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Quoi de nouveau dans les SMD ?

Quoi de nouveau dans les SMD ?. Pierre Fenaux H ôpital Avicenne Paris 13 University Inserm U 848 France Tunis 11/ 2009. Quoi de neuf dans les SMD. Physiopathologie Tests diagnostiques, classification et pronostic Traitement. Quoi de neuf dans les SMD. Physiopathologie

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Quoi de nouveau dans les SMD ?

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  1. Quoi de nouveau dans les SMD ? Pierre Fenaux Hôpital AvicenneParis 13 UniversityInserm U 848France Tunis 11/ 2009

  2. Quoi de neuf dans les SMD • Physiopathologie • Tests diagnostiques, classification et pronostic • Traitement

  3. Quoi de neuf dans les SMD • Physiopathologie • Tests diagnostiques, classification et pronostic • Traitement

  4. Physiopathologie des SMD • Toujours mal connue • Mais apparition de nouvelles méthodes d’analyse génétique: • Profils d’expression géniques ? • +++ SNP arrays • ++Etude des profils de méthylation

  5. Phase précoce des SMD apoptose excessive des précurseurs médullaires • Affection néoplasique dès ce stade • Anomalies chromosomiques (del 5q, del 20q, del 12p) • Délétions de très petite taille (4q, 11q) • Anomalies géniques • RPS 14 (5q) • TET 2 (4q) • C-cbl (11q)

  6. Phase tardive des SMD Apparition d’un blocage de maturation avec évolution possible en LAM • Mécanismes de la progression ? • Nouvelles anomalies chromosomiques (-7,+8, complexes) • Délétions de petite taille ( del 7q) • Mutations géniques: ras, p53 • +++ hyperméthylation génique • Activation de NF kappa B • Instabilité génétique

  7. Quoi de neuf dans les SMD • Physiopathologie • Tests diagnostiques, classification et pronostic • Traitement

  8. RA RARS RA Refractory cytopenia with multilineage dysplasia RARS RCMD-RS 5q- syndrome RAEB-t (20-30%bl) CMML • AML • MDS/MPD WHO classification WHO 2001 FAB • RAEB-1 (<10% blasts) • RAEB-2 (>10% blasts) • RAEB

  9. WHO Proposals for the Classification 2008 of MDS I Subtype blood marrow Refractory Cytopenia(RCUD) Uni-or BicytopeniaAnemia Dyserythropoiesis only Refr. Thrombocytopenia <1% Blasts <5% Blasts Refr. Neutropenia <15% Ringsideroblasts Refr. Anemia Refractory Anemia with Anemia Dyserythropoiesis only Ringed sideroblasts no Blasts <5% Blasts (RARS) >15% Ringsideroblasts Refractory Cytopenia with Cytopenia(s) Dysplasia in >10% of the cells of 2 multilineage Dysplasia <1% Blasts cell lines with or without Ring sid. no Auer rods <5% Blasts, no Auer rods (RCMD) <1000 /ml Monocytes +15% Ringsideroblasts MDS with isolated Anemia <5% Blasts , no Auer rods del(5q) normal or elevated Megakaryocytes platelets, <1%blasts with hypolobulated nuclei MDS-Unclassifiable Cytopenia <5% blasts

  10. WHO Proposals 2008 for the Classification of MDS II Subtype blood marrow Refractory Anemia Cytopenia(s) Unilineage or oder multilineage With excess blasts I <5% Blasts Dysplasia (RAEB I) no Auer rodsno Auer rods <1000 /ml Monocytes5-9 % Blasts Refractory Anemia Cytopenia(s) Unilineage or multilineage With excess blasts I I <19% Blasts Dysplasia (RAEB II) Auer rods possible 10-19 % Blasts <1000 /ml Monocytes Auer rods possible

  11. Autres tests diagnostiques ? • Cytométrie de flux ? • Profils d’expression géniques ?

  12. International Prognostic Scoring System (IPSS)

  13. SMD: autres facteurs pronostiques • Dysplasie multilignée • Myelofibrose • Besoin transfusionnel en GR • mutations géniques (ras, p53, AML 1, TET 2, etc…) • cytometrie de flux ? Sont ils indépendants ?

  14. WHO classification-based Prognostic Scoring System (WPSS) *Good: normal, -Y, del(5q), del(20q); Poor: complex, chromosome 7 anomalies; Intermediate: other abnormalities. °Transfusion dependency: at least one transfusion every 8 weeks over a period of 4 months. Risk groups: very low (score 0), low(1), intermediate (2), high (3-4), very high (5-6).

