Etiology and Epidemiology of MDS David T. Bowen

(1)

Contents

3.1 Introduction . . . 15 3.1.1 MDS Is a Heterogeneous Disease . . 15 3.1.2 Demographic Study . . . 15 3.1.3 Latency of Onset . . . 16 3.2 Established Causative Factors for MDS:

Cytotoxic Chemotherapeutic Drugs . . 16 3.3 Probable Causative Factors for MDS . . 17 3.3.1 Ionizing Radiation . . . 17 3.3.2 Benzene . . . 17 3.4 Miscellaneous Potential Causative

Factors: Case-Control Studies . . . 18 3.5 Aging and MDS . . . 20 3.6 Is There a Genetic Predisposition

to MDS? . . . 20 3.7Conclusion . . . 21 References . . . 21

3.1 Introduction

Despite at least two decades of epidemiological re- search, the causative factors leading to the development of myelodysplastic syndrome (MDS) remain largely unknown. The study of the causes of these relatively rare diseases is proving difficult for several reasons:

1. MDS comprises a spectrum of heterogeneous disorders.

2. Few comprehensive patient registries exist to accu- rately determine the demographics of subtypes of MDS (e.g. age/sex distribution).

3. Determining the latency of onset of de novo MDS is not possible without large cross-sectional population studies.

3.1.1MDS Is a Heterogeneous Disease

The diagnostic process involves categorizing an individual's disease into one of five French-American-British (FAB) groups or one of six World Health Organization (WHO) subgroups (the latter excluding sub-types of chronic myelomonocytic leukemia (CMML), and the FAB-defined refractory anemia with excess blasts in transformation (RAEB-t)). It seems likely that morpho- logically or molecularly distinct diseases (albeit with overlapping features) will have different causes.

3.1.2Demographic Study

MDS is a rare disease, with an estimated incidence of 4 per 100,000 per year. The disease becomes more common with increasing age, such that the incidence rises to >30 per 100,000 per year for people over 70 years of age (Germing et al. 2004; Williamson et al. 1994).

Males are more commonly affected than females, although there is evidence that this is not so for refractory anemia with ring sideroblasts (RARS) (Germing et al. 2004). Recent data (Germing et al. 2004) do not support the widely held view that the incidence of MDS is increasing (Reizenstein and Dabrowski 1991). Neverthe- David T. Bowen

(2)

less, an aging population will produce an increase in the absolute number of patients diagnosed as will more in- terventional investigation of older patients (Aul et al.

1998).

MDS in children is more infrequent still, and has characteristics different from those in adults. Examples of these differences include the spectrum of FAB/WHO types (RARS and 5q± syndrome are almost never seen in childhood), and of chromosome abnormalities (a higher proportion of children have abnormalities of chromosome 7; see Chapter 7).

3.1.3Latency of Onset

For patients with de novo MDS, the latency time of the disease is unknown. From a biological angle, there will be at least two phases of disease development, namely:

1) the time from the first damage in the bone marrow to the appearance of changes in the blood counts; and then 2) the time from the first blood count abnormality to the presentation with clinically relevant disease (usually symptoms of anemia) (Fig. 3.1). Both are impossible to study systematically at present. Physiological changes in hematological parameters with aging such as a reduction in hemoglobin concentration will need to be distinguished from those attributed to early MDS (Nils- son-Ehle et al. 2000).

For cases of MDS developing after exposure to an agent known or presumed to cause MDS, the latency period varies. This may be from 1±41 years for different radiation exposures (Moloney 1987), 1±10 years for alkylator cytotoxic drugs (Mauritzson et al. 2002; Peder-

sen-Bjergaard et al. 2002a), and even more difficult to assess for benzene (up to 30 years?) (Voytek and Thor- slund 1991).

MDS may also evolve from related disorders such as aplastic anemia, following immunosuppressive therapy, with a latency of up to 10 years (Kojima et al. 2002; Ma- ciejewski et al. 2002; Soci 1996).

