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Epidémiologie des SMD

Epidémiologie des SMD. Pierre Fenaux (Université Paris 13, Hôpital Avicenne). 18 Juin 2004 – 5èmes journées du GFM - Rouen. Incidence of MDS. Author Study basis Study period Incidence in 100.000 habitants/year

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Epidémiologie des SMD

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  1. Epidémiologie des SMD Pierre Fenaux (Université Paris 13, Hôpital Avicenne) 18 Juin 2004 – 5èmes journées du GFM - Rouen

  2. Incidence of MDS Author Study basis Study period Incidence in 100.000 habitants/year ___________________________________________________________________________________ Aul et al Dusseldorf region 1976-1980 1.29** (1992) 1.200.000 inhabitants 1981-1985 2.12** all ages 1986-1990 4.11** Cartwright Great Britain 1984-1986 2.14 ** (1992) all ages Fenaux et al Nord-Pas de Calais (France) 1991-1992 2.6 * (1993) 4.000.000 inhabitants all ages Williamson et al Bournemouth region 1981-1990 12.6 * (1994) 203 to 226.000 inhabitants all ages Radlung et al Jonkoping region (Sweden) 1978-1982 3.2 * (1995) 218 to 230.000 inhabitants 1983-1987 4.1 * Age > 19 years 1988-1992 3.5 * Bauduer et al French Basque region (France) 1993-1996 7.7 (2000) 290.000 inhabitants * standartized ratio ** crude ratio

  3. Facteurs étiologiques dans les SMD • Facteurs génétiques • Expositions professionnelles et environnementales • Exposition à la chimio et la radiothérapie • Facteurs immunologiques

  4. Genetic predisposition to MDS 1) 35 to 50 % childhood MDS have genetic abnormalities - Down’s syndrome - neurofibromatosis (NF1) - Noonan’s syndrome (PTPN 11) -Fanconi anemia 2) Familial cases of MDS

  5. Allelic variants in xenobiotic-metabolising genes Xenobiotic Haematopoietic Progenitor Cell Phase 1 enzyme Reactive intermediate Accelerated Accumulation • Mutation • Apoptosis Phase 2 enzyme Slowed Excretion

  6. Genetic Predisposition to MDS • NQO1 mutations • GSTT1 mutations • CYP2E1 mutations

  7. Occupational and environmental factors in MDS

  8. Benzene and MDS/AML/aplastic anemia - Solvent used in leather, rubber, paint and plastic industries - « Aplastic anemia » and « acute leukemia » first described with benzene in 1897 - At least 25 % of AML preceded by a phase strongly suggestive of MDS (Aksoy, 1985)

  9. Benzene and MDS/AML/Aplastic anemia - Latency period ranging from 1 to 50 years (median 10 years) - Relative risk (RR) of MDS/AML : 2 to 20 - Risk proportional to intensity and duration of exposure . May be present at doses < 10 ppm (Rinsky, 1987) . RR = 98 at > 400 ppm/year (Wong, 1995)

  10. Other compounds or exposures in MDS - Generally remains uncertain - Results from case control studies required - Problems with most published studies : . Small size (maximum 400) . Choice of sex and age matched controls . Relatively limited increases in odds ratio . Contents of the questionnaire . Problem of the reality and quantity of exposures

  11. Case control studies Questionaires based on : 1. environmental factors outside work : smoking, gardening, having pets, family status, medical history, treatments… 2. Jobs occupied (International Labour Office) 3. Exposure to a list of defined substances

  12. Occupational and environmental risk factors of MDS (Nisse, 2001) Non occupational exposures OR p smoking 3.4 0.0003 gardening 2.1 0.0008 living near an industrial plant 3.1 0.00003 Job titles skilled agricultural 2.6 0.012 plant and machine operators 1.8 0.017 elementary occupations 2.5 0.001

  13. Occupational exposure OR p solvents 2.6 0.03 oil 4.2 0.001 cotton and flax dusts 3.4 0.013 Multivariante analysis agricultural workers 3.66 0.0001 textile operators 3.66 0.001 health professionals 10 0.004 living next to an industrial plant 2.4 0.007 smoking 1.74 0.015 machine operators 2.7 0.015 oil use 2 0.029

  14. Environmental factors West Nisse Rigolin Ido Goldberg Crane 400 204 178 111 52 46 Smoking + + + Alcohol drinking + Diagnostic X ray (dental) + Living close to power plant + Living in a farm + Hairdyes gardening + Childless + Effect of smoking confirmed in 2 further case control studies : Pasqualetti (1997) : 85 cases ; Bjork (2001) : 330 cases

