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Manejo de los SMD de riesgo bajo

Manejo de los SMD de riesgo bajo. Pierre Fenaux H ôpital Avicenne Paris 13 University Inserm U 848 France Oviedo 3/2011. Manejo de las citopenias en SMD de riesgo bajo ?. Anemia Neutropenia Trombopenia. EPO. 14. Blood transfusion. Transfusion given. 12. 10. Hb (g/dL). 8. 6. 4.

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Manejo de los SMD de riesgo bajo

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

  2. Manejo de las citopenias en SMD de riesgo bajo ? • Anemia • Neutropenia • Trombopenia

  3. EPO 14 Blood transfusion Transfusion given 12 10 Hb (g/dL) 8 6 4 0 30 60 90 120 150 180 210 Days of treatment

  4. Quality of Life is correlated to Hb levels 65 60 Quality of Life (LASA, mm) 55 50 45 7 8 9 10 11 12 13 14 Hb level (g/dl) Crawford et al. Cancer 2002; 95: 888–95 LASA: Linear Analog Scale Assessment

  5. RBC transfusions in MDS( Bardiaux et al 2003) MDS represent - 3% of all RBC units transfused - 24% of hospitalizations for transfusion Mean monthly cost for transfusions: 810 euros

  6. Como evitar trasfusiones de GR en SMD de riesgo bajo? • Tratamiento de primera linea • ASE (EPO y darbepoetina) • Tratamiento de secunda linea • Lenalidomida ( del 5q) • Immunosupression (ATG+/- ciclo) • Talidomidea • Lenalidomida (non del 5q) • Hipometilantes

  7. Como evitar trasfusiones de GR en SMD de riesgo bajo? • Tratamiento de primera linea • ASE (EPO y darbepoetina) • Tratamiento de secunda linea • Lenalidomida ( del 5q) • Immunosupression (ATG+/- ciclo) • Talidomidea • Lenalidomida (non del 5q) • Hipometilantes

  8. A simplified validated decision model for treatment of the anemia in MDS with G-CSF + EPOPredictive value of model :p<0.001 Variable value score value score Transf. need <2 U/m 0 ≥2 U/m 1 Serum-epo <500 U/l 0 ≥500 U/l 1 Probability of response: Total score 0: 74%, score 1: 23%, score 2: 7% QoL improved in responding patients Hellstrom-Lindberg, et al, Br J Haem, 2003

  9. EPO +/- G-CSF in MDS: prognostic factors of response(Park , Kelaidi,Blood 2007) • N= 403 pts treated with EPO+/- G-CSF or Darbepoetin alpha • Hb<10g/dl (54%transfused) • 63% response (43% major, 20% minor) • Median response duration: 24 months

  10. Duration ofresponse (IWG 2006) (Park, Kelaidi, Blood 2008) Median 24 months

  11. EPO treated versus IMRAW cohort (transfusions only):Time to AML progression (Park ,Blood 2008) Comparison between IMRAW and French-EPO cohort restricted to IPSS LOW INT1 patients without unfavorable karyotype (IMRAW n=447 patients, French-EPO= 284) a) progression to AML ,p= NS

  12. EPO treated versus IMRAW cohort (transfusions only): Overall survival (Park, Blood 2008)

  13. EPO + ATRA (Itzykson, Leukemia, 2009) -inclusioncriteria : lowerrisk MDS EPO > 500 UI or previousfailure of EPO -59 ptsevaluable - Erythroidresponse overall: 49 % (IWG 2000)36% (IWG 2006) EPO resistant: 43% 32% EPO> 500 11%, 19% > 2CGR/month: 43% 39% • :

  14. Early introduction of ESA in low risk MDS patients may delay the need for RBC transfusion: a retrospective analysis on 112 patients( Park,ASH, 2009)

  15. Causes of relapse in MDS responding to EPO • Nordic MDS group(Jadersten, 2005) 39/48 relapses. Cause: • Overt Progression (n=7) • Discontinuation(n= 14)) • No clear evolution (n=18/39) • GFM(Park, Kelaidi 2008) 54/251 relapses. Cause: • Progression:28% • No clear evolution: 72%

