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Manejo de los SMD de riesgo alto:

Manejo de los SMD de riesgo alto:. Pierre Fenaux H ôpital Avicenne Paris 13 University Inserm U 848 France Oviedo 3/2011. SMD: riesgo « alto » vs  « bajo ». Riesgo alto IPSS intermedio-2 or alto Riesgo bajo IPSS bajo o intermedio-1. Objetivos del tratamiento de los SMD.

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Manejo de los SMD de riesgo alto:

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  1. Manejo de los SMD de riesgo alto: Pierre Fenaux Hôpital AvicenneParis 13 UniversityInserm U 848France Oviedo 3/2011

  2. SMD: riesgo « alto » vs  « bajo » • Riesgo alto • IPSS intermedio-2 or alto • Riesgo bajo • IPSS bajo o intermedio-1

  3. Objetivos del tratamiento de los SMD • Retrasar la progresion • aumentar la supervivencia • Mejorar las citopenias • Mejorar la calidad de vida

  4. Objetivos del tratamiento (SMD de riesgo bajo) • Retrasar la progresion • aumentar la supervivencia • Mejorar las citopenias • Mejorar la calidad de vida

  5. Objetivos del tratamiento( SMD de riesgo alto) • Retrasar la progresion • aumentar la supervivencia • Mejorar las citopenias • Mejorar la calidad de vida

  6. Tratamiento de los SMD de riesgo alto • Alo TPH • Quimoterapia clasica (intensiva o no) • Agentes hipometilantes • Otros (en combinacion con hipometilantes, o como secunda linea) • SMD de alto riesgo especificos

  7. Tratamiento de los SMD de riesgo alto • Alo TPH • Quimoterapia clasica (intensiva o no) • Agentes hipometilantes • Otros (en combinacion con hipometilantes, o como secunda linea) • SMD de alto riesgo especificos

  8. SMD: alo transplante « clasico » • Necesita • Donante HLA identical • Edad <45-50 • Resultados: • 45-50% curacion • 25% recaidas • 25% MRT

  9. SMD: alo trasplante no mielo ablativo - Extende la indication hasta 65-70 anos - meno toxicidad…pero mas recaidas

  10. 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%

  11. Fewer relapses after allo SCT than chemotherapy Retrospective analysis of 36 non myeloablative allografts and 110 patients treated with intensivechemotherapy Abs 1125 – Po I-230 – Y A EFEBERA et al. 1.0 0.9 0.8 allo Chemotherapy 0.7 0.6 0.5 0.4 0.3 0.2 0.1 P<0.0004 0 25 20 0 5 10 15 Années

  12. Alo TPH sigue siendo el unico tratamiento curativo de SMD • 39% de supervivencia a los 3 anos con alo TPH vs 7% con Azacitidina (programa ATU frances) (1) • 48 % supervivencia a los 2 anos con donante, vs 23% sin donante(2) 1) U. Platzbeckeet al., ASH 2010, # 3500 – 2) Field et al., ASH 2010, # 2381

  13. Alo TPH: como tratamiento de primera linea o precedido por QT o hipometilantes ? Depiende del % de blastos medulares, cariotipo y tipo de trasplante : • blastos <10% ( alo TPH clasico) y < 5% (mini trasplante): trasplante inmediato • mas blastos medulares • Cariotipo normal : QT intensiva antes del trasplante • Cariotipo desfavorable : hipometilantes antes del trasplante

  14. Hypomethylating agents prior to all HSCT ? • In « DAC »tion instead of Induction (Lubbert,BMT, 2009) • N=15 (MDS or AML) • Median age 69 • RIC • 14 engraftment • 6 alive in RC, 4 relapses, 4 TRM

  15. Tratamiento de los SMD de riesgo alto • Alo TPH • quimoterapia clasica (intensiva o no) • Agentes hipometilantes • Otros (en combinacion con hipometilantes, o como secunda linea) • SMD de alto riesgo especificos

  16. Quimoterapia intensiva en SMD de riesgo alto • Generalmente antraciclina- AraC • Tasa de RC 40-60% • Duracion de RC generalmente < 1 ano • Malos resultados en caso de cariotipo desfavorable

  17. 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.

