THE MDS NEWS the Newsletter of the Myelodysplastic Syndromes Foundation from the Guest 1
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Summer 2004 • Volume 9, Issue 2 THE MDS NEWS The Newsletter of The Myelodysplastic Syndromes Foundation From the Guest 1. MDS is more than one disease 2. Few comprehensive patient registries exist to Editor’s Desk accurately determine who gets the different subtypes of MDS (e.g. age/sex distribution) David T. Bowen, MD University of Dundee Medical School 3. Determining the length of time to develop MDS Dundee, Scotland is difficult WHAT CAUSES MDS? More Than One Disease The diagnostic process involves categorising an Introduction individual’s disease into one of five French-American- Amongst the most frequent questions asked by British (FAB) groups or one of six World Health patients soon after the diagnosis of MDS are: Organisation (WHO) subgroups (the latter excluding sub-types CMML and the old RAEB-t). These “Why me?” classification systems recognise the differences in “What causes MDS?” the bone marrow appearance and the chromosome “Could I have done anything different to avoid abnormalities within the different subgroups of MDS. getting MDS?” and “Can my children get it?” It does not therefore require a large leap of faith to The simple answer to these questions is that for the expect that diseases that look different down a vast majority of patients, we have few clues as to microscope (albeit with certain overlapping the cause of their MDS. similarities), might have different causes. The study of the causes of these diseases is proving Attempts to study the cause of MDS (“epidemiology”) difficult for the following reasons: have focussed mainly on case-control studies, consisting of questionnaires requesting information about the work and recreational background of Contents MDS patients, compared with a “control” group of individuals who do not have MDS. Whilst these MDS Awareness Year 4 efforts are commendable, and the best that can be FDA Approves Pharmion’s Vidaza 5 achieved, there are many limitations to such studies. PBS Presents 5 These include “recall bias”, relying on the patient’s Response to TRISENOX® in MDS 6 memory for accuracy, and size of the patient group A Living Endowment 11 studied, which in turn determines the “power” of the study, and hence the confidence that the results are Blood & Marrow Transplant News 11 truly accurate and not simply statistical chance. For MDS Membership Information 11 the purposes of most of these studies, MDS has 8th International Symposium in Japan 12 been considered as one disease, given that the About the Foundation 13 numbers in each subgroup will be small. MDS Patient Registry 13 MDS Centers of Excellence 14 Who Gets MDS? MDS Educational Resources 15 MDS is a rare disease, whose incidence is 4 per Patient Referrals 15 100,000. The disease becomes more common with International Clinical Trials: An Update 16 increasing age, such that the incidence rises to >30 per 100,000 for people over 70 years of age. Be a Bone Marrow Donor 27 Males are more commonly affected than females, MDS Foundation Golf Tournament 27 although there is some evidence that this is not In Memorium 28 so for Refractory Anemia with Ring Sideroblasts Patient Services 30 (RARS) (Dr. U. Germing, personal communication). Gifts to the Foundation 32 MDS Board of Directors 32 (continued on page 2) MDS in children is more infrequent still, and has cytotoxic drugs are implicated, but alkylators most different characteristics to the adult form. Examples frequently cause an MDS phase. One of the major of these differences include the spectrum of FAB/WHO challenges in the treatment of highly curable diseases types (RARS and 5q- syndrome are almost never such as Hodgkin’s lymphoma is now to reduce the seen in childhood), and of chromosome abnormalities risk of late complications, and newer therapies (a higher proportion of children have abnormalities should prove less likely to produce t-MDS/AML. of chromosome 7). t-MDS/AML constitute <10% all cases of adult MDS MDS may also evolve from related disorders however, and the study of t-MDS/AML as a model such as Aplastic Anemia (following immuno- for the causes of de novo MDS is problematic. suppression treatment) or Paroxysmal Nocturnal Many cases of t-MDS cannot be easily classified Haemoglobinuria (PNH). due to bone marrow fibrosis (scarring). RARS and CMML are relatively under-represented, and the How Long Does it Take to Develop MDS? chromosome abnormalities in t-MDS/AML differ from 3 For patients with de novo MDS, the latency time to those of the de novo diseases. Survival of patients disease development is unknown. From a biological with t-MDS is also poorer than for de novo MDS. 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 a change in the blood count, then 2) the time from the first blood count abnormality to the presentation with clinically relevant disease (usually symptoms of anaemia) (Figure 1). Both are impossible to study systematically at present. 