  15. Occupational exposures West Nisse Rigolin Ido Goldberg Crane Chemical exposure + + + + Inorganic gases/fumes +/- Halogenated organics + Hydrogen peroxide + Exhaust gases + Metals + Pesticides - + + + + Organic solvents +/- + + + Electro-magnetic fields +/- +

  16. Other chemical exposures in MDS ?(no case controls) - Toluene and xylene (but contain benzene impurities) - Kerosene for cooking (Kwong, 1995)

  17. Previous exposures, clinical parameters and morphology in MDS - « High risk » MDS (RAEB, CMML) more frequent in exposed cases (Goldberg, 1990) - More frequent incidence of multilineage involvement, and CD34+ cells in exposed MDS cases (Fagioli, 1992) - AML : trilineage dysplasia more frequent in exposed cases (Cuneo, 1992)

  18. Previous exposures and cytogenetic/molecular abnormalities in MDS - Rigolin ( 1998) . Abnormal karyotype in 68 % exposed vs 43 % non exposed MDS . More -7/7q-, +8, 7p, 17p, complex karyotypes and fewer isolated 5q- and 20q- in exposed MDS - Goldberg (1990) . No correlation between abn 5 and/or 7 and exposure to pesticides or solvents - AML : chromosome 5 and/or 7 more frequently involved in exposed cases (Cuneo, 1992)

  19. Previous exposures and cytogenetic/molecular abnormalities in MDS - West et al (2000) : 214 cases . More frequent exposures with abnormal karyotypes, expecially metals organic dusts and radiation . Abnormal chromosome 5 : inorganic gases and fumes . Abnormal chromosome 7 : organics, inorganic dusts and gases . Abnormal chromosome 8 : organics, metals, radiation

  20. Pathogenesis of MDS after benzene poisoning (1) - Mice treated with hydroquinone have aneuploidy and chromosome breakage in marrow cells (Chen, 1995) - Hydroquinone induces +8 and -7 in vitro in CD34 cells (Smith, 2000) - in vivo, benzene workers have aneuploidy, especially 5q- and 7q- in lymphocytes (Zhang, 1998)

  21. Benzene metabolism sulfate gluthathione conjugation benzene benzene oxyde phenol hydroquinone . CYP 2 E1 NQ01 benzoquinone . Hydroquinone and derivatives can form DNA adducts . They can be detoxified through sulfate and glutathion conjugation

  22. SMD après chimio et radiothérapie

  23. Therapy related MDS and AML 2 types schematically opposed (Pedersen Bjergaard) 1) “classical” tMDS and AML - after alkylating agents (mechlorethamine > chlorambucil-melphalan > cyclophosphamide) - relatively long interval from chemotherapy - usual preleukemic phase - rearrangements of chromosome 7 and 5, often complex - poor response to chemotherapy

  24. 2) “recently described” tAML - after epipodophyllotoxins or other agents targeted at topo II - short interval from chemotherapy - no preleukemic phase - 11q23 (or less often 21q22) rearrangements : t(9;11), t(10;11), t(6;11) etc... - response to chemotherapy similar to that of their “de novo” counterpart

  25. Cytostatic drugs associated with an increased risk of t-MDS and t-AML

  26. Tous les cas LAM SMD 202 / 594 témoins 138 / 403 témoins 44 / 131 témoins Traitement Mitoxantrone Anthracyclines Agents alkylants G-CSF Radiothérapie OR ajustés et IC95% dans un modèle incluant mitoxantrone, anthracyclines, G-CSF et radiothérapie SMD et LA après cancer du sein(Le Deley et coll)

  27. Rôle leucémogène des radiations ionisantes • Démontré pour : • Explosions nucléaires de 1945 • Irradiations rachidiennes pour SPA? • Cancer du sein (RR = 2) • Cancer de la prostate (0,1% LAM dans • certaines séries) • . Association avec la chimio dans le Hodgkin

  28. t AML/MDS after autologous stem cell transplantation(Pedersen Bjergaard, 2000) • 1.5 to 14% • Generally MDS,and abnormal chrom 5 and/or 7 • Risk factors: -previous treatment (alkylators) +++ -age -radiotherapy (TBI) -peripheral stem cell source?

