Transcript AZA

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
allo
Chemotherapy
0.7
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
1.
0
80
0.8
Survival (%)
100
Survival
Probability
N = 99
60
0.6
40
0.4
20
0.2
0
0
20
40
60
80
100 120 140
Wattel E. et al.
Br J Haematology