3.2 Established Causative Factors for MDS:

Cytotoxic Chemotherapeutic Drugs

Therapy-related MDS and AML (t-MDS/AML) are well- recognized, though rare complications following cytotoxic drug therapy for malignant and some non-malignant (mainly autoimmune) diseases. It is estimated that prior exposure to chemotherapy increases the risk of developing MDS at least 100-fold (Pedersen-Bjergaard et al. 2002b). Several classes of cytotoxic drugs are implicated, but alkylators most frequently cause an MDS phase. The increased risk following autologous stem cell transplantation may be more a function of prior exposure to relevant cytotoxic therapy than to the pathology of transplantation, and the cumulative incidence of t- MDS/AML may be no higher than for conventional chemotherapy alone (Metayer et al. 2003; Pedersen-Bjer- gaard et al. 1997). One of the major challenges in the treatment of highly curable diseases such as Hodgkin lymphoma is now to reduce the risk of late complications, and early indications are that newer therapies will prove less likely to produce t-MDS/AML. Unfortunately, effective new agents for treating lymphoid malignancies such as fludarabine and radioimmunoconjugates may also be associated with an increased leukemogenic risk (Armitage et al. 2003).

At least two subgroups of alkylator-induced t-MDS/

AML have been identified, with distinct cytogenetic, molecular and gene expression profiles (Pedersen-Bjer- gaard et al. 2002b; Qian et al. 2002). One group consists of patients with abnormalities of chromosome 7 and normal chromosome 5, in whom mutations in the RAS oncogene are common. In the second group chromosome 5 abnormalities predominate, with or without abnormalities of chromosome 7, often associated with a complex karyotype and mutation of the p53 tumor sup- pressor gene (see Chapter 6). The second group has a poorer clinical outcome. The latency of onset from start of previous therapy to the development of t-MDS/AML following exposure to alkylating agent chemotherapy 16 Chapter 3 ´ Etiology and Epidemiology of MDS

Fig. 3.1. Biological stages in the development of MDS

(3)

was 63 months (range 7±173) in a recent large series.

However, t-MDS/AML constitute <10% of all cases of adult MDS, and the study of t-MDS/AML as a model for the causes of de novo MDS is problematic. Many cases of t-MDS cannot be easily classified due to bone marrow fibrosis. RARS and CMML are relatively under-represented, and the chromosome abnormalities in t-MDS/AML, while qualitatively similar, are propor- tionately different from those of the de novo diseases (Mauritzson et al. 2002). Survival of patients with t- MDS is also poorer than for de novo MDS. Nevertheless, the cytogenetic and molecular abnormalities identified in t-MDS (Pedersen-Bjergaard et al. 2002a) (predomi- nantly deletions involving chromosomes 5, 7, 17, 12 and 3) are similar to those in poor-risk de novo MDS, and detailed characterization of the pathways involved may lead to a better understanding of potential causative mechanisms in this subgroup of de novo MDS patients.

3.3 Probable Causative Factors for MDS 3.3.1Ionizing Radiation

MDS cases are reported in cohorts of individuals exposed to radiation, for treatment of diseases such as ankylosing spondylitis (Brown and Doll 1965), or following exposure to the A-bomb in Hiroshima and Nagasaki (Matsuo et al. 1988). Some of these cases occurred up to 40 years after exposure and thus the precise association

between the development of MDS and exposure to radiation is impossible to quantify. Mauritzson et al.

(2002) also identified a longer latency period for the development of t-MDS/AML following radiotherapy exposure (median 207 months) compared with alkylating agent chemotherapy Ô radiotherapy (median 63 months). The incidence of t-MDS/AML does not appear to be increased following local radiotherapy for lymphoma, but is probably increased following total body irradiation (TBI) exposure at autologous stem cell transplant (Armitage et al. 2003). Similarly, weak associations between radiation exposure and MDS are identified in some (but not all) case-control epidemiology studies (vide infra).

