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					Manejo de los SMD de riesgo alto:

                    Pierre Fenaux
                      Hôpital 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

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


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


•   Retrasar la progresion
•   aumentar la supervivencia
•   Mejorar las citopenias
•   Mejorar la calidad de vida
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
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
    SMD: alo transplante « clasico »


• Necesita
  – Donante HLA identical
  – Edad <45-50



• Resultados:
  – 45-50% curacion
  – 25% recaidas
  – 25% MRT
           SMD: alo trasplante
            no mielo ablativo

- Extende la indication hasta 65-70 anos
- meno toxicidad…pero mas recaidas
    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%
Fewer relapses after allo SCT than chemotherapy

 • Retrospective analysis of 36 non myeloablative allografts and 110
   patients treated with intensive chemotherapy

      1.0

      0.9

      0.8

      0.7                                              allo
                                                       Chemotherapy
      0.6

      0.5

      0.4

      0.3

      0.2

      0.1
                P<0.0004
       0

            0              5   10            15       20                 25
                                    Années



                                                           Abs 1125 – Po I-230 – Y A EFEBERA et al.
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. Platzbecke et al., ASH 2010, # 3500 – 2) Field et al., ASH 2010, # 2381
 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
  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
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
    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
               Survival
with Anthracycline-AraC Chemotherapy
100                                                      1.
                                                          0
80                                                    0.8
 Survival (%)




                                     N = 99




                                                  Probability
60




                                                   Survival
                                                      0.6

40
                                                      0.4

20
                                                      0.2

  0
   0            20   40   60   80   100 120 140       0.0
                                                         0          100     200   310       410   520
                                                                               Weeks
          Wattel E. et al.                                      With Permission of E Estey, MD
          Br J Haematology. 1997;98:983-991.
                                   Intensive Chemotherapy
                                  (MDAnderson Experience)

                             1.0
                             0.8
Probability of Relapse or




                                                                  Idarubicin-AraC
    Death After CR




                                                                  Fludarabin-AraC
                            0.6




                                                                  Topotecan-AraC
                            0.4
                            0.2
                            0.0




                                   0   100       200        300        400
                                             Time (weeks)
     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
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
          Azacitidine Survival Study
              (Lancet Oncol, 2009)

                                      AZA 75 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
                                  Overall Survival: Azacitidine vs CCR
                                                  ITT Population
                                                               Log-Rank p=0.0001
                            1.0
                                                           HR = 0.58 [95% CI: 0.43, 0.77]
                            0.9
                                                           Deaths: AZA = 82, CCR = 113
     Proportion Surviving




                            0.8
                            0.7
                                                              Difference: 9.4 months
                            0.6                                  50.8%
                            0.5                                       24.4 months
                            0.4           15 months                 26.2%
                            0.3                                                        AZA
                            0.2                                                  CCR
                            0.1
                            0.0
                                  0   5      10       15    20     25       30   35    40
                                             Time (months) from Randomization


22
     Hazard Ratio and 95% CI for Overall Survival
     ITT Subgroups                                                             Total - Event / N
                                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
             Cytogenetics: Good                                                     80 / 167
                     Intermediate                                                   38 / 76
                              Poor                                                  67 / 100
            Karyotype: -7/del (7q)                                                  42 / 57
                  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
                   LDH: ≤ 240 U/I                                                   97 / 208
                          > 240 U/I                                                 94 / 145
                                      0.125   0.250   0.500   1    2       4
23
                                        Favors Azacitidine        Favors CCR
         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
Prolonged treatment with Azacytidine improves responses
in MDS
  •   response after 2 to more than 6 cycles
  • Continuing treatment improves responses in 48% of the cases



                                    1.0

                                    0.9

                                    0.8
              Probabilité cumulée




                                                               87%
                                    0.7                     (6 cycles)
                                    0.6

                                    0.5

                                    0.4           50%                         Extrêmes : 1-22 cycles
                                    0.3        (2 cycles)
                                    0.2

                                    0.1

                                      0
       Temps (cycles) :                   0    3       6           9     12       15        18         21         24

       Nombre de cas :                    91   34      12          6     3         1        1          1
                                                                                                            Abs 227 – CO – L R SILVERMAN et al.
                   Secondary Endpoints:
                  IWG (2000) CR,PR and HI

                    AZA   CCR               P-Value
                   N=179 N=179              AZA vs
Response            (%)   (%)                CCR
Overall (CR+PR)     29    12                0.0001
 CR                 17     8                  0.02
 PR                 12     4                 0.009
IWG HI
 Major+Minor        49    29                <0.0001
      AZA-001: 2-year OS with azacitidine by best
                 response (IWG 2000)

