10 increasing incidence of mds: real or fictitious?

1
Epidemiology and Classification s3 8 THE HISTORY OF &DS: THE ROLE OF THE F.A.B. CLASSIFICATION AND THE DEVELOPMENT OF RISK ASSESSMENT. John M. Bennett, The University of Rochester Cancer Center, Rochester. NY, USA. MDS represent a group of potentially leukemic events (AML) that were poorly characterized until 20 years ago. The FAB provided reasonably precise definitions of 5 morphologic subtypes (refractory anemia with or without ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation and chronic myelomonocytic leukemia). All are characterized by varying degrees of cytopenias, normo to hypercellular (occasional hypocellular) bone marrows, morphologic dysplasia and a variable ? of blasts (types I,II,III). With the widespread adoption of the classification by the mid 1980’s several groups had published data indicating striking survival differences between the 5 groups ranging from a few months to several years. CMML, however, has a variable clinical course. To improve upon the FAB system requires additional information, including the degree of cytopenias, chromosomal abnormalities and the precise % of marrow blasts. Prognostic indices can be utilized to select appropriate management strategies, ranging from supportive care to intensive chemotherapy and transplantation. 10 INCREASMG INCIDENCE OF MDS: REAL OR FICTITIOUS? C. Aul, U. Germing, N. Gattermann,Diisseldorf, Germany Although mosthematologists perceive a rising prevalence andinci- dence of myelodysplastic syndromes, reliable epidemiologicaldata on thesedisorders are largely lacking. Due to difficulties of dia- gnosis,classificationand epidemiological recording, patient regi- strationin population-based registersis far from complete.At pre- sent, accuraryof diagnosis and completeness of caseregistration seem to be confined to specialized registers suchasregional cancer surveysor hospital-based statistics.Data from these registerssug- gestthat MDS arerather commonhematological disorders. While the overall incidence is about2-13/100,OOO/year, incidencefigures rise steeplywith age.Age-specific incidence rates have beenesti- mated at 3-15/1OO.OOO/year for 50-70-year old persons, and 15- 50/100,000/year for people older than 70 years). Differences in incidence figures between regional studies may be ataibuted to severalcauses, including regional variations in disease incidence, small and ill-defined reference populations, bias due to patient referral patterns, expansion and intensity of diagnostic procedures anddifferentperiodsof patientrecruitment. Although MDS are increasingly diagnosed as a cause of bone marrow failure, it is unclear whether the incidence of these dis- orders is really rising. According to the datamaterial of the DSssel- dorf bone marrow register, the recent increase in MDS can be suf- ficiently explainedby increased physician awareness and extented use of bone marrow biopsies in elderly people. This is suggested by a close correlationbetween the proportion of over 60 year-old patients and the number of h4D.S cases identified in our rcgisny. Although thepresence of cytogenetic abnomalities in MDS patients hasbeen linked to exposure to occupational or environmental leuk- emogens, the epidemiological evidence is still insufficient to vali- date this hypothesis. However, there may be risks from low-dose widespread exposures to genotoxic agents that are difficult to de- tect andprove by currentepidemiologicalinvestigations. 9 BENZENE EXPOSURE AND RISK OF MDS ! AML M.T. Smith’, N. Rothman’, S-N Yin’, L. Zhang’, M. Dosemec?, Y. Wang’, G-L L?, R.B. Hayes’, ‘School of Public Health, University of California, Berkeley, CA, 2Division of Cancer Epidemiology and Genetics, National CancerInstitute, Bethesda, MD; ‘Chinese Academy of Preventive Medicine, Institute of Occupational Medicine, Beijing, China. This year marks the 100th anniversary of the first descriptions of blood dyscrasias in people exposed to benzene. Despite this fact, benzene continues to be used as a solvent in a number of countries and exposures remain high. Further, in almost all countries environmentalexposure to benzeneis significant as a result of gasoline