  15. Quoi de neuf dans les SMD • Physiopathologie • Tests diagnostiques, classification et pronostic • Traitement

  16. SMD: « haut » vs  « faible » Risque • Haut risque • IPSS intermediaire-2 ou élevé • Faible risque • IPSS faible ou intermediaire-1

  17. SMD:Objectifs du Traitement • Ralentir la progression (en LAM) • Prolonger la survie • Améliorer les cytopénies sanguines • Améliorer la qualité de vie

  18. SMD:Objectifs du Traitement: Haut risque • Ralentir la progression (en LAM) • Prolonger la survie • Améliorer les cytopénies sanguines • Améliorer la qualité de vie

  19. SMD:Objectifs du Traitement: faible risque • Ralentir la progression (en LAM) • Prolonger la survie • Améliorer les cytopénies sanguines • Améliorer la qualité de vie

  20. Traitement des SMD de haut risque

  21. Traitement des SMD de haut risque • Allogreffe • Chimiotherapie (intensive ou non) • Agents Hypométhylants • autres

  22. Traitement des SMD de haut risque • Allogreffe • Chimiotherapie (intensive ou non) • Agents Hypométhylants • autres

  23. MDS: « classical » myeloablative allogeneic SCT • Requires • HLA identical donor • Age< 45-50 • Results: • 45-50% cure • 25-30% relapses • 25% transplant related mortality

  24. MDS non myeloablative allo SCT - extend indication to 65-70 years - less toxicity…but more relapses

  25. Non myeloablative allo SCT is associated to a substantial % of prolonged remissions in MDS • Valcarcel (JCO, 2008) • 99 MDS and AML • 4 year relapse rate 37% • 4 year DFS and OS: 43 and 45% • Marks (Blood, 2008) • 81 MDS (or AML) • 5 year deaths due to relapse: 20% • 3 and 5 y EFS:46 and 42 % • 3 and 5 year OS:53 and 46% • Laport (BBMT, 2008) • About 90 MDS • 3 year RFS 25 to 30%

  26. Figure 1 Standard RIC REL REL NRM NRM Months post-transplant Months post-transplant

  27. Allo SCT: chemotherapy or hypomethylating agents before transplant ? Treatment before allo based on marrow blasts, karyotype and type of transplant : • Marrow blasts <10% ( classical allo) and < 5% (non myelo ablative allo): immediate transplant • increased marrow blasts • Normal karyotype: intensive chemo prior to transplant • Unfavorable karyotype: hypomethylating agent prior to transplant

  28. Traitement des SMD de haut risque • Allogreffe • Chimiotherapie (intensive ou non) • Agents Hypométhylants • autres

  29. 1.0 100 0.8 80 60 0.6 Survival (%) Survival Probability 40 0.4 20 0.2 0 0 20 40 60 80 100 120 140 0.0 0 100 200 310 410 520 Weeks Survivalwith Anthracycline-AraC Chemotherapy N = 99 Wattel E. et al. With Permission of E Estey, MD Br J Haematology. 1997;98:983-991.

  30. MDS : low dose chemotherapy: LD AraC • LD AraC : 20mg/m2/d • 15% CR, 20% PR, 20% HI • Fairly myelotoxic (10% toxic deaths) • response only in the absence of unfavorable karyotype • Better survival than BSC in AML in the elderly (UK-MRC results)

  31. Clofarabine in MDS: Faderl et al. ASH2008, Abstract 222

  32. Traitement des SMD de haut risque • Allogreffe • Chimiotherapie (intensive ou non) • Agents Hypométhylants • autres

  33. Azacitidine Survival Study(Lancet Oncol, 2009) AZA75 mg/m2/d x 7 d q28 d Screening/Central Pathology Review Investigator CCR Tx Selection CCR Randomization • Best Supportive Care (BSC) only • Low Dose Ara-C (LDAC, 20 mg/m2/d x 14 d q28-42 d) • Std Chemo (7 + 3) BSC was included with each arm Tx continued until unacceptable toxicity or AML transformation or disease progression 33

  34. Overall Survival: Azacitidine vs CCR ITT Population 1.0 0.9 0.8 0.7 50.8% 0.6 0.5 26.2% 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 25 30 35 40 Log-Rank p=0.0001 HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 Difference: 9.4 months Proportion Surviving 24.4 months 15 months AZA CCR Time (months) from Randomization 34