                                                    1.0
                                                                                              78.4%
                                                    0.8                                        71.7%
                                                                                                                   HI
                 Proportion of patients surviving




                                                    0.6                                                PR
                                                                                                             CR
                                                    0.4

                                                    0.2                                                          CCR


                                                     0
                                                          0   5   10      15       20       25       30       35            40
                                                                  Time from randomisation (months)

IWG = International Working Group; HI = haematological improvement                                          Adapted from List AF, et al. Oral presentation at
PR = partial response; CR = complete response                                                                     ASCO 2008, Chicago, IL [abstract 7006]
  Response and OS in 282 higher-risk MDS
treated with Azacitidine:French ATU program
             (Itzykson,Blood, 2011)
                          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
        Subanalisis del ensayo AZA 001

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

• Analisis azacitidina vs LD araC
• Pacientes con 20 -30% blastos medulares
• Ancianos (> 75 de edad)
• Papel del cariotipo
AZA-001 additional analysis: investigator treatment selection of
                             CCR

                           N=358

      BSC                    LDAC                   Chemo
      222                     94                     42
                        Randomisation



AZA         BSC        AZA          LDAC      AZA         Chemo

117         105         45           49        17              25
                                                      Lancet Oncol 2009;10:223–32
        Additional Analysis: Median OS by Investigator
                           Selection
                                      Differences
                           K-M OS    K-M OS Time   Hazard    Log-
     Treatment            Time mos       mos        Ratio   rank P
                           21.1
     AZA (N=117)
     vs
     BSC (N=105)           11.5         9.6        0.56     0.002
                           24.5
     AZA (N=45)
     vs
     LDAC (N=49)           15.3         9.2        0.58     0.015
                           25.1
     AZA (N=17)
     vs
     Stand Chemo (N=25)    15.7         9.4        0.87     0.75
33
         AZA-001: OS – azacitidine versus
                     LDAC
                                    (Brit J Haematol, 2010)

                          1.0
                                                                             Azacitidine
                          0.9                                                LDAC
                          0.8
Probability of survival




                          0.7

                          0.6

                          0.5

                          0.4

                          0.3

                          0.2
                                0   10                 20               30                 40
                                     Time from randomisation (months)
                   AZA 001 trial: azacytidine vs LD AraC
                         (Brit J Haematol, 2010)

                         AZA          LD araC
n                        45           49
Median n° cycles         9            4.5
Median OS                24.5         15.3         P<0.001
OS fav karyotype         NR           19           HR=0.46
OS unfav karyo           24.5         2.9          HR=0.07
CR+PR                    31%          12%          P=0.046
HI                       53%          25%          P=0.006
Transf indep             45%          13%          P=0.01

Severe infections/pt year 0.44        1            P=0.017

Median days in           18           27           P<10-4
hospital/pt year
                   AZA 001 trial: azacytidine vs LD AraC
                         (Brit J Haematol, 2010)

                         AZA          LD araC
n                        45           49
Median n° cycles         9            4.5
Median OS                24.5         15.3         P<0.001
OS fav karyotype         NR           19           HR=0.46
OS unfav karyo           24.5         2.9          HR=0.07
CR+PR                    31%          12%          P=0.046
HI                       53%          25%          P=0.006
Transf indep             45%          13%          P=0.01

Severe infections/pt year 0.44        1            P=0.017

Median days in           18           27           P<10-4
hospital/pt year
                   AZA 001 trial: azacytidine vs LD AraC
                         (Brit J Haematol, 2010)

                         AZA          LD araC
n                        45           49
Median n° cycles         9            4.5
Median OS                24.5         15.3         P<0.001
OS fav karyotype         NR           19           HR=0.46
OS unfav karyo           24.5         2.9          HR=0.07
CR+PR                    31%          12%          P=0.046
HI                       53%          25%          P=0.006
Transf indep             45%          13%          P=0.01

Severe infections/pt year 0.44        1            P=0.017

Median days in           18           27           P<10-4
hospital/pt year
                   AZA 001 trial: azacytidine vs LD AraC
                         (Brit J Haematol, 2010)

                         AZA          LD araC
n                        45           49
Median n° cycles         9            4.5
Median OS                24.5         15.3         P<0.001
OS fav karyotype         NR           19           HR=0.46
OS unfav karyo           24.5         2.9          HR=0.07
CR+PR                    31%          12%          P=0.046
HI                       53%          25%          P=0.006
Transf indep             45%          13%          P=0.01