usage and tobaccosmoking.There remainsa great deal of controversy over the types of blood dyscrasiasand malignancies caused by benzene and the risk it poses at low exposure levels. Early reports described cases of benzene-poisoned mows that were hypercellular. Certain authors suspected that these were, in fact, myelodysplastic syndromes (MDS). From a large cohort study of workers in China it is now clear that benzene causes MDS (Yin S-N et al. Am. J. Indust. Med. 29:227, 1996). A total 74,828 workers and 35,805 matched controls were followed from 1972-1987. ‘Ihere were 7 cases of MLX among the benzene- exposed workers and none in the control group. The combined relative risk for AML and MDS was 4.1. We are currently performing studies on a sub-group of Chinese workers from this cohort with current high-level benzene exposure or prior hematotoxicity. These studies have identified benzene-related cytogenetic effects and pointed to associated genetic susceptibility factors. Otherwise healthy workers exposed to benzene had higher levels of specific chmmosomal aberrations, including monosomy 5f7, de1 5q, de17q and t(8;21), in their circulating white blood cells detected by chromosomepainting and PCR. These specific aberrations may serve as usefui biomarkers of increased risk for hematologic malignancy in populations exposed to benzene and other leukemogens, including chemotherapeutic drugs. 11 GLUTATHIONE S TRANSFERASE THETA 1 (GSTTl) GENE DEFECTS IN MYELODYSPLASTIC SYNDROMES (MDS) AND THEIR CORRELATION WITH KARYOTYPE AND EXPOSURE TO POTENTIAL CARCINOGENS. C.Preudhomme, C.Nibse, M.Hebbar. M.Vanrumbeke. A.Brizard, JL. L1, , P.Fenaux CHU Lflle. France GSlTl enzyme is involved in the detoxification of several carcinogens. Recently. a higher incidence of the GS7ll null genotype (associated to absent GSlTl) was found in MDS. by comparfson to controls (Lancet 1996.347295). The presence or absence of GSTTl gene was assessed by muftiplex PCA using GSlll primers and primers for coagulation factor V gene (which selved as control for amplification) in 175 MDS cases and 99 age and sex matched normal controls fbfood donors). Katvotwe wea available in 142 of the MDS. 16 MDS were seebndary to e&sure~to’&Wneoplastic agents (therapy related cases). The remainfna 159 ots had ‘de nova” MDS and 66 of them had been included in a case control-study of occupational and environmental exposures, where a higher incidence of m was found in smokers, in jobs exposing to chemicals and h persons axposed to mineral dusts, exhaust gases, aromatic hydrocarbons and pesticides (Leukemia, 1995, 6 : 63) &s&&39 MDS (22%) and 19 contmfs (19%) had the GSlll null wnotype (p&67). lbe incidence of GSlTl null genotype was 19% in female MDS and 23% in mala MDS (p=O.7), 20%. 37%, 23%, 18%. 21% in RA, RARS, RAEB, CMMt RAEB-T, respectively (p;O.6), 16/92 (17%), o/10, 2/9, 3/11. Y15, l/5 in patfents with normal Karyotype. dal 5q. +6, -7, other single atm and other complex cytogenetic findings respectively (p&4) and 31% in therapy related MDS. as compared to 21% in “de nova’ casas @0.3). In the 66 “de nova” m cases studied epidamfokgkxlly. the incidence of GSlTl null genotype was 17% in smokers or ex smokers and 31% in non smokers (p=O.15), 4% in unqualified jobs exposing to industrial compounds (categories 5, 7. 6. 9 of International fabour office classification) and 30 36 in other jobs (p = 0.01). 9% in former coal miners (12 cases) versus 26% in other jobs (p=O.D6). A sfgnffkantfy lawer incidence of the GSlTl null genotype was found in MDS cases exposed to mineral dusts (9% vs 30 % in MDS not exposed to mineral dusts, p=O.O2). and to exhaust gases (5% M 26% in MDS not exposed to exhaust gases, p=O.W) but n-~ signfficant differences mere found for other chemlcats. &r&Iu&n. This study did not conftnn the higher incidence of GSrrl nufl genotype previously found in MDS. MDS occurring in pts with GSTTl null genotype had no particular hematological characteristics. but were unexoectedlv associated with lower orevfous exposure to &me potentially leukemdgenic compounds (expect& to be detoxified bv GST enzymes) than cases wfth normal GSlTl genotype. This relationship will have tobe f&her explored.