  16. Treatment of MDS with del 5q: EPO (or darbepoetin) +/- G-CSF (Kelaidi, ASH 2006, abstr n° 2678 )Park ,ASH 2006, abstr n° 522)

  17. Como evitar trasfusiones de GR en SMD de riesgo bajo? • Tratamiento de primera linea • ASE (EPO y darbepoetina) • Tratamiento de secunda linea • Lenalidomida ( del 5q) • Immunosupression (ATG+/- ciclo) • Talidomidea • Lenalidomida (non del 5q) • Hipometilantes

  18. Lenalidomide Erythroid Response:lower riskDel 5q (List, 2006) No . Patients 148 Erythroid Response Transf -Indep Minor (>50%) TI +Minor 99 (67%) 13 (9%) 112 (76%) Time to Response 4.6 wks (1- 49)

  19. Cytogenetic response in patients with del 5q *All cytogenetic responders achieved an erythroid response. List AF, et al. Updated data presented at ASH Annual Meeting, 2006 [Abstract 251].

  20. Censored patients who remain TI at time of data cutoff or at time of study discontinuation. Duration of major erythroid response in patients with del 5q (N = 168) 100 Median duration of TI = 2.2 years Median follow-up: 1.3 years (min–max: 0.1–4.4 years) 80 60 Patients (%) 40 min–max = 0.2–4.4+ years 73% TI response ≥ 1 year 46% TI response ≥ 2 years 20 50% ongoing responders 0 0 1 2 3 4 5 Time (years) Data cutoff 4 Dec 2006 (N = 114). List AF, et al. Updated data presented at ASH Annual Meeting, 2006 [Abstract 251].

  21. Adverse Event All Grades >Grade 3 (%) Thrombocytopenia 58% 54%* Neutropenia 57% 55%** Pruritus 32% 2% Rash 28% 7% Diarrhea 24% 2% Fatigue * 12% 3% Drug-Related Adverse Events

  22. Lenalidomide in lower risk MDS with del 5q: French ATU (M Sébert, F Le Bras, ASH 2009) 95 pts 2/3 tranfusion independence (TI) Median TI duration not reached 3 deaths from cytopenias 7 cases of deep venous thrombosis 6 progressions to AML

  23. Risk of progression in lower risk MDS with del 5q treated without lenalidomide (Germing, ASH 2009) • International retrospective study in IPSS low ou int-1 with del 5q : 303 patients • variable treatments, mainly ESAs • AML progression: • 7% at 2 y • 18% at 5 y • Main predictive factors of AML progression: • % marrow blasts • Cytogenetic complexity • RBC transfusion dependence • AML risk comparable to MDS-003 and MDS-004 studies #xxx

  24. KM Kurven AML Progression nach Transfusionsbedarf

  25. Baseline characteristics of patients of patients treated with or without Lenalidomide

  26. Overall Outcome 100 100 80 80 Cum. Inc. Of AML Overall Survival 60 60 40 40 20 20 0 0 0 0 50 50 100 100 150 150 200 200 Times (Months) Times (Months) Control group Lenalidomide group Median OS 150 months vs 72.8 , p= 0.10 4 y CIR of AML 8.9% vs 15.8%; p=0.14

  27. MDS-004: study design (ASH 2009) Planned enrollment (n = 205) Double-blind phase** * LEN,orally 5 mg/day for 28 days of each 28-day cycle R A N D O M I Z E D R E S P O N S E S T R A T I F Y Responders (at least minor erythroid response at week 16): Continued double-blind treatment for up to 52 weeks, relapse or progression LEN, orally 10 mg/day for 21 days of each 28-day cycle Non responders: Discontinued double-blind treatment and entered open-label treatment or withdrew from study Placebo Week 0 4 8 12 16 52 *Patients stratified by IPSS score and cytogenetic complexity prior to randomization.**Bone marrow assessments were performed at baseline, 12 weeks, and every 24 weeks thereafter.

  28. MDS-004: RBC-TI (mITT population) * * * 61 56 * 50 *P < 0.001 vs placebo Bars represent 95% CI 41 8 6 6 IWG (≥8 weeks) Protocol defined (≥ 26 weeks)

  29. MDS-004: cytogenetic response (mITT population) *P = 0.01 vs placebo **P < 0.001 vs placebo Assessed by standard cytogenetics and FISH. CR defined as absence of chromosome 5q31 abnormality;PR defined as reduction of abnormality by > 50%.