Severe infections/pt year 0.44        1            P=0.017

Median days in           18           27           P<10-4
hospital/pt year
       Subanalisis del ensayo AZA 001

• Analisis azacitidina vs LD araC
• Pacientes con 20-30% blastos medulares
• Ancianos (> 75 de edad)
• Papel del cariotipo
                                         AZA-001: OS with azacitidine in patients
                                                  with 20–30% blasts
                          1.0
                                                                               Log-rank p=0.005
                          0.9                                                  HR= 0.47 (95% CI: 0.28–0.79)
                          0.8                                                  Deaths: azacitidine = 24, CCR = 41
   Proportion surviving




                          0.7
                                                                                50.2%
                          0.6
                                                                                        24.46 months        Azacitidine
                          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
                                     Marrow CR Rates
                   70

                   60
                                                                (6/11)
% of pts with CR




                   50    P value, P=0.80

                   40

                   30
                           18              16
                   20
                        (10/55)            (9/58)   (3/20)                  (0/27)
                   10

                    0
                          AZA          CCR


                                                             CCR Regimens
                                             Infections, Hospitalizations
      Rates of Infections Requiring IV Antibiotics
             and Rates of Hospitalization

                        6
                                               P=0.05

                        5
Rate Per Patient Year




                                                   4,3
                        4
                              P=0.003
                                             3,4
                        3

                        2
                                   1,14
                        1   0,58
                            AZA CCR          AZA CCR
                        0
                              Infections     Hospitalization
                              Requiring
                            IV Antibiotics
OS according to response
                              Landmark Analysis




                                          Hematological Improvement
                                          Progression
    1
                                          RC+RP
                                          Stable disease

   0.8



   0.6



   0.4



   0.2

             p < 0.0001

    0


         0      3         6          9       12       15        18




  Landmark analysis day 90 after C1
        Subanalisis del ensayo AZA 001

• Analisis azacitidina vs LD araC
• Pacientes con 20 -30% blastos medulares
• Ancianos (> 75 de edad)
• Papel del cariotipo
         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).
         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)
                                                1
                                                                           Age <80
                                                ,8
• survival                                                                 Age ≥80




                                  Survie Cum.
                                                ,6

  – Median OS 17.1 months

                                    OS
                                                ,4


  – Similar in pts < 80 (p=0.6)                 ,2


                                                0

                                                     0   5   10   15   20   25   30   35   40   4
                                                                        Temps
                                                                        months
        Subanalisis del ensayo AZA 001

• Analisis azacitidina vs LD araC
• Pacientes con 20 -30% blastos medulares
• Ancianos (> 75 de edad)
• Papel del cariotipo
       Median overall survival per
   frequent cytogenetic abnormalities
                            (Mufti, ASH 2009)

karyotype      Patient n°    Median OS AZA   Median OS CCR   HR

Del 5q
-not complex   15            25.1            17.3            0.43
- complex      29            9.9             4.9             0.55
- 7/ 7q-
-not complex   27            24.5            8.1             0.33
- complex      30            5.3             3.9             0.45
+8
-not complex   28            26.3            8.7             0.20

- complex      18            17.3            4.9             0.43
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”
Improvement in progression free survival, but not
survival


 100
                                                                       100
  90
                         progression free survival                                                 Overall survival
                                                                       90
  80
                                                                        80
  70                                                                                                     Médian (mnthss) : 10,1 vs 8,5
                                 Médian (months) : 6,6 vs 3            70                                HR = 0,88, 95% CI (0,66; 1,17)
  60                             HR = 0,68, 65% CI (0,52, 0,88)                                          p=0,38
                                                                        60
                                 p=0,004
  50
                                                                       50
  40
                                                                       40
                                                                                                    Decitabine
  30                               Decitabine                          30
                                                                                 Supportive care
  20                                                                    20
           Supportive care
  10                                                                   10
   0                                                                     0
       0        6        12       18       24        30           36         0    6                 18         24        30          36          42
                                                                                       12
                                   Mois                                                                   Mois


                                                                                                                      Abs 226 – CO – P WIJERMANS et al.
                   Alternative protocols of decitabine?
                        Decitabine 20mg/m2/jx5 IV

Dose ( 4 w cycles )                        Nb CR(IWG 2006) /Total (%)

20 mg/m2/j x 5 d IV                                  33 (39)*

10 mg/m2 x2/j x 5 dSC                                  3 (21)