3.3.2Benzene

Early observations on the link between high concentration benzene exposure in Turkish shoe workers and leukemia/bone marrow failure identified a preleukemic pancytopenic phase in 13 of 51 patients (Aksoy et al.

1972). In a later follow up of this cohort (n=44), ap- proximately half of the pancytopenic patients had probable aplastic anemia, and the remainder had normo- or hypercellular marrows (Aksoy and Erdem 1978). A recent prospective cohort study has suggested a high incidence of morphological dysplasia in subjects exposed to benzene and a high rate of subsequently developing MDS or acute myeloid leukemia (Travis et al. 1994).

The same cohort of benzene-exposed workers (74,828 subjects) showed a significantly elevated relative risk for the development of MDS (95%-confidence interval, 1.7±?) compared with a non-exposed cohort (35,805 subjects) (Yin et al. 1996). Legislation now ensures that exposure to high concentrations of benzene in the workplace or the environment must not occur. Thus, the main sources of exposure to low concentrations of benzene in daily life are tobacco smoke and petrol. Ex- posure to high concentrations of benzene clearly causes bone marrow toxicity, usually aplasia, some of which will progress to MDS or AML (Aksoy et al. 1972; Roth- man et al. 1997). There are in vitro biological data to support a role for relevant cytotoxicity of benzene on hematopoietic cells. Incubation of human hematopoietic cells with benzene metabolites in vitro produces a variety of cytogenetic abnormalities also found in MDS and AML (Smith et al. 2000). Strong epidemiolog-

Table 3.1. Potential causative agents in the etiology off MDS

Definite

Cytotoxic chemotherapeutic drugs, particularly alkylating agents

Probable Benzene Ionizing radiation Tobacco smoke Possible

Hair dye Pesticides Solvents

(4)

ical evidence definitively incriminating benzene as a cause of MDS is, however, still lacking.

3.4 Miscellaneous Potential Causative Factors:

Case-Control Studies

Attempts to study the environmental/occupational etiology of MDS have focused mainly on case-control studies. These are usually questionnaire-based studies, re- questing information about the work and recreational background of MDS patients, compared with a ªcontrolº group of individuals who do not have MDS. Many of these studies are supported by occupational hygienists with knowledge of likely exposures within each line of work.

While these efforts are commendable, and the best that can be achieved at present, there are many limita- tions to such studies. These include: 1) ªrecall biasª, relying on the patient's memory for accuracy; 2) consider- ing MDS as one disease in order to produce a sample

size with sufficient power to answer the specific ques- tions posed (something which has been done for the purposes of most of these studies); and 3) relying upon subgroup analysis to draw conclusions (all studies to date have done this).

While each individual published case-control study has identified a number of occupations and substances that may be risk factors for MDS, there is little consis- tency between these studies. Many of the ªassociationsº are likely to represent statistical chance or very weak relative risks.

Several modest size case-control studies of MDS patients and appropriate control subjects have now been reported. Most have involved a self-completed or as- sisted questionnaire exploring potential occupational, recreational and environmental factors associated with an increased odds ratio for MDS patients compared with controls. In the largest and most detailed study, 400 cases and controls (individually matched) were compared (West et al. 1995). Exposure histories including intensity assessment were obtained for 70 chemicals, 18 Chapter 3 ´ Etiology and Epidemiology of MDS

Table 3.2. Environmental agents most consistently associated with MDS in larger case-control studies (>100 cases) ex- pressed as Odds ratio (95% confidence intervals where quoted in original references)

Study Tobacco

smoking

Hair-dye use Alcohol Pesticides Solvents

West et al. 1995 1.16 (0.8±1.6) 2.38 (1.0±5.9) (hydrogen per- oxide exposure)

NA 1.0 (agro-

chemicals)

0.9 (combined paints, solvents, glues) Mele et al. 1994 P<0.05 (trend

test for increased pack years)

1.5 NA NA NA

Ido et al. 1996 1.8 (0.8±3.9) 1.77 (0.9±3.5) P<0.02 (trend test for increasing consumption)

NA 1.5 (0.9±2.6)

(organic only)

Pasqualetti et al.