Upload: c-aul

Post on 15-Sep-2016

216 views

Category:

Documents


0 download

TRANSCRIPT

Epidemiology and Classification s3

8

THE HISTORY OF &DS: THE ROLE OF THE F.A.B. CLASSIFICATION AND THE DEVELOPMENT OF RISK ASSESSMENT. John M. Bennett, The University of Rochester Cancer Center, Rochester. NY, USA.

MDS represent a group of potentially leukemic events (AML) that were poorly characterized until 20 years ago. The FAB provided reasonably precise definitions of 5 morphologic subtypes (refractory anemia with or without ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation and chronic myelomonocytic leukemia). All are characterized by varying degrees of cytopenias, normo to hypercellular (occasional hypocellular) bone marrows, morphologic dysplasia and a variable ? of blasts (types I,II,III). With the widespread adoption of the classification by the mid 1980’s several groups had published data indicating striking survival differences between the 5 groups ranging from a few months to several years. CMML, however, has a variable clinical course. To improve upon the FAB system requires additional information, including the degree of cytopenias, chromosomal abnormalities and the precise % of marrow blasts. Prognostic indices can be utilized to select appropriate management strategies, ranging from supportive care to intensive chemotherapy and transplantation.

10

INCREASMG INCIDENCE OF MDS: REAL OR FICTITIOUS? C. Aul, U. Germing, N. Gattermann, Diisseldorf, Germany

Although most hematologists perceive a rising prevalence and inci- dence of myelodysplastic syndromes, reliable epidemiological data on these disorders are largely lacking. Due to difficulties of dia- gnosis, classification and epidemiological recording, patient regi- stration in population-based registers is far from complete. At pre- sent, accurary of diagnosis and completeness of case registration seem to be confined to specialized registers such as regional cancer surveys or hospital-based statistics. Data from these registers sug- gest that MDS are rather common hematological disorders. While the overall incidence is about 2-13/100,OOO/year, incidence figures rise steeply with age. Age-specific incidence rates have been esti- mated at 3-15/1OO.OOO/year for 50-70-year old persons, and 15- 50/100,000/year for people older than 70 years). Differences in incidence figures between regional studies may be ataibuted to several causes, including regional variations in disease incidence, small and ill-defined reference populations, bias due to patient referral patterns, expansion and intensity of diagnostic procedures and different periods of patient recruitment. Although MDS are increasingly diagnosed as a cause of bone marrow failure, it is unclear whether the incidence of these dis- orders is really rising. According to the data material of the DSssel- dorf bone marrow register, the recent increase in MDS can be suf- ficiently explained by increased physician awareness and extented use of bone marrow biopsies in elderly people. This is suggested by a close correlation between the proportion of over 60 year-old patients and the number of h4D.S cases identified in our rcgisny. Although the presence of cytogenetic abnomalities in MDS patients has been linked to exposure to occupational or environmental leuk- emogens, the epidemiological evidence is still insufficient to vali- date this hypothesis. However, there may be risks from low-dose widespread exposures to genotoxic agents that are difficult to de- tect and prove by current epidemiological investigations.

9

BENZENE EXPOSURE AND RISK OF MDS ! AML M.T. Smith’, N. Rothman’, S-N Yin’, L. Zhang’, M. Dosemec?, Y. Wang’, G-L L?, R.B. Hayes’, ‘School of Public Health, University of California, Berkeley, CA, 2Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; ‘Chinese Academy of Preventive Medicine, Institute of Occupational Medicine, Beijing, China.

