Pergamon Leukemia Research Vol. 19, No. 6, 361-365, 1995. pp.

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REVIEW

EPIDEMIOLOGIC PERSPECTIVES ON MYELODYSPLASTIC SYNDROMES AND LEUKEMIA*

Philip Cole, Warren Sateren and Elizabeth Delzell Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham,

AL 35294-0008, U.S.A.

(Received and accepted 11 November 1994)

Abstrad-The ICD classification of the myelodysplastic syndromes (MDS), and the four main features of the descriptive epidemiology of the condition are discussed. MDS is: (I) a rare disease; which may be, (2) on the increase; (3) which primarily affects the elderly; and (4) which predominantly affects men. We reviewed four causal models pertaining to the relationship between MDS and leukemia. These models may be described as: (I) non-biological correlates; (2) biological correlates; (3) early phase; and (4) interactive cause. Each model is described and the evidence in support of or against each is presented.

Key words: Myelodysplastic syndromes, epidemiologic causation models, leukemia.

Introduction

The myelodysplastic syndromes (MDS) are both un- appealing and alluring to the cancer epidemiologist. We are put off by the fact that MDS is a heterogeneous, vaguely defined group of conditions with seemingly ever-changing names. Such an entity, if it can be called that, is not a good object for epidemiologic investiga- tion. The diseases best suited for epidemiologic investigations of causes are those with clear and consistent clinical and histological features. Yet, the allure of MDS is easy to understand. MDS, or at least some of them, have a precursor relationship to one or

Abbreviations: AZSA, acquired idiopathic sideroblastic anemia; AML, acute myelogenous leukemia; ANLL, acute non-lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; FAB, French-American-British (classification sys- tem); L4RC, International Agency for Research on Cancer; ZCD8, International Classification of Diseases, 8th revision; ZCD9, International Classification of Diseases, 9th revision; MDS, myelodysplastic syndromes; RA , refractory anemia; RAEB, refractory anemia with excess blasts; Z&MB-t, refrac- tory anemia with excess blasts in transformation; RARS, refractory anemia with ringed sideroblasts.

Correspondence to: Philip Cole, MD, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294-0008, U.S.A.

*Presented at the Third International Symposium on Myelodysplastic Syndromes, October 1994, Chicago, Illinois.

more of the leukemias, diseases of considerable public health importance. In fact one of the forms of MDS is a type of leukemia, namely chronic myelomonocytic leukemia (CMML).

We wish to achieve two goals in this paper: first we review the descriptive and analytic epidemiology of MDS. This is an overview of what is known about the vital statistics and the causes of these conditions. Second, we present a set of models, in pictorial form, of the possible relationships among MDS, leukemia and their causes. We might think of this as an effort to describe the early natural history of leukemia.

Terminology and Descriptive Epidemiology

The development of the terminology and classifi- cation of MDS is presented before the four main features of the descriptive epidemiology of the disease. Problems in terminology and classification have made it difficult for epidemiologists to estimate the incidence and mortality rates of MDS. For example, as shown in Table 1, MDS has had at least 16 different names over the last 50 years [l].

The oldest names, emphasizing anemia, epitomize the early views surrounding MDS, while later terms correctly focus on describing the condition as a neoplastic or preneoplastic process.

In 1982 the current French-American-British (FAB) classification system was adopted. This system describes

361

362 P. Cole et af.

Table 1. The evolving terminology of the myelodysplastic syndromes

Year of Publication

1938 1949 1953 1956 1959 1963 1969 1973 1974 1974 1975 1976 1978 1979 1980 1982

Name

Refractory anemia Preleukemic anemia Preleukemia Refractory anemia with ringed sideroblasts Refractory nonnoblastic anemia Smoldering acute leukemia Chronic erythemic myelosis Preleukemic syndrome Subacute myelomonoeytic leukemia Chronic myelomonocytic leukemia Hypoplastic acute myelogenous leukemia Refractory anemia with excess myeloblasts Hematopoietic dysplasia Subacute myeloid leukemia Dysmyelopoietic syndrome Myelodysplastic syndromes

Adapted from [l].

five subtypes of MDS: refractory anemia @A), refractory anemia with ringed sideroblasts @AU-also called acquired idiopathic sideroblastic anemia [AISA]), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML). RA, RARS and RAEB are recognized as the most common subtypes of MDS.