1997

2.33 (1.1±5.1) NA NA NA NA

Rigolin et al. 1998 NA NA NA 2.1 (1.3±3.6) 7.1 (2.4±21)

Nagata et al. 1999 0.8 (0.4±1.6) (former)

1.99 (1.2±3.4) 1.01 (0.4±2.7) (former)

NA 1.99 (0.97±4.1)

(organic only) 0.9 (0.5±1.8)

(current)

0.8 (0.5±1.4) (current)

Bjork et al. 2000 1.8 (1.2±2.7) NA NA NA NA

Nisse et al. 2001 1.74 (1.1±2.7) 1.1 (0.4±3.1) NA 3.2 (1.1±11.2) 2.6 (1.6±5.4)

NA not available

(5)

and other hazards or radiation. An increased or possi- bly increased odds ratio was found for MDS patients exposed to radiation, halogenated organics and metals.

Elevated odds ratios at higher exposure thresholds were found for copper, arc welding fumes and hydrogen per- oxide, with borderline associations for degreasing agents, nickel, exhaust gases and radio transmissions.

Pesticides were etiologically implicated in a smaller study (Goldberg et al. 1990), while a further study implicated plant and machine operation, and exposure to exhaust fumes, stone dust, cereal dust, fertilizers as well as petrol and diesel derivatives (Nisse et al. 1995). The data for exposure to commonly studied environmental toxins are summarized in Table 3.2. Tobacco smoking may represent the greatest source of benzene exposure for the population at large, with a 10-fold increase in benzene inhalation in smokers compared with non-smokers (Brownson et al. 1993). Cigarette smoke contains several thousand chemicals and in addition to benzene, many of these are known or suspected human carcinogens

(e.g., ethylbenzene, octane and radioactive lead-210) (Pasqualetti et al. 1997).

Other factors with an elevated odds ratio for MDS that have emerged from case-control studies include alcohol excess (including a possible dose effect) (Ido et al.

1996) and childlessness (West et al. 1995), although this could not be confirmed in another smaller study (Nisse et al. 1995). Each of these studies is limited by insuffi- cient numbers of cases and controls to identify signifi- cant odds ratios with high statistical power. It is clear that an association between exposure to an agent and the development of MDS is a long way from establishing cause and effect. Alternative explanations must always be considered, such as hair-dye use commonly associated with grey hair and the possibility that it is grey hair and not hair-dye chemicals that are associated with the development of MDS.

Two studies have attempted to correlate cytogenetic abnormalities with exposure to environmental toxins (Table 3.3) (Rigolin et al. 1998; West et al. 2000). Both

Table 3.3. Cytogenetic abnormalities and their association with exposure to environmental toxins in MDS patients versus controls

Study MDS patients

(number)

Controls (number)

Exposed vs. non-exposed Exposure to specific agents vs. cytogenetic abnormalities Rigolin et al.

1998

178 (cytogenetics known=134)

178 P<0.001 (trend test through IPSS good, intermediate to poor risk cytogenetic categories; poor risk category had highest ratio of exposed:non-exposed* cases)

NA

West et al.