10 mg/m2/j x 10 d IV                                   4 (24)




* Statistically significant




                                         Kantarjian et al. Cancer 2007;109:1133, 207
    Biological prognostic factors of response to
             hypomethylating agents ?
• Early epigenetic changes do not predict clinical
  response to AZA+ entinostat (Fandy, Blood, 2009)
• A methylation score predicts clinical response to
  decitabine (Shen ,JCO, 2010)
• Reduction in Phosphoinosisitide-phospholipase(PI-PL)C
  beta 1 methylation precedes response to azacitidine
  (Follo MY, PNAS 2009
• High levels of miR-29b associated to clinical response
  to decitabine (Blum ,PNAS, 2010)
• P53 inducible ribonucleotide reductase (p53R2) ? (a DNA
  hypomethylation independent decitabine gene target) correlates
  with clinical response in MDS/AML (Link, Cancer Res, 2008)
Factores pronosticos del tratamiento con AZA ?

                                ATU francesa 282 pacientes
                                validacion con los pacientes del estudio AZA-001 161 pacientes

                                                                                                Analisis multivariada                       HR 95% CI         p        puntuacion
                                           Cohorte d’ATU (développement)
                                                                                                Performance status                         2,0 [1,4-2,9]      <10-4            1
                                                                      bajo
                                                                      Intermedio                ≥ 4 unidades de GR/8 semanas               1,9 [1,4-2,6]      <10-4            1
                                                                      alto                      Presencia de blastos circulantes           2,0 [1,5-2,7]      <10-4            1
                                 1,0

                                                                                                Citogenetica (IPSS)                                           <10-4
                                 0,8                                                            Riesgo intermedio                          1,4 [0,8-2,3]                       1
                                                                                p<0,0001
 Probabilité cumulée de survie




                                                                                                Desfavorable                               3,0 [2,0-4,3]                       2
                                 0,6                                                                                                   ATU (n=269)             AZA-001 (n=152)
                                                                                                                                              Survie                      Survie
                                                                                                Grupo, de riesgo      Score                  médiane                     médiane
                                 0,4                                                                                           (N,%)                       (N,%)
                                                                                                                                             globale                     globale
                                                                                                                                              (mois)                      (mois)

                                 0,2                                                                                             30                          23
                                                                                                bajo                   0                        NR                          NR
                                                                                                                               (11%)                       (15%)
                                                                                                                                191                         114
                                                                                                Intermedio             1-3                     15,0                         21,4
                                 0,0                                                                                           (71%)                       (75%)
                                       0    6   12   18   24    30    36   42    48   54   60                                    48                          15
                                                                                                Elevado                4-5                      6,1                         9,3
                                                               Mois                                                            (18%)                       (10%)


                                                                                                                                                           R. Itzykson et al.,Blood , 2011
mutaciones de TET2: factor predictivo
de respuesta a Azacitidina
  Résultatos

                                   Todos     TET2 mutado   TET2 non mutado               p*
      Pacientes                     103       17 (17%)        86 (83%)
      Ciclos de AZA               7 [1-39]     11 [4-34]       6 [1-39]               0,016
      Citogénética desfavorable
                                  30 (34%)      1 (7%)        29 (39%)                 0,01
      (IPSS)
      RC                          24 (23%)     7 (41%)        17 (20%)                 0,07
      RC+ HI                      53 (52%)    14 (82%)        39 (45%)                0,007



  Impacto de TET2 sobre la respuesta, independiente de otros factores
  Sin impacto sobre duracion de respuesta o supervivencia



                                                                   R.   Itzykson et al.,Leukemia, in press
Otros factores pronosticos de respuesta a AZA?



           Mutaciones d’EZH2                       V.

            GROSSMAN et al. ASH 2010, # 296 – CO


           Citometria de flujo?
            C. ALHAN et al., ASH 2010, # 441 – CO
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
El pronostico de SMD despues del fracaso de Azacitidina es muy
desfavorable
Introduction
 Despues del fracaso de decitabina : mediana de supervivencia de 4 meses (Jabbour, Cancer 2010)

Pacientes de 3 estudios                                   prospectives
 AZA 001 n=138
 J9950/J0443 n=58                                                                              Population