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,1 1–10 years for alkylator cytotoxic drugs,2,3 and more difficult to assess (but up to 30 years?) for benzene.4 Normal Bone Marrow Cell (+/– genetic predisposition) EVENT(S) A Initiation of MDS Latency EVENT(S) B period Possible Causative Factors for MDS Symptoms of MDS develop Radiation EVENT(S) C MDS cases are reported in cohorts of people exposed to radiation, for treatment of diseases such Transformation to AML in some patients as ankylosing spondylitis, or following exposure to the A-bomb in Hiroshima and Nagasaki. Some of Figure 1. Biological steps in the development of MDS these cases occurred up to 40 years after exposure and thus the precise association between the Established Causative Factors for MDS development of MDS and exposure to radiation is Cytotoxic drugs not possible to quantify. Similarly, weak associations between radiation exposure and MDS are identified Therapy-related MDS and AML (t-MDS/AML) are in some (but not all) case-control epidemiology studies. well-recognised though rare complications following cytotoxic drug therapy for malignant and some non- Benzene malignant (mainly autoimmune) diseases. The risk Legislation now ensures that exposure to high of developing t-MDS/AML following therapeutic concentrations of benzene in the workplace or the radiotherapy remains less clear.5 Several classes of environment should not occur. Thus, the main 2 sources of exposure to low concentrations of natural functions of a cell, such as neutralising toxic benzene in daily life are tobacco smoke and petrol chemicals that enter the body. To date, no definite (cartoon). Tobacco smoking is a weak but consistent natural variation in a gene has been associated with risk factor (less than two-fold) for MDS in several increasing the risk of developing MDS, but this field case-control studies,6 but also contains many other is only in its infancy. Large numbers of patient carcinogens in addition to benzene. samples are needed for such studies, particularly In contrast, exposure to high concentrations of benzene in MDS, where these large numbers are required for clearly causes bone marrow toxicity, usually aplasia, each of the FAB/WHO groups. some of which will progress to MDS and/or AML.7,8 This initiative requires the development of large Miscellaneous Biobanks, married to high-quality registries of clinical and laboratory information cataloguing Whilst each individual published case-control study the characteristics of each patient’s disease. has identified a number of occupations and substances, which may be risk factors for MDS, there is little consistency between these studies. CONCLUSION An exhaustive list of these possible risk factors is Despite more than a decade of dedicated effort from therefore not helpful, as many will represent statistical epidemiologists, clinicians and scientists, the cause chance or very weak relative risks. of MDS remains largely unknown. It is inevitable that the different subtypes of MDS will have The incidence of MDS increases with increasing age. different causes. We must use the little high-quality This has been interpreted in two ways; the disease demographic data (Who gets MDS?) to develop must result from a progressive accumulation of a hypotheses, and test these in a combination of lifetime’s exposure to a toxic agent or, the aged clinical and molecular epidemiology studies, which bone marrow “stem” cell is easier to damage than its by definition will need to involve very large patient younger counterpart. The process of “ageing” is not numbers. National and international collaborative well defined, though much blame is heaped upon efforts are underway to attempt to achieve this. “free radicals”,9 defence against which deteriorates with age. It remains unclear in what way this may be relevant to diseases of older age such as MDS. REFERENCES 01. Moloney WC. Radiogenic leukemia revisited. Blood. Is There an Inherited Tendency to 1987;70:905–908. Develop MDS? 02. Pedersen-Bjergaard J, Andersen MK, Christiansen The vast majority of MDS patients presenting in DH, Nerlov C. Genetic pathways in therapy-related adulthood have no relatives with the disease, and myelodysplasia and acute myeloid leukemia. Blood. no obvious inherited disease with a tendency to 2002;99:1909–1912. MDS. 30% children with MDS have other associated 03. Mauritzson N, Albin M, Rylander L et al. Pooled abnormalities, and some of these are part of well- analysis of clinical and cytogenetic features in treatment- recognised syndromes including Fanconi Anaemia, related and de novo adult acute myeloid leukemia and and Blooms Syndrome. myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976–1993 and on Families with several cases of MDS are described, 5098 unselected cases reported in the literature but are exceptionally rare.