2000

214 (cytogenetics known)

400 Cytogenetics abnormal: OR=2 (0.8±5.9)

Chromosomes 5: inor- ganic gases/fumes, OR=8** (1.1±356) and OR=4.3*** (1.3±13.6) 186 (cytoge-

netics unknown)

Cytogenetics normal: OR=1 (0.6±1.8) Chromosome 7: inorgan- ic gases/fumes, OR=5.1**

(0.6±237) and OR=8.4***

(1.7±42)

Chromosome 8: radiation, OR=6.0** (0.7±28) and OR=1.7*** (0.6±5.5) OR odds ratio, NA not available

*** Exposure studied only to pesticides and organic solvents

*** Paired comparison: chromosome abnormalities with normal

*** Unpaired comparison: chromosome abnormalities with normal

(6)

studies suggest that a history of exposure to environmental toxins is more common in patients with an abnormal karyotype. Weak associations were also found for exposure to selected toxins and specific karyotypic abnormalities (e.g., higher incidence of exposure to in- organic gases and fumes in patients with abnormalities of chromosomes 5 and 7), although numbers were small and confidence intervals large (West et al. 2000).

3.5 Aging and MDS

The incidence of MDS increases with age. This observa- tion has been interpreted in two ways: the disease must result from a progressive accumulation of a lifetime's exposure to a toxic agent, or the aged bone marrow ªstemº cell is easier to damage than its younger counterpart.

Considerable evidence for genetic traits as determinants of stem cell function, including longevity, has emerged from the study of inbred mouse strains (Van Zant and Liang 2003). Although human progenitor numbers do not convincingly decrease with increasing age, their re- plating efficiency does decrease, suggesting a reduction in self-renewal (Marley et al. 1999). The process of ªagingº is not well defined, though much blame is heaped upon ªfree radicalsº (Kirkwood and Austad 2000), defense against which deteriorates with age. Mi- tochondrial DNA mutation would be potentially both caused by and result in increased intracellular oxidative stress. Although specific mutations in enzymes associated with electron transport have been identified in

MDS patients (Gattermann 2004) and appear to be associated with clonal expansion (Gattermann et al.

2004), the pathogenetic role and, indeed, the patholog- ical relevance of these mutations remains debatable (Shin et al. 2003). It remains unclear in what way those changes are relevant to diseases of older age such as MDS (Fig. 3.2).

3.6 Is There a Genetic Predisposition to MDS?

The vast majority of MDS patients presenting in adult- hood have no relatives with the disease, and no obvious inherited disease with a tendency for the development of MDS. In 30% of children with MDS, other abnormalities are present, and some of these are part of well-recognized syndromes including Fanconi anemia or Bloom Syndrome. Fanconi anemia may represent the best nat- ural model for the mechanistic study of MDS, with 30%

of patients developing MDS/AML by the age of 40 years (Kutler et al. 2003), and the spectrum of karyotypic abnormalities is similar to that seen with de novo MDS.

Families with several members affected by MDS are described, but are exceptionally rare (Lucas et al. 1989).

Although still very rare, familial MDS may be more likely in the family of a child with monosomy 7 (Luna-Fineman et al. 1995). An increased risk for autoimmune disease has been correlated with specific Hu- man Leukocyte Antigen (HLA) subtypes. The response of selected MDS patients to immunosuppressive therapy catalyzed the search for an HLA restriction in MDS.

Although an increased prevalence of HLA-DR2(15) has been reported in MDS (Saunthararajah et al. 2002), this finding has not been consistent (Deeg et al. 2004; Go- wans et al. 2002).

While the mechanisms underlying familial MDS are likely to involve abnormalities of high-penetrance genes, the emerging science of the study of interactions between variants in low-penetrance genes is now pro- ducing results. Polymorphic variants in genes encoding enzymes that metabolize xenobiotic environmental toxins are now widely studied as potential predisposing factors for cancer. No systematic study has yet been reported for MDS patients, although a study of a common variant in the NADP(H) quinone oxidoreductase 1 gene (NQO1) in patients developing hematopoietic toxicity after benzene exposure has suggested that this genetic variant may predispose to the development of MDS in this setting (Rothman et al. 1997). As for many of these 20 Chapter 3 ´ Etiology and Epidemiology of MDS

Fig. 3.2. Age-related changes in hematopoietic stem cells (modified from Van Zant 2003)

(7)

studies, the number of cases in this study was too small to draw confident conclusions.