For most diseases there is a wealth of information derived from such sources as registry data or national mortality figures. Many of these sources use the International Classification of Diseases (ICD), a system used for the classification and coding of diseases [2]. (ICDB, the 8th revision, was used from 1968 to 1978; ICD9, the 9th revision, is now in use.) Epidemiologists use this coding scheme in their descriptive and analytical epidemiologic research. However, problems with the ICD have hindered MDS research. Some specific limitations of the ICD classification system for MDS have included: (1) the use of the most specific ICD9 code available for MDS for other, unrelated conditions; (2) changes over time in reporting and coding practices for MDS; (3) inconsistency between ICD9 and the FAB classification in terminology for MIX and conditions classified as MDS; (4) confusion between MDS and conditions with similar names; and (5) the fact that ICDB had only one relevant category, code 209, for the entity ‘myelofibrosis’, and it was a subcategory under malignant neoplasms of lymphatic and hematopoietic tissue.

The current ICD9 does have a specific category, 289.8, for MDS. Although this is an improvement over ICDB, problems persist. The ICD9 assigns codes other than 289.8 to conditions that may be described as MDS

using FAB subtype terminology. One of the FAB subtypes, CMML, is grouped with the chronic myeloid leukemias rather than with MDS. The ICD9 code is 284.9 for RA and 285.0 for RAW. Additional misclassification of MDS may occur because the term ‘myelodysplasia’, when it appears in isolation on a death certificate, may be misinterpreted by a nosologist and assigned an incorrect ICD9 code. Conditions recorded as ‘myeloproliferative disease’ and ‘myeloproliferative syndrome’ are assigned the ICD code of 238.7 and, thus, are classified as ‘neoplasms of uncertain behavior’.

In summary, diseases other than MDS are assigned the ICD9 code 289.8 and MDS, if reported using FAB subtype terminology or other, ambiguous terminology, may be assigned to any of several ICD9 codes. Therefore, it is not possible to obtain accurate general population incidence and mortality rates for MDS.

Epidemiologic studies have benefited, however, from use of the new FAB classification system. Epidemio- logic studies can be broadly placed in either of two categories. Descriptive epidemiologic studies char- acterize disease incidence, or mortality, by demographic variables such as sex, age and race. Analytical epidemiologic studies characterize risk factors or causes of a disease. There are four main aspects of MDS descriptive epidemiology to be reviewed in this paper. MDS is: (1) a rare disease, which may; (2) be on the increase, and which primarily affects; (3) the elderly; and (4) males.

Recent studies by Cartwright in England [3] and Au1 et al. in the Dusseldorf area [4] confirm the rarity of MDS. Cartwright found an annual age-adjusted inci- dence rate of about 2.0/100,000 person-years (py),

Epidemiologic perspectives on myelodysplastic syndromes and leukemia 363

while Au1 found a crude annual incidence rate of 4.1/100,000 py.

Although MDS is rare, the incidence may be increasing. Au1 reported that the overall incidence rate (excluding children under 15 years) increased from 1.3/ 100,000 py to 4.1/100,000 py in the 10 year period from 1976-1980 to 1986-1990. Au1 suggested that this increase was due primarily to physicians gradually becoming more likely to diagnose MDS. This is because physicians are currently more knowledgeable than they previously were about MDS and MDS classification, and more diagnostic tests are being performed on the elderly. However, Reizenstein and Dabrowski conducted a survey of 41 hematologists and reported a consensus that there had been a substantial true increase in MDS incidence over the last 10-20 years [5]. The possibility that MDS is becoming a more common disease among the elderly is of concern due to the high case fatality. Bennett reported that median survival times ranged from 4 years for RARS to 3 years for RA to approximately 1 year for RAEB or CMML, and to less than 1 year for RAEB-t [6].

In any event more MDS patients are being seen by physicians today. Among the possible explanations for this are: (1) MDS is truly increasing in incidence due to an increase in exposure to the causes of the disease, resulting in a rise in age-specific incidence rates; (2) MDS is being recognized and diagnosed more often by physicians, even though the age-specific incidence rates are stable; (3) MDS incidence only appears to be on the increase due to an aging population (as the population ages, more cases of MDS will be found, even though age-specific incidence rates remain constant); (4) some combination of the above. We have no means to evaluate the first explanation because the etiology of MDS is unknown. Au1 et al. conclude that the second explanation is supported by their data. There is evidence that the third explanation is correct since MDS is a disease of the elderly.