  30. Como evitar trasfusiones de GR en SMD de riesgo bajo? • Tratamiento de primera linea • ASE (EPO y darbepoetina) • Tratamiento de secunda linea • Lenalidomida ( del 5q) • Immunosupression (ATG+/- ciclo) • Talidomidea • Lenalidomida (non del 5q) • Hipometilantes

  31. Immunosuppression in MDS(Sloand, JCO, 2008) 129 pts • 24% response (CR+PR) to ATG • 48% response to ATG+ CsA • 8% response to CsA Prognostic factors of response : • Younger age (<60 y) • HLA DR 15 • ATG+ CsA • IPSS low or int 1 If compared to IPSS data base: immunosuppression improves survival in younger patients

  32. Alemtuzumab in lower risk MDS (Sloand, ASH 2009) • IPSS int-1 et int-2, RBC transfusion dependent and/or platelets < 50 G/L and/or ANC < 0,5 G/L and predictive factors of response to immunosuppression (younger age and HLADR15+) • Campath: 1mg IV test , then 10 mg IV/d x 10 d • 24 patients evaluable; median FU 12 months, • 20 (83%) responses, after a median of 96 d, • 16 still responders, 4 relapses • Cytogenetic response in 5 of 7 patients with anomalies , including monosomy 7 #116 Olnes ORAL

  33. Should Immunosuppressive Therapy (IST) be used more often in lower risk MDS? Cereja S, Bréchignac S, Ades L, Braun T, Boehrer S, Lim EM, Hebibi Z, 2-3 gros centres du register, Sapena R Dreyfus F, Fenaux P, Gardin C GFM database: transfusion dependent anemia: • and IPSS low or int-1: 20% (<60 y) 22% (<65 y), 24% (<70 y) • and IPSS int-1 with <5 % marrow blasts (iethrombocytopenia or int karyotype): 5.5% (<60 y) 6.5% (<65 y), 6.5% (<70 y)

  34. Como evitar trasfusiones de GR en SMD de riesgo bajo? • Tratamiento de primera linea • ASE (EPO y darbepoetina) • Tratamiento de secunda linea • Lenalidomida ( del 5q) • Immunosupression (ATG+/- ciclo) • Talidomida • Lenalidomida (non del 5q) • Hipometilantes

  35. Thalidomide and lower risk MDS(D Bouscary,BJH 2005; F Tamburini, Leuk Res, 2009) • > 130pts • 50 tp 800 mg /d • 35 % responses • Short and medium term side effects

  36. Como evitar trasfusiones de GR en SMD de riesgo bajo? • Tratamiento de primera linea • ASE (EPO y darbepoetina) • Tratamiento de secunda linea • Lenalidomida ( del 5q) • Immunosupression (ATG+/- ciclo) • Talidomida • Lenalidomida (non del 5q) • Hipometilantes

  37. Feature Total n 166 Erythroid response, n (%) major Minor (> 50% ) major + minor 58 (27) 36 (17) 94 (44) , Median time to response, weeks [range] 4.5 [0.3–39.1] Lenalidomide erythroid response non del 5q Raza, Blood, 2008)

  38. 1.0 0.9 Del 5q 0.8 0.7 0.6 Non del 5q Proportion transfusion free 0.5 Median follow-up: 58 weeks Median duration TI MDS-003: > 47 weeks MDS-002: 43 weeks Range: 8.6–66+ weeks 0.4 Ongoing Discontinued 0.3 0.2 0.1 0 0 10 20 30 40 50 60 70 Time (weeks) Duration of transfusion independence

  39. Lenalidomide (LEN) in lower-risk myelodysplastic syndromes (MDS) with karyotypes other than deletion 5q and refractory to erythropoiesis-stimulating agents (ESAs) ( ASH 2010) David Sibon, Giovanna Cannas, Fiorenza Baracco, Thomas Prebet, Norbert Vey, Anne Banos, Caroline Besson, Selim Corm, Michel Blanc, Borhane Slama, Hervé Perrier, Pierre Fenaux, and Eric Wattel. -31 patients -13 (42%) erythroid response (IWG 2006 criteria) - Median response duration was 12 months - erythroid responses lower patients who developed neutropenia or thrombocytopenia: 1/8 vs 12/23, p = 0.038.