 ATU française n=369                                 Âge médian (ans)                             69 ans
                                                      SMD/LAM                                     341/224
                                                      Blastes médullaires avant AZA
                                                      - < 10%                                    129 (23%)
                                                      - 10% à 20%                                269 (47%)
                                                      - > 20%                                    167 (30%)
 fracaso:                                             Cytogénétique
      primario 55%,                                   - Favorable                                219 (39%)
                                                      - Intermédiaire                            138 (24%)
     recaida 37%                                      - Haut risque                              208 (37%)
     intolerencia 8%                                  Traitement de 1ère ligne par AZA           294 (52%)
                                                      Durée médiane de traitement             6 cycles (1-41)


                                                                                         T. Prébet et al., ASH 2010, # 443
El pronostico de SMD despues del fracaso de Azacitidina es muy
desfavorable

                               Supervivencia segun el tratamiento recibido (n=350)



                                     Traitement de support
                                     Chimiothérapie
                   100               Médicaments à l’étude
                                     Inconnu                                                                       OS mediana
                                     Allogreffe                               Tratamiento     N=    ORR
                                                                                                                    (meses)
                   75
  Survie globale




                                                                              desconocido     215    NA                   3.6
                   50
                                                                              supporte        160    NA                   3.3
                                                                                                                                            *
                                                                                                    1/25 et
                                                                              quimoterapia    84                          7.6
                   25                                                                                5/33
                                                                                                                                            **
                                                                              Nuevas drogas   56     4/39                13.2
                    0
                         0   365       730      1095      1460         1825
                                                                              Alo TPH         50    17/25                18.3
                             Jours après échec du traitement par AZA




                                                                                                              T. Prébet et al., ASH 2010, # 443
Otros farmacos en SMD de riesgo alto


  Clofarabina oral          Flinn et al., # 4015, ASH 2010

  Vorinostat - G. Garcia-Manero et al., # 232, P. Wu et al, # 782, ASH 2010

  Panobinostat - IW. Flinn et al., # 4015, ASH 2010



  Entinostat -        T. Prebet et al., # 601, ASH 2010


  Lenalidomida -           U. Platzbecker et al., # 4000, DA. Pollyea et al., # 3288,
   ML. Huetter et al., # 3297, ASH 2010


  On 01910. Na -          LR. Silverman et al., # 3998, M. Seetharam et al., # 4010, ASH 2010


  Gemtuzumab -            ED. Ball et al., # 3286, ASH 2010


  Inhibitores de mTOR-               AH. Wei et al., # 3301, ASH 2010
                   Clofarabine in MDS:
Response                   IV-15 (n = 20)   IV-30 (n = 16)
Overall Response             10 (50%)         6 (33%)
 Complete response           7 (35%)          4 (25%)
 Hematologic improvement     3 (15%)          2 (13%)




Grade ≥ 3 Adverse Events   IV-15 (n = 20)   IV-30 (n = 16)
Edema                           5%              25%
Increased ALT/AST               0/0           13%/6%
Hyperbilirubinemia              5%              13%
Acute Renal Failure            10%              19%
6-Week Mortality             2 (10%)          2 (13%)


                                                        Faderl et al. ASH 2008, Abstract 222
  Tratamineto de secunda linea en
        SMD de riesgo alto

• Clofarabine bajas dosis (C Gardin, T Braun)

• Erlotinib (S Boehrer)

• On 01910. Na (Onconova)
Valorar combinaciones con Azacitidina, para mejorar sus
resultados

  Clofarabina oral          Flinn et al., # 4015, ASH 2010

  Vorinostat - G. Garcia-Manero et al., # 232, P. Wu et al, # 782, ASH 2010

  Panobinostat - IW. Flinn et al., # 4015, ASH 2010



  Entinostat -        T. Prebet et al., # 601, ASH 2010


  Lenalidomida -           U. Platzbecker et al., # 4000, DA. Pollyea et al., # 3288,
   ML. Huetter et al., # 3297, ASH 2010


  On 01910. Na -          LR. Silverman et al., # 3998, M. Seetharam et al., # 4010, ASH 2010


  Gemtuzumab -            ED. Ball et al., # 3286, ASH 2010


  Inhibitores de mTOR-               AH. Wei et al., # 3301, ASH 2010


          Todavia no hay prueba de la eficacidad de estas asociaciones
                   Histone deacetylase (HDAC)
                            inhibitors
                                                  Butyrate derivatives,
Short-chain fatty acids (SCFA)
                                                  Valproic acid

                                                  Trichostatin A, SAHA (Vorinostat)
Hydroxamic acids
                                                  LHB 589 Pyroxamide


Epoxyketone-containing cyclic tetrapeptides       Trapoxins



Non-epoxyketone-containing cyclic tetrapeptides   FK228, Apicidin



Benzamides                                        MGCD-0103, MS-275
   5-AZA + Valproic acid + ATRA in Leukemia (Soriano,
                               Blood, 2007)