Aul’s report of MDS subjects from the Dusseldorf area bone marrow registry indicates that 80% of cases occurred in people over 60 years. At ages 50-69 years the incidence rate was 4.9/100,000 py, while at age 70 years and over the rate was 22.8/100,000 py. Cartwright found similar results in England. Although the incidence rate was only 1.0/100,000 py for persons aged 55-64 years, it increased to 7.4/100,000 py for persons aged 75-84 years. It is of interest that MDS incidence apparently does not drop off in the oldest age groups, as does that of many chronic diseases, but continues to rise. This continued rise is also seen for leukemia and is evidence of the close association of these two diseases. If the age-specific incidence patterns of the two diseases had been markedly different this would have been some

evidence that the two conditions were not closely related.

Both Cartwright and Au1 found that MDS patients were predominantly male. Cartwright reported that men were affected about 25% more often than women. Au1 found that among persons aged 70 years or over, incidence rates for men were higher than those for women by 40%, 110% and 90% for the time periods of 19761980, 1981-1985 and 1986-1990.

Analytic Epidemiology

Problems in the classification and terminology of MDS affect not only descriptive epidemiologic studies, but also research into its causation; little is known of the etiology of MDS. Reizenstein and Dabrowski’s survey presented a consensus review of possible causal factors. The list included organic solvents (e.g. benzene), ionizing radiation, drugs (including cytostatics), pesti- cides, herbicides and air pollution.

The causal relationship between benzene and ANLL has been established but that between benzene and MDS has not. The evidence linking benzene to MDS does not meet the criteria of causality that are usually used by an epidemiologist. In part this may be due again to the paucity of data: in most epidemiologic studies a comparison is made of the number of cases or deaths from MDS in an exposed group with the number of deaths expected. But the number of deaths expected to be due to MDS cannot be estimated accurately. For example, Honda et al. [7] reported a large follow-up study of workers at a petroleum refinery. Six deaths were found to be due to MDS among a total of 3627 deaths. The expected number of deaths due to MDS in the group studied could have ranged from about 0.5 to 2.0. Thus, the magnitude of the increase would range from about 3-fold to 12-fold, and it should be added that such data as these do not necessarily incriminate benzene, for there are many exposures within a refinery. However, recent studies by Travis et al. [S] and Mele et al. [9] suggest that benzene exposure may be associated with MDS. Mele also found an association of MDS with smoking, and with certain occupations, including shoe- makers, painters, child care workers/teachers, agricul- tural workers, hairdressers and electrical workers.

Ionizing radiation is probably a cause of MDS, as it is of some forms of leukemia. Recent evidence includes the finding of seven cases of MDS among 1000 people who received diagnostic tests with thorotrast, which emits alpha particles [lo]. This supports a number of earlier studies that found excesses of MDS (or what we now call MDS) among people exposed to radiation, including survivors of the bombings of Hiroshima and Nagasaki.

A number of studies also suggest alkylating agents

364 P. Cole et al.

and other chemotherapeutic agents as increasing, or even being entirely responsible for, secondary MDS that occurs among people treated for malignancy. The drugs of interest are: the nitrogen mustards meclorethamine, chlorambucil, cyclophosphamide, and melphalan, the epoxide dibromoducitol, the nitrosoureas BCNU and methyl-CCNU; the alkyl alkone sulphonates busulphan and dihydroxybusulphan, and the nonclassic alkylating agent procarbazine [ll]. In spite of this, the magnitude of the increased risk of secondary MDS associated with chemotherapeutic agents has not been estimated and this will prove difficult.

As the above review of hypothesized etiologic factors shows, further epidemiologic studies are needed to identify the causes of MDS. A report is published periodically by the International Agency for Research on Cancer (IARC) listing ongoing epidemiologic research projects. The most recent report lists seven relating to MDS [ 121. This research should further our knowledge of the causes of MDS.