  29. Detection of pretransplant clones in progenitor cells of patients who develop MDS after autologous transplantation • Bone marrow or stem cells of 12 patients who developed MDS after ABMT or ASCT analyzed before the procedure by FISH • The bone marrow smear was normal, and karyotype was normal (4/4) • 9 of 12 patients had the clonal anomaly before stem cell collection (Abruzzese, Blood 1999, 94, 1814)

  30. Therapy related MDS and AML with 17p deletion(Lai ,Preudhomme,Zandecki et coll) - 69 cases of AML and MDS with 17p deletion diagnosed over 15 years (4.6% of AML and MDS) - 25 were therapy related - 21 MDS (18 with an excess of blasts) 4 AML

  31. Two types according to primary tumor and antineoplastic agents used 1) 11 patients with a lymphoid neoplasm . chemotherapy with an alkylating agent in 10 cases . -7/del7q in 10 cases 2) 14 patients with previous myeloproliferative disorder . chemotherapy with hydroxyurea(10 cases) pipobroman(8 cases)32P (6 cases) classical alkylating agent in 2 cases -7/del 7q in only 3 cases (2 had received busulfan)

  32. G-CSF et SMD/LA induits?(Relling, 2003) - 412 LAL de l’enfant traitées par VP16 et anthracycline - 99 ont aussi reçu du G-CSF - fréquence de LAM induite accrue par le G-CSF(à doses identiques de chimio) 2

  33. MDS after aplastic anemia.Role of G-CSF?(Kojima, 2002) - 113 children treated by ALG,13 MDS - Correlation with absence of response to ALG and use of G-CSF

  34. Genetic Pathways of t-MDS and t-AML Blood 99:1909-1912, 2002

  35. Predisposition aux SMD/LA induits • Liée à la tumeur initiale • génétique

  36. Prédisposition génétique aux LAM chimio-induites 37% de cas avec cancers (66/179) au 1er degré de patients atteints de tLAM vs 27% dans les LAM de novo (757/2785) (OR: 2.6, p<0.005) (Pagano, Brit J Haematol 2001, 112, 109)

  37. NQO1 609CT &SMD induits • 104 Hémopathies myéloïdes • 9 LAM de novo • 56 tLAM • 30 MDS • 9 LMC Augmentation de la proportion de 609CT dans le groupe tLAM avec anomalies 5/7 Blood 1999 Vol 94

  38. XRCC1 & Sites abasiques • Complexe APE1 initie la réparation des sites abasiques • Spontanés • Radicaux libres • Erreurs de réparation • XRCC1 initie cette réparation • Impliqué dans la stabilité du génome. The EMBO Journal 2001 - Vol 20

  39. Polymorphisme de XRCC1 • Population étudiée • 34 tAML • 134 AML • 178 contrôles • XRCC1 Arg399 gln • Différence significative entre entre tAML et les contrôle (p=.03) • Effet protecteur de cet allèle (OR=.44) • Pas d’influence des autres polymorphismes Blood 2002 - Vol 100

  40. Mismatch DNA repair system in therapy related MDS(Ben Yehuda, 2003) • 6 human genes involved in DNA mismatch repair. Defects lead to microsatellite instability (MSI) • MSI in 41 % of 96 t MDS • Reduced expression of MSH 2 and MLH 1 in most patients with MSI • MLH 1 deficiency accelerates leukemogenesis in an NF1 +/- mouse model (Gutmann, 2003)

  41. Fréquence des LAM/ SMD chimio induites: rôle de la tumeur initiale Chlorambucil au long cours - 1,4% LAM/SMD dans les LLC - 11,3% LAM/SMD dans la maladie de Vaquez (contre < 1% chez les patients traités par saignées) (Dighiero, NEJM, 1998, 924)

  42. Risque de SMD / LA induit selon la pathologie • TE ou PV traitée par Hydréa : 4 à 5 % de SMD / LAM • Drépanocytose traitée par Hydréa : pas d’excès de SMD / LAM

  43. Stabilité du génome et clones myéloprolifératifs • Régulation négative de BRCA1 et des proteines DNA -PKc dans les cellules exprimant BCR-ABL (Deutsch,2001 et 2003)

  44. SMD:facteurs immunologiquesAssociation SMD et: • Polychondrite atrophiante,arthrites séronégatives,vascularites • Crohn,Behcet?

  45. Immune Abnormalities in (some cases) of MDS • Oligoclonal expansion of T cell populationswith inhibitory effect on CFU-GM of MDS cases • Possible reversal with immunosuppressive drugs (antithymocyte globulin)

  46. Perspectives épidémiologiques dans les SMD • Registre national des SMD • Possibilité de registres départementaux et régionaux GRACE AU REGISTRE ONLINE DU GFM !

  47. Perspectives épidémiologiques : SMD et LA induits (L Ades, V Coiteux) 1) registre des SMD et LA induits en France 2) analyse rétrospective et prospective des SMD et LA induits dans les protocoles des groupes coopératifs français -rétrospective (TBI dans les LNH autogreffés) -prospective (ex : BEACOPP dans les Hodgkin)

  48. ACVBP dans les LNH et SMD/LA induits(Leleu, 2003, GELA et GFM) • 2849 patients traités • 7LAM,5 SMD,2LMC • La moitié des cas après rechûte

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