      VPA                                       OR       Courses to
                     N    CR   CRp    BM
     (mg/kg)                                   N (%)      response

       50            40   10    3      6       19 (47)     1(1-3)


       62.5          7    1     0      0       1 (14)        2


       75            6    1     0      1       2 (33)        1


      Total          53   12    3      7       22 (42)    1 (1-3)



  Untreated          33   11    3      3      17 (52)     1 (1-3)



Previously Treated   20   1     0      4       5 (25)      1(1-2)
A Phase I/II study of vorinostat in combination with 5-
           azacitidine in patients with MDS


                                  5-azacitidine

                                                     Vorinostat – cohorts 1-4

                                                     Vorinostat – cohorts 5-7

                                                     Vorinostat – cohort 8
        0                   7             14                  21              28
                                          Day
            This represents 1 cycle. Cycles repeated every
                  28 days for a minimum of 4 cycles

                                    Silverman et al. J Clin Oncol 26: 2008 (May 20 Suppl; abs 7000)
            Azacitidine and Vorinostat in MDS / AML – NYCC 6898
                                              Response


                     Enrolled                            28
                     Evaluable for response              22
                     Overall Response*                   18 (82%)+
                     CR                                   9   (41%)
                     CRi                                  3   (14%)
                     CR+CRi                              12   (55%)
                     PR                                   5 (05%)
                     HI                                   5   (23%)

*IWG 2000 MDS        Stable                               2   (09%)
 IWG 2006 MDS        NR                                   2   (09%)
 IWG AML             Too Early                            1
+ResponseConfirmed   IE for response                      3
by NCI Audit
                     Withdrew prior to Rx/Ineligible      2
                     Transfusion Independence (n = 13)   11 (84%)
          Decitabine With or Without Valproic
          Acid in Patients With MDS and AML




Eligibility criteria:        R
• MDS by FAB of any age      A
• AML age > 60               N   Decitabine 20 mg/m2 IV/1 h daily days 1-5 q 4 weeks
• No good-risk AML           D
• No prior high-dose         O
  chemotherapy               M
• No prior decitabine > 1    I   Decitabine 20 mg/m2 IV/1 h daily days 1-5 q 4 weeks
  cycle or azacitidine > 2   Z   Valproic acid 50 mg/kg/day p.o. days 1-7 q 4 weeks
  cycles                     E


                                                                Issa et al. ASH 2008, Abstract 228
Ensayo fase II de AZA ± Entinostat
                                                                                 Supervivencia Global
  Respuesta (IWG 2000)                                          1.00

                                                                0.80
                                                                                                          Suivi 17 mois
                           Bras A         Bras B
                         AZA seule   AZA + Entinostat
                                                                0.60
 RC                        12%             7%
                                                                0.40
 RP                         9%             7%
 HI (3 lineas)             10%            10%                   0.20
                                                                           p=0.15
 HI (1 o 2 linaes)         12%            19%                   0. 0

 Ausencia de respuesta     57%            56%                          0            10             20            30           40
                                                                                                   Mois

                                                                                                                             Médiane
                                                        Traitement                       Total10   Décès        Censure
                                                                                                                            SG (mois)

                                                        Azacitidine                       68         40           28           17.7

                                                        Azacitidine+Entinostat            68         47           21           12.8




                                                                                                   T. Prebet et al., ASH 2010, # 601 & # 4013
           Azacitidine plus lenalidomide in patients
             with higher-risk MDS: phase I study
                                                                               Treatment regimen
                                                                            (28-day cycles; ≤7 cycles)
                                                                                                              Lenalidomide
        Aim                                                       Regimen     Azacitidine schedule              schedule
                                             Patients (n=18)
    Azacitidine +
                                                                   1                                         5mg days 1–14
  lenalidomide in                         RAEB-1 = 21% RAEB-
 six dose regimens                        2 = 53% CMML = 5%
                                          Int-1 = 16%              2               75mg/m2                   5mg days 1–21
     Objectives:                          Int-2 = 47%                              days 1–5
       safety,                            High = 32%               3                                        10mg days 1–21
        MTD,
        DLTs,                             Only one patient with
                                                                   4                                         5mg days 1–14
      efficacy                            chromosome 5q
                                          deletion
                                                                   5              50mg/m2                    5mg days 1–21
                                                                                days 1–5, 8–12
                                                                   6                                        10mg days 1–21