This year marks the 100th anniversary of the first descriptions of blood dyscrasias in people exposed to benzene. Despite this fact, benzene continues to be used as a solvent in a number of countries and exposures remain high. Further, in almost all countries environmental exposure to benzene is significant as a result of gasoline usage and tobacco smoking. There remains a great deal of controversy over the types of blood dyscrasias and malignancies caused by benzene and the risk it poses at low exposure levels. Early reports described cases of benzene-poisoned mows that were hypercellular. Certain authors suspected that these were, in fact, myelodysplastic syndromes (MDS). From a large cohort study of workers in China it is now clear that benzene causes MDS (Yin S-N et al. Am. J. Indust. Med. 29:227, 1996). A total 74,828 workers and 35,805 matched controls were followed from 1972-1987. ‘Ihere were 7 cases of MLX among the benzene- exposed workers and none in the control group. The combined relative risk for AML and MDS was 4.1. We are currently performing studies on a sub-group of Chinese workers from this cohort with current high-level benzene exposure or prior hematotoxicity. These studies have identified benzene-related cytogenetic effects and pointed to associated genetic susceptibility factors. Otherwise healthy workers exposed to benzene had higher levels of specific chmmosomal aberrations, including monosomy 5f7, de1 5q, de1 7q and t(8;21), in their circulating white blood cells detected by chromosome painting and PCR. These specific aberrations may serve as usefui biomarkers of increased risk for hematologic malignancy in populations exposed to benzene and other leukemogens, including chemotherapeutic drugs.

11

GLUTATHIONE S TRANSFERASE THETA 1 (GSTTl) GENE DEFECTS IN MYELODYSPLASTIC SYNDROMES (MDS) AND THEIR CORRELATION WITH KARYOTYPE AND EXPOSURE TO POTENTIAL CARCINOGENS. C.Preudhomme, C.Nibse, M.Hebbar. M.Vanrumbeke. A.Brizard, JL. L1, , P.Fenaux CHU Lflle. France

GSlTl enzyme is involved in the detoxification of several carcinogens. Recently. a higher incidence of the GS7ll null genotype (associated to absent GSlTl) was found in MDS. by comparfson to controls (Lancet 1996.347295). The presence or absence of GSTTl gene was assessed by muftiplex PCA using GSlll primers and primers for coagulation factor V gene (which selved as control for amplification) in 175 MDS cases and 99 age and sex matched normal controls fbfood donors). Katvotwe wea available in 142 of the MDS. 16 MDS were seebndary to e&sure~to’&Wneoplastic agents (therapy related cases). The remainfna 159 ots had ‘de nova” MDS and 66 of them had been included in a case control-study of occupational and environmental exposures, where a higher incidence of m was found in smokers, in jobs exposing to chemicals and h persons axposed to mineral dusts, exhaust gases, aromatic hydrocarbons and pesticides (Leukemia, 1995, 6 : 63) &s&&39 MDS (22%) and 19 contmfs (19%) had the GSlll null wnotype (p&67). lbe incidence of GSlTl null genotype was 19% in female MDS and 23% in mala MDS (p=O.7), 20%. 37%, 23%, 18%. 21% in RA, RARS, RAEB, CMMt RAEB-T, respectively (p;O.6), 16/92 (17%), o/10, 2/9, 3/11. Y15, l/5 in patfents with normal Karyotype. dal 5q. +6, -7, other single atm and other complex cytogenetic findings respectively (p&4) and 31% in therapy related MDS. as compared to 21% in “de nova’ casas @0.3). In the 66 “de nova” m cases studied epidamfokgkxlly. the incidence of GSlTl null genotype was 17% in smokers or ex smokers and 31% in non smokers (p=O.15), 4% in unqualified jobs exposing to industrial compounds (categories 5, 7. 6. 9 of International fabour office classification) and 30 36 in other jobs (p = 0.01). 9% in former coal miners (12 cases) versus 26% in other jobs (p=O.D6). A sfgnffkantfy lawer incidence of the GSlTl null genotype was found in MDS cases exposed to mineral dusts (9% vs 30 % in MDS not exposed to mineral dusts, p=O.O2). and to exhaust gases (5% M 26% in MDS not exposed to exhaust gases, p=O.W) but n-~ signfficant differences mere found for other chemlcats. &r&Iu&n. This study did not conftnn the higher incidence of GSrrl nufl genotype previously found in MDS. MDS occurring in pts with GSTTl null genotype had no particular hematological characteristics. but were unexoectedlv associated with lower orevfous exposure to &me potentially leukemdgenic compounds (expect& to be detoxified bv GST enzymes) than cases wfth normal GSlTl genotype. This relationship will have tobe f&her explored.