3.7 Conclusion

Despite more than a decade of dedicated effort from epi- demiologists, clinicians and scientists, the cause of MDS remains largely unknown. It is inevitable that the different subtypes of MDS will have different causes. Patients with RARS appear to have a different gender distribution and are under-represented in t-MDS; the cause of this disease is likely to be different from patients with RAEB, for example. We must use the limited high-qual- ity demographic data to develop hypotheses, and test these in a combination of clinical and molecular epidemiology studies, which by definition will need to involve very large patient numbers.

References

Aksoy M, Erdem S (1978) Followup study on the mortality and the development of leukemia in 44 pancytopenic patients with chronic exposure to benzene. Blood 52:285±292

Aksoy M, Dincol K, Erdem S, Dincol G (1972) Acute leukemia due to chronic exposure to benzene. Am J Med 52:160±166

Armitage JO, Carbone PP, Connors JM, Levine A, Bennett JM, Kroll S (2003) Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients (Review). J Clin Oncol 21:897±906

Aul C, Germing U, Gattermann N, Minning H (1998) Increasing incidence of myelodysplastic syndromes: real or fictitious? Leuk Res 22:93±100

Bjork J, Albin M, Mauritzson N, Stromberg U, Johansson B, Hagmar L (2000) Smoking and myelodysplastic syndromes. Epidemiology 11:285±291

Brown WM, Doll R (1965) Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. Br Med J 5474:1327±1332 Brownson RC, Novotny TE, Perry MC (1993) Cigarette smoking and adult leukemia. A meta-analysis. Arch Intern Med 153:469±475 Deeg HJ, Jiang PYZ, Holmberg LA, Scott B, Petersdorf EW, Appelbaum

FR (2004) Hematologic responses of patients with MDS to anti- thymocyte globulin plus etanercept correlate with improved flow scores of marrow cells. Leuk Res 28:1177±1180

Gattermann N (2004) Mitochondrial DNA mutations in the hematopoietic system. Leukemia 18:18±22

Gattermann N, Wulfert M, Junge B, Germing U, Haas R, Hofhaus G (2004) Ineffective hematopoiesis linked with a mitochondrial tRNA mutation (G3242A) in a patient with myelodysplastic syndrome. Blood 103:1499±1502

Germing U, Strupp C, Kundgen A, Bowen D, Aul C, Haas R, Gattermann N (2004) No increase in age-specific incidence of myelodysplastic syndromes. Haematologica 89:905±910

Goldberg H, Lusk E, Moore J, Nowell PC, Besa EC (1990) Survey of exposure to genotoxic agents in primary myelodysplastic syndrome:

correlation with chromosome patterns and data on patients without hematological disease. Cancer Res 50:6876±6881

Gowans D, O'Sullivan A, Rollinson S, Roddam P, Groves M, Fegan C, Morgan G, Bowen D (2002) Allele and haplotype frequency at human leucocyte antigen class I/II and immunomodulatory cytokine loci in patients with myelodysplasia and acute myeloid leukaemia:

in search of an autoimmune aetiology. Br J Haematol 117:541±545 Ido M, Nagata C, Kawakami N, Shimizu H, Yoshida Y, Nomura T, Mizo- guchi H (1996) A case-control study of myelodysplastic syndromes among Japanese men and women. Leuk Res 20:727±731 Kirkwood TB, Austad SN (2000) Why do we age? (Review). Nature

408:233±238

Kojima S, Ohara A, Tsuchida M, Kudoh T, Hanada R, Okimoto Y, Kaneko T, Takano T, Ikuta K, Tsukimoto I (2002) Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood 100:786±790

Kutler DI, Singh B, Satagopan J, Batish SD, Berwick M, Giampietro PF, Hanenberg H, Auerbach AD (2003) A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 101:1249±

1256

Lucas GS, West RR, Jacobs A (1989) Familial myelodysplasia. BMJ 299:551

Luna-Fineman S, Shannon KM, Lange BJ (1995) Childhood monosomy 7: epidemiology, biology, and mechanistic implications (Review).