                                                                                     Sekeres MA, et al. Oral presentation at ASH 2008
MTD = maximum tolerated dose; DLT = dose-limiting toxicity                                             Blood 2008;112:[abstract 221]
                                      Azacitidine plus lenalidomide in patients
                                           with higher-risk MDS: efficacy
 RR (% evaluable patients, n=17)




                                                                         Cohort   Grade 3–4 toxicity          Maximum response
                                                                         1                1                           2 CR,
                                                                                                                  1 progression
                                                                         2                2                     1 CR, 1 PR, 1 HI
                                                                         3                0                        2 CR, 1 SD
                                                             ORR = 71%   4                2                        2 CR, 1 SD
                                                                         5                2                        1 HI, 1 SD,
                                                                                                                  1 progression
                                                                         6                2                     1 HI, 1 BM CR,
                                                                                                                1 not evaluable



•                                  These early results suggest superior efficacy versus monotherapy in patients
                                   with higher-risk MDS
                                                                                              Sekeres MA, et al. Oral presentation at ASH 2008
RR = response rate; ORR = overall RR; SD = stable disease                                                       Blood 2008;112:[abstract 221]
    « Pick a winner approach » with AZA

            5 AZACYTIDINE
           75 mg/m2 x 7 jours   Raffoux et al. ‘08

            VALPROIC ACID


            5 AZACYTIDINE
           75 mg/m2 x 7 jours

              IDARUBICIN
R                                                    6 cycles
            5 AZACYTIDINE
           75 mg/m2 x 7 jours   Sekeres et al. ‘07
               REVLIMID


            5 AZACYTIDINE
           75 mg/m2 x 7 jours
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
     SMD de riesgo alto especificos

• LMMC
• SMD (o LMA) despues de SMP
• SMD de alto riesgo (o LMA) con del 5q
              Decitabine in CMML
• N=31
• WBC > 20000/mm3 in 29%, marrow blasts >
  5%in 39%
• 14% CR, 11% PR, 11% HI
• Median survival 19 months (Wijermans, Leuk Res, 2008)


• N=19
• 5 day schedule; median 9 courses (1-18)
• 11 (58%) CR, and 2(11%) HI (Aribi, Cancer, 2007)
Hipometilantes en LMMC: experiencia del GFM


     Estudio fase II con décitabina :
         LMMC «desfavorables» (WBC< 13 G/L : IPSS int-2/alto ; WBC> 13 G/L :
         criterios de gravedad segun Wattel et al. Blood 1996)

         Décitabina 20 mg/m²/J 5 jours/28 jours au moins 3 cycles

         41 pacientes , 39 évaluables (médiana 9 cycles)

         Tasa de respuesta global : 39%
         (RC : 10%, RP : 0%, Respuseta medular : 21%, HI : 8%)

         Supervivencia global a los 2 anos : 60% (vs 20 meses con HU en el ensayo Wattel Blood 1996)



     Serie rétrospectiva ATU de azacitidina :
         LMMC «désfavorables» ( n=26) ou transformadas
          ( n=12) ; médiana de 4 ciclos de AZA
         Tasa de respuesta global : 53%
         (RC : 24%, RP : 3%, respuesta medular : 8%, HI : 16%)

         Supervivencia global a los 2 anos : 50 % (médiana : 24 mois)
                                                                     T. Braun et al., ASH 2010, # 1873 - A. Wolfromm et al., ASH 2010 # 4023
AZA in MDS/AML post MPD (S Thépot, Blood
                     2010)




• 54 patients with MDS or AML post
  myeloproliferative disorder

• 52% responses, with reversal to features
  of MPD (polycythemia, thrombocythemia )
  in 39% of responders
 SMD de riesgo alto y LMA con del
               5q

• 5-10% SMD de alto riesgo y LMA
• Generalmente cariotipo complejo (del 5q y
  otros)
• Supervivencia mediana de 7 meses
• Respuesta desfavorable a:
  – Quimoterapia intensiva
  – AZA sola
           Lenalidomida…

• Muy activo en SMD de riesgo bajo con Del
  5q
• Probablemente un tratamiento con diana
  genetica en 5q (« targeted therapy)
• Interes en SMD de riesgo alto y LMA con
  del 5q ?
        Lenalidomide in higher risk MDS and AML
         with del 5q :phase I-II trial (Ades,Blood, 2009)



•     LEN 10mg/d 21 days/ month
•     43 patients evaluable after at least one cycle
•     Overall response 28%
          –   7 CR
          –   2 mCR
          –   3 HI-E


