lead to a marked increase in all age-related disorders, among them the myelodysplastic syndromes which may turn out to be the most common haematological neoplasias.

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age-related incidence and other epidemiological aspects of myelodysplastic syndromes

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