Blood 85:1985±1999

Maciejewski JP, Risitano A, Sloand EM, Nunez O, Young NS (2002) Dis- tinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood 99:3129±3135

Marley SB, Lewis JL, Davidson RJ, Roberts IA, Dokal I, Goldman JM, Gor- don MY (1999) Evidence for a continuous decline in haemopoietic cell function from birth: application to evaluating bone marrow failure in children. Br J Haematol 106:162±166

Matsuo T, Tomonaga M, Bennett JM, Kuriyama K, Imanaka F, Kuramoto A, Kamada N, Ichimaru M, Finch SC, Pisciotta AV (1988) Reclassi- fication of leukemia among A-bomb survivors in Nagasaki using French-American-British (FAB) classification for acute leukemia.

Jpn J Clin Oncol 18:91±96

Mauritzson N, Albin M, Rylander L, Billstrom R, Ahlgren T, Mikoczy Z, Bjork J, Stromberg U, Nilsson PG, Mitelman F, Hagmar L, Johans- son B (2002) Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976±1993 and on 5098 unselected cases reported in the literature 1974±2001. Leukemia 16:2366±2378 Mele A, Szklo M, Visani G, Stazi MA, Castelli G, Pasquini P, Mandelli F

(1994) Hair dye use and other risk factors for leukemia and pre- leukemia: a case-control study. Italian Leukemia Study Group.

Am J Epidemiol 139:609±619

Metayer C, Curtis RE, Vose J, Sobocinski KA, Horowitz MM, Bhatia S, Fay JW, Freytes CO, Goldstein SC, Herzig RH, Keating A, Miller CB, Ne- vill TJ, Pecora AL, Rizzo JD, Williams SF, Li CY, Travis LB, Weisdorf DJ (2003) Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study. Blood 101:2015±2023

Moloney WC (1987) Radiogenic leukemia revisited. Blood 70:905±908

(8)

Nagata C, Shimizu H, Hirashima K, Kakishita E, Fujimura K, Niho Y, Ka- rasawa M, Oguma S, Yoshida Y, Mizoguchi H (1999) Hair dye use and occupational exposure to organic solvents as risk factors for myelodysplastic syndrome. Leuk Res 23:57±62

Nilsson-Ehle H, Jagenburg R, Landahl S, Svanborg A (2000) Blood hae- moglobin declines in the elderly: implications for reference intervals from age 70 to 88. Eur J Haematol 65:297±305

Nisse C, Lorthois C, Dorp V, Eloy E, Haguenoer JM, Fenaux P (1995) Ex- posure to occupational and environmental factors in myelodysplastic syndromes. Preliminary results of a case-control study. Leu- kemia 9:693±699

Nisse C, Haguenoer JM, Grandbastien B, Preudhomme C, Fontaine B, Brillet JM, Lejeune R, Fenaux P (2001) Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France. Br J Haematol 112:927±935

Pasqualetti P, Festuccia V, Acitelli P, Collacciani A, Giusti A, Casale R (1997) Tobacco smoking and risk of haematological malignancies in adults: a case-control study. Br J Haematol 97:659±662 Pedersen-Bjergaard J, Pedersen M, Myhre J, Geisler C (1997) High risk

of therapy-related leukemia after BEAM chemotherapy and autologous stem cell transplantation for previously treated lympho- mas is mainly related to primary chemotherapy and not to the BEAM-transplantation procedure. Leukemia 11:16541±660 Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C (2002a)

Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 99:1909±1912

Pedersen-Bjergaard J, Christiansen DH, Andersen MK, Skovby F (2002 b) Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities (Review). Leukemia 16:2177±2184 Qian Z, Fernald AA, Godley LA, Larson RA, Le Beau MM (2002) Expres- sion profiling of CD34+ hematopoietic stem/ progenitor cells re- veals distinct subtypes of therapy-related acute myeloid leukemia. Proc Natl Acad Sci USA 99:14925±14930

Reizenstein P, Dabrowski L (1991) Increasing prevalence of the myelodysplastic syndrome: an international Delphi study. Anticancer Res 11:1069±1070

Rigolin GM, Cuneo A, Roberti MG, Bardi A, Bigoni R, Piva N, Minotto C, Agostini P, De Angeli C, Del Senno L, Spanedda R, Castoldi G (1998) Exposure to myelotoxic agents and myelodysplasia:

case-control study and correlation with clinicobiological findings.

Br J Haematol 103:189±197

Rothman N, Smith MT, Hayes RB, Traver RD, Hoener B, Campleman S, Li GL, Dosemeci M, Linet M, Zhang L, Xi L, Wacholder S, Lu W, Meyer KB, Titenko-Holland N, Stewart JT, Yin S, Ross D (1997) Benzene

poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C±>T mutation and rapid fractional ex- cretion of chlorzoxazone. Cancer Res 57:2839±2842

Saunthararajah Y, Nakamura R, Nam JM, Robyn J, Loberiza F, Macie- jewski JP, Simonis T, Molldrem J, Young NS, Barrett AJ (2002) HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppres- sion in myelodysplastic syndrome. Blood 100:1570±1574 Shin MG, Kajigaya S, Levin BC, Young NS (2003) Mitochondrial DNA

mutations in patients with myelodysplastic syndromes. Blood 101:3118±3125

Smith MT, Zhang L, Jeng M, Wang Y, Guo W, Duramad P, Hubbard AE, Hofstadler G, Holland NT (2000) Hydroquinone, a benzene metab- olite, increases the level of aneusomy of chromosomes 7and 8 in human CD34-positive blood progenitor cells. Carcinogenesis 21:1485±1490

Soci G (1996) Could aplastic anaemia be considered a pre-pre-leukae- mic disorder? (Review). Eur J Haematol Supplementum 60:60±63 Travis LB, Li CY, Zhang ZN, Li DG, Yin SN, Chow WH, Li GL, Dosemeci M, Blot W, Fraumeni JFJ (1994) Hematopoietic malignancies and related disorders among benzene-exposed workers in China (Re- view). Leukemia & Lymphoma 14:91±102

Van Zant G (2003) Genetic control of stem cells: implications for aging (Review). Int J Hematol 77:29±36

Van Zant G, Liang Y (2003) The role of stem cells in aging (Review). Exp Hematol 31:659±672

Voytek PE, Thorslund TW (1991) Benzene risk assessment: status of quantifying the leukemogenic risk associated with the low-dose inhalation of benzene (Review). Risk Anal 11:355±357

West RR, Stafford DA, Farrow A, Jacobs A (1995) Occupational and environmental exposures and myelodysplasia: a case-control study.

Leuk Res 19:127±139

West RR, Stafford DA, White AD, Bowen DT, Padua RA (2000) Cytoge- netic abnormalities in the myelodysplastic syndromes and occupational or environmental exposure. Blood 95:2093±2097 Williamson PJ, Kruger AR, Reynolds PJ, Hamblin TJ, Oscier DG (1994)

Establishing the incidence of myelodysplastic syndrome. Br J Hae- matol 87:743±745

Yin SN, Hayes RB, Linet MS, Li GL, Dosemeci M, Travis LB, Zhang ZN, Li DG, Chow WH, Wacholder S, Blot WJ (1996) An expanded cohort study of cancer among benzene-exposed workers in China. Ben- zene Study Group. Environmental Health Perspectives 104[Suppl 6]:1339±1341

22 Chapter 3 ´ Etiology and Epidemiology of MDS