  35. Hazard Ratio and 95% CI for Overall Survival ITT 195 / 358 RAEB & RAEB-T: AGE ≥ 65 138 / 240 AGE: < 65 45 / 100 ≥ 65 150 / 258 ≥ 75 50 / 87 Male 134 / 251 Female 61 / 107 FAB: RAEB 95 / 207 RAEB-T 80 / 123 WHO: RAEB-1 15 / 31 RAEB-2 102 / 193 IPSS: INT-2 71 / 146 High 98 / 167 80 / 167 Cytogenetics: Good Intermediate 38 / 76 Poor 67 / 100 Cytopenias: 0/1 20 / 53 2/3 167 / 290 BM Blasts: ≥ 5% to < 11% 34 / 61 ≥ 11% to < 21% 98 / 192 ≥ 21% to < 31% 58 / 99 42 / 57 Karyotype: -7/del (7q) LDH: ≤ 240 U/I 97 / 208 > 240 U/I 94 / 145 Total - Event / N ITT Subgroups 0.125 0.250 0.500 1 2 4 35 Favors Azacitidine Favors CCR

  36. Additional Analysis: Median OS by Investigator Selection 36

  37. AZA-001: OS – azacitidine versus LDAC 1.0 Azacitidine 0.9 LDAC 0.8 0.7 Probability of survival 0.6 0.5 0.4 0.3 0.2 0 10 20 30 40 Time from randomisation (months) Data on file, Celgene

  38. AZA 001 trial: azacytidine vs LD AraC(EHA 1009)

  39. Abs 3636 – Po III-718 – P FENAUX et al. (2) 1.0 p=0,0038 HR = 0.47 (95% CI : 0,28 ; 0,79) Décès : AZA = 24, CCR = 41 0.9 0.8 0.7 50,2% 24,46 mois 0.6 0.5 Proportion Survivants AZA 0.4 15,97 mois 0.3 0.2 0.1 CCR 15,9% 0 0 Temps (mois) après randomisation # at risk Azacytidine in patients with 20 to 30% blasts (JCO, in press) 20 25 35 30 40 5 10 15

  40. Secondary Endpoints: IWG (2000) CR,PR and HI

  41. Mean Hemoglobin (g/L) for AZA vs CCR – ITT Population 41

  42. Mean Platelets (109/L) for AZA vs CCR – ITT Population 42

  43. Mean ANC (109/L) for AZA vs CCR – ITT Population 43

  44. 0 5 10 15 20 25 30 35 40 AZA-001: 2-year OS with azacitidine by best response (IWG 2000) 1.0 78.4% 0.8 71.7% HI 0.6 PR CR Proportion of patients surviving 0.4 CCR 0.2 0 Time from randomisation (months) IWG = International Working Group; HI = haematological improvementPR = partial response; CR = complete response Adapted from List AF, et al. Oral presentation at ASCO 2008, Chicago, IL [abstract 7006]

  45. response after 2 to more than 6 cycles Continuing treatment improves responses in 48% of the cases Abs 227 – CO – L R SILVERMAN et al. Prolonged treatment with Azacytidine improves responses in MDS 1.0 0.9 0.8 0.7 0.6 0.5 Probabilité cumulée 0.4 50% (2 cycles) Extrêmes : 1-22 cycles 0.3 0.2 87% (6 cycles) 0.1 0 24 12 3 21 1 18 1 0 91 3 34 6 12 9 6 15 1 Temps (cycles) : Nombre de cas :

  46. EORTC Decitabine Phase III study(Wijermans et al, ASH 2008 n° 228) “Low-dose intravenous decitabine vs best supportive care in MDS with 11–30% blasts”

  47. Abs 226 – CO – P WIJERMANS et al. 100 progression free survival 90 80 70 Médian (months) : 6,6 vs3 HR = 0,68, 65% CI (0,52, 0,88) p=0,004 60 100 Overall survival 50 90 40 80 Médian (mnthss) : 10,1vs 8,5 HR = 0,88, 95% CI (0,66; 1,17) p=0,38 30 70 20 60 Supportive care 10 50 0 40 Decitabine 0 Decitabine 30 Mois Supportive care 20 10 0 0 Mois Improvement in progression free survival, but not survival 30 36 42 30 36 24 24 6 12 18 18 12 6

  48. Perspectives avec les agents hypométhylants Comme traitement de maintenance après chimiothérapie ou allogreffe Avant allogreffe Autes situations SMD et LAM après SMP LAM prolifératives SMD de faible risque In combination to other agents

  49. AZA in MDS/AML post MPD (S Thépot, EHA 2009) 45 patients with MDS or AML post myeloproliferative disorder (in the French ATU program) 52% responses, with reversal to features of MPD (polycythemia, thrombocythemia ) in some cases

  50. AZA as first line treatment in AML(S Thépot, ASH 2009) • N=138 patients, median age 73 • ATU program • Factors associated with better survival • non complex karyotype • WBC <10 G/l • …. But not % marrow blasts PRESENTED AT ASH 2009

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