     Cytogenetic response : 9 patients achieved cytogenetic response:
    5    complete, 4 partial
Prognostic factors of CR achievement

                            n    CR   %
            isolated del
               5q
                            9    6    67%
            Single
cytogenetic    additional   11   1    9%
     s         abn
                 >1         27   0    0%




                                            g fm
 Treatment of higher risk MDS (and AML)with complex
karyotypes including del 5q: GFM perspectives (L Ades)


• Patients « fit » for intensive
  chemotherapy: DNR+ AraC+ REV



• Patients « unfit » for intensive
  chemotherapy: AZA+ REV
Fase II quimoterapia intensiva et Lenalidomida SMD de riesgo alto y
LMA con del 5q

   Pacientes (n=63, edad médiana 66 anos)
      AREB2 IPSS int-2/alot (n=15) , LMA(n=48)
      del 5q31 (complejo en 81% de los casos)
      Leucocytosis : médianea : 2,65 G/L


   Tratamiento

    Induccion                          Consolidations (x6)         Mantenimiento
    1ère cohorte
    - DNR 45 mg/m² x3                  - DNR 45 mg/m² x1
                                                                    Lénalidomide
    - ARAC 200 mg/m²x7                 - ARAC 60 mg/m²x 10
                                                                   10 mg x 14/mois
    - Lénalidomide 10 mg x 21          - Lénalidomide 10 mg x 14

    2ème cohorte

    - DNR 60 mg/m² x3                  - DNR 60 mg/m² x1
                                                                    Lénalidomide
    - ARAC 200 mg/m²x7                 - ARAC 60 mg/m²x 10
                                                                   10 mg x 14/mois
    - Lénalidomide 10 mg x 21          - Lénalidomide 10 mg x 14

                                                                        L. Ades et al., ASH 2010, # 508
Fase II quimoterapia intensiva et Lenalidomida SMD de riesgo alto y
LMA con del 5q

Toxicidad
     Duracion médiana de neutropénia et trombopénia : 23dias

Muerte precooz    : 11%

Respuesta    global : 63%
RC:   49%
        • Pour les Del 5q complexes : RC 47%
        • Si > 30% blastes médullaires : RC seulement 38%
        • Pas de différence entre cohortes
     RP : 8% RCp : 2% R médullaire : 5%

SLE   : médiana 9 meses

Supervivencia      : médiana 8 meses (13 mois si respuesta)




                                                                L. Ades et al., ASH 2010, # 508
                                        Intermediate-2 or High
                                              IPSS risk



             >65 yrs or                                                 <65 yrs
       poor performance status                                   Good performance status




Supportive care            <75 yrs           No suitable stem cell                   Available stem cell
   (Rec. D)                                         donor                                  donor


                                                                         <10% BM                           >10% BM
                                                                           blasts                            blasts


                      Hypomethylating         Hypomethylating                                  Poor risk              No poor risk
                          agents                  agents                                     cytogenetics             cytogenetics
                         (Rec. B)                  OR
                                               AML-like CT
                                                 (Rec. B)                                  Hypomethylating             AML-like
                                                                                               agents                    CT


                                                                          Allo-SCT            Allo-SCT                 Allo-SCT
                                                                          (Rec. B)            (Rec. B)                 (Rec. B)
           Grupo Francofono
          de las Mielodisplasias

• Activa ensayos clinicos en los SMD (35 centros en Francia y
  Belgica Suiza, Tunisia)

• Website: www. gfmgroup.org

• Registro Online de los SMD franceses

• Estrecha cooperacion con:
  - una asociacion de pacientes con SMD
  - la International MDS Foundation
  - el European Leukemia Net
        Groupe SMD :Hopital Avicenne (Paris 13 University) and Institut
                          Gustave Roussy (IGR)


•   Clinical department (Avicenne/Paris   •   INSERM U 848
    13)                                   •   Simone Bohrer
•   Claude Gardin                         •   Thorsten Braun
•   Lionel Ades                           •   Lionel Ades
•   Fatiha Chermat                        •   Marie Sebert
•   Raphael Itzykson                      •   Pierre Fenaux
•   Sylvain Thépot                        •   Guido Kroemer
•   Hajer Chehimi
•   Eng Mong Mer
•   Zehaira Hebibi
•   Charikleia Kelaidi                        Hematology and cytogenetics lab
•   Blandine Bève                             Avicenne/paris 13
•   Pierre Fenaux                             •Fanny Baran
                                              •Virginie Eclache
                                              •Florence Cymbalista

				
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