  18. Intensive Chemotherapy (MDAnderson Experience) 1.0 0.8 Idarubicin-AraC Fludarabin-AraC 0.6 Probability of Relapse or Death After CR Topotecan-AraC 0.4 0.2 0.0 0 100 200 300 400 Time (weeks)

  19. 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

  20. Tratamiento de los SMD de riesgo alto • Alo TPH • quimoterapia (intensiva o no) • Agentes hipometilantes • Otros (en combinacion con hipometilantes, o como secunda linea) • SMD de alto riesgo especificos

  21. 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 21

  22. 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 22

  23. 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 23 Favors Azacitidine Favors CCR

  24. Secondary endpoints Time to AML 26.1 mos with AZA vs 12.4 with CCR, p=0.004 RBC transfusion independence 45% with AZA vs 11% with CCR, p<0.0001 Infections requiring IV antimicrobials Reduced by 33% with AZA vs CCR

  25. 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 :

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

  27. 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]

  28. Response and OS in 282 higher-risk MDS treated with Azacitidine:French ATU program (Itzykson,Blood, 2011)

  29. Azacitidine is approved in EU • Azacitidine is indicated for adults who are not eligible for haematopoietic stem cell transplantation with • intermediate-2 or high-risk MDS according to the International Prognostic Scoring System • AML with 20–30% blasts and multi-lineage dysplasia (WHO classification) • CMML with 10–29% marrow blasts without myeloproliferative disorder • The recommended dosing regimen for azacitidine is 75mg/m2 q.d. for 7 days q.28d • It is recommended that patients are treated for a minimum of 6 cycles • treatment should be continued as long as the patient continues to benefit or until disease progression CMML = chronic myelomonocytic leukaemia Azacitidine EU Summary of Product Characteristics

  30. Subanalisis del ensayo AZA 001 • Analisis azacitidina vs LD araC • Pacientes con 20 -30% blastos medulares • Ancianos (> 75 de edad) • Papel del cariotipo

  31. Subanalisis del ensayo AZA 001 • Analisis azacitidina vs LD araC • Pacientes con 20 -30% blastos medulares • Ancianos (> 75 de edad) • Papel del cariotipo

  32. AZA-001 additional analysis: investigator treatment selection of CCR N=358 BSC LDAC Chemo 222 94 42 Randomisation AZA 117 BSC 105 AZA 45 LDAC 49 AZA 17 Chemo 25 Lancet Oncol 2009;10:223–32

  33. Additional Analysis: Median OS by Investigator Selection 33

  34. AZA-001: OS – azacitidine versus LDAC(Brit J Haematol, 2010) 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)

  35. AZA 001 trial: azacytidine vs LD AraC(Brit J Haematol, 2010)

  36. AZA 001 trial: azacytidine vs LD AraC(Brit J Haematol, 2010)

  37. AZA 001 trial: azacytidine vs LD AraC(Brit J Haematol, 2010)

  38. AZA 001 trial: azacytidine vs LD AraC(Brit J Haematol, 2010)

  39. Subanalisis del ensayo AZA 001 • Analisis azacitidina vs LD araC • Pacientescon 20-30% blastos medulares • Ancianos (> 75 de edad) • Papel del cariotipo

  40. AZA-001: OS with azacitidine in patientswith 20–30% blasts 1.0 Log-rank p=0.005 HR= 0.47 (95% CI: 0.28–0.79) Deaths: azacitidine = 24, CCR = 41 0.9 0.8 0.7 50.2% 0.6 24.46 months Azacitidine Proportion surviving 0.5 0.4 15.9 months 0.3 0.2 0.1 15.9% CCR 0 0 5 10 15 20 25 30 35 40 Time (months) from randomisation Number at risk AZA 55 43 38 26 15 10 4 1 0 CCR 58 43 36 22 6 3 0 0 0 JCO , in press

  41. Marrow CR Rates (6/11) P value, P=0.80 % of pts with CR (10/55) (9/58) (0/27) (3/20) CCR Regimens

  42. Infections, Hospitalizations Rates of Infections Requiring IV Antibiotics and Rates of Hospitalization P=0.05 P=0.003 AZA CCR AZA CCR InfectionsRequiringIV Antibiotics Hospitalization

  43. OS according to response Landmark analysis day 90 after C1

  44. Subanalisis del ensayo AZA 001 • Analisis azacitidina vs LD araC • Pacientes con 20 -30% blastos medulares • Ancianos (> 75 de edad) • Papel del cariotipo

  45. AZA 001 trial: results in patients > 75 years(Seymour J, 2011) • 87 patients (24%) ≥75 years • Median age 78 • Median OS : AZA group not reached vs 10.8 months in the CCR group (HR: 0.48 p = 0.0193). • 2 year OS rates : AZA vs CCR: 55% vs 15% (p = 0.0003).

  46. AZA in patients aged over 80 • response : • Overall response rate : 34% (CR: 15%. PR 5%. marrow CR 7%. SD with HI 7%) • Similar to that of patients < 80 (p=0.6) • survival • Median OS 17.1 months • Similar in pts < 80 (p=0.6) Age <80 Age ≥80 OS months

  47. Subanalisis del ensayo AZA 001 • Analisis azacitidina vs LD araC • Pacientes con 20 -30% blastos medulares • Ancianos (> 75 de edad) • Papel del cariotipo

  48. Median overall survival per frequent cytogenetic abnormalities (Mufti, ASH 2009)

  49. 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”

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