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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 Pierre Fenaux Hôpital AvicenneParis 13 UniversityInserm U 848France 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 0 30 60 90 120 150 180 210 Days of treatment
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
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
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
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
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
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
Duration ofresponse (IWG 2006) (Park, Kelaidi, Blood 2008) Median 24 months
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
EPO treated versus IMRAW cohort (transfusions only): Overall survival (Park, Blood 2008)
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% • :
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)
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%
Treatment of MDS with del 5q: EPO (or darbepoetin) +/- G-CSF (Kelaidi, ASH 2006, abstr n° 2678 )Park ,ASH 2006, abstr n° 522)
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
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)
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].
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].
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
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
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
Baseline characteristics of patients of patients treated with or without Lenalidomide
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
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.
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)
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%.
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
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
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
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)
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
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
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
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)
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
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.
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)
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
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
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)
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
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
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)
Tratamiento de la trombopenia • Interleukinas (3, 6,11) ? • Androgenos (danazol) • A veces: destruccion periferica de las plaquetas • Agonistos de receptores de TPO
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.
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
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