  40. Lenalidomide in lowerrisk MDS without del 5q (A Toma, F Dreyfus) • Randomized GFM phase II trial Lenalidomide +/- EPO beta In patients CLEARLY resistant to ESAs (at least 12 weeks using 60000 U/ w EPO or 250ug/w Darbepoetin)

  41. MDS 005 study (Celgene) • Lenalidomide versus placebo • Low and int risk MDs without del 5q • Resistant to ESA, or having both baseline EPO> 500 U/l and RBC transfusion requirement >2 units /month

  42. Hypomethylating agents in lower risk MDS • 30 to 40% erythroid responses • Azacytidine (Silverman, 2002; Lyons, 2007) • Decitabine (Wijermans, 2005; Kantarjian, 2007) • Italian experience with azacitidine(Musto, Cancer, 2010) • 61 patients • 41% tranfusion independence

  43. AZA in lower risk MDS (S Boehrer, C Gardin) • Randomized phase II trial AZA+/- EPO beta In patients CLEARLY resistant to ESAs (at least 12 weeks using 60000 U/ w EPO or 250ug/w Darbepoetin)

  44. Ensayo aleatorizado AZA ± EPO en SMD de riesgo bajo resistentes a EPO(analisis intermedia) • AZA 75 mg/m²/j 5 j/28j ± EPOβ 60 000 UI/semana Pacientes Respuestas IWG 2000 a 6 ciclos (n=52) S. Boeher et al,. ASH 2010, # 1880

  45. Azacitidina en el registro AVIDA en EEUU (Komrokji, EHA 2010) • N=434, 52% > 75 anos • AZA 7d(13%) ou 5 d (52%) /4semanas, o 5-2-2 (16%) • 68% faible riesgo bajo, 32% riesgo alto • Numero mediano ce ciclos: 4 • 60% HI

  46. Tratamiento de la neutropenia • No beneficio demostrado de utilizar G-CSF a lo largo plazo • antibioticos and antifungales profilacticos ? • antibioticos largo spectro en caso de fiebre (Amoxicilina- acido clavulanico-ciprofloxacina)

  47. Tratamiento de la trombopenia • Interleukinas (3, 6,11) ? • Androgenos (danazol) • A veces: destruccion periferica de las plaquetas • Agonistos de receptores de TPO

  48. Treatment of thrombocytopenia Romiplostin (AMG 531 in lower risk MDS) (Kantarjian, JCO, in press) 67% 70 64% 60 50% 50 36% 40 Responsea Rate (%) 30 20 10 0 300 μg n = 6 700 μg n = 11 1000 μg n = 11 1500 μg n = 16 a: increase from baseline in platelet count by 30 x 109/L for patients starting with >20 x 109/L platelets, or an increase from <20 x 109/L to >20 x 109/L and by at least 100%.7 • Platelet response achieved in 52% of patients overall.

  49. R A N D O M I Z A T I O N ENROL LMENT Romiplostim in MDS (Kantarjian, ASH 2008) Treatment Period S C R E E N I N G Four 28-day cycles of azacitidine Placebo Romiplostim 500 µg Romiplostim 750 µg Stratification by pre Rx PLTs < or ≥ 50 X 109/L Romiplostim and placebo s.c. weekly

  50. Platelet Counts Per Azacitidine Cycle Nadir Baseline (Day 1) 350 150 300 125 250 100 200 Platelet Counts (x 109/L) 75 150 50 100 25 50 13 11 11 10 13 10 10 9 14 13 11 10 13 11 11 10 13 10 10 9 14 13 11 10 0 0 Aza Cycles 1-4 AzaCycles 1-4 AzaCycles 1-4 Aza Cycles 1-4 AzaCycles 1-4 AzaCycles 1-4 Placebo 500 µg 750 µg Placebo 500 µg 750 µg

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