Models of Natural History

Previous writers have developed pictorial models in an effort to describe early events in the development of MDS and leukemia. These models, especially those of Galton and Brito-Babapulle [13] and List and Jacobs [14] provide a guide to our thinking with respect to cellular and sub-cellular events that may connect these two conditions. In addition, Galton has pointed out correctly that there are semantic as well as actual biological issues to be considered in thinking about the relationships between a premalignant lesion and its malignant sequel.

In an effort parallel to that of Galton and List we now describe models of possible relationships between MDS and leukemia. However, our models are not intended to describe early cellular events. Rather, they are intended to suggest the way in which these two entities, MDS and

A NON-BIOLOGICAL CORRELATE B BIOLOGICAL CORRELATE

cl - MDS MDS

t

I C /

1 \ L c2 - L

C EARLY PHASE D INTERACTIVE CAUSE

MDS

C MDS ) L C L

Fig. 1. Four models showing possible relationships between MDS, leukemia, and their causes.

leukemia, and their causes, relate to one another in a conceptual manner. This presentation is modified from one that appeared earlier on the more general subject of the role of host factors in relation to cancer [15]. None of the four models offered is known to be either correct or incorrect. However, they provide a context for our thinking about the natural history of MDS and leukemia.

There are four types of relationships among causes, premalignant lesions and cancer. The first type is labeled a ‘non-biological correlate’ and is represented in Fig. l(A). This describes a premalignant lesion, hereafter MDS, and a cancer, hereafter leukemia, that have no causal relationship. They each have a separate and distinct cause. Yet, in clinical practice, the two lesions may seem to be related to each other because they both exist in the same organ (the marrow) and, to an inordinate degree, in the same people. However, the only reason they co-exist clinically is that their distinct causes tend to co-exist in the same people for socio- cultural reasons or because these causes tend to co-exist in nature. This model seems quite unlikely to be correct. The major reason is that the subsequent risk of leukemia among people with MDS is at least 20%. This is more than 20 times the risk of ANLL in the general population. This is a far greater relative risk than is likely to occur due to the concordance of sociocultural or environmental factors. It suggests instead a more direct relationship between the two diseases or their causes. This model seems uninteresting to clinical and basic science researchers. Yet, it has proven useful to epidemiologists whose focus early in the investigation of a disease is on sociocultural factors as correlates of disease.

In the second model MDS and leukemia are described as ‘biological correlates’. This is shown in Fig. l(B) which shows a common cause of the two entities. This is something of an oversimplification since we usually use the term ‘a cause’ to mean a set of factors--so, in effect, Fig. l(B) is meant to imply that MDS and leukemia have only some part of their cause in common. This is a credible model and one candidate for the common cause is benzene.

The third model describes MDS as an ‘early phase’ of leukemia and is pictured in Fig. l(C). It may be interpreted to mean that some cases of leukemia have an early or premalignant phase, which if detected, meets the criteria of one subtype or another of MDS. The model is also consistent with the well-recognized phenomenon that at least some cases of MDS progress to leukemia. This model seems plausible because it is easily reconciled with the observation that many cases of acute myelogenous leukemia (AML) may have had an MDS phase but that not all MDS cases progress to AML.

The fourth model is shown in Fig. l(D) and describes

Epidemiologic perspectives on myelodysplastic syndromes and leukemia 365

MDS as an interactive cause of leukemia. More descriptively, epidemiologists describe this as the ‘fertile soil’ model. The idea is straightforward: MDS causes cells to be altered in such a way that they become more susceptible than they otherwise would have been to the effect of a leukemogen. In this ‘fertile soil’ model, the condition MDS is itself seen as a contributing cause of leukemia. This is a plausible model but one observation against it is the seemingly relatively short time that elapses between the appearance of MDS and leukemia. This interval is too short to fit our concept of an appropriate induction period of leukemia.

As we look at the four models together we should keep in mind that they are not mutually exclusive. We think that they are collectively exhaustive but other possibilities may suggest themselves later.

We suggest that both the models in Fig. l(B) (‘biological correlate’) and l(C) (‘early phase’) are the most likely to be correct. Both are consistent with the idea that benzene (and perhaps other agents) causes both conditions, that the interval between the appearance of MDS and AML is relatively short and that a substantial proportion of MDS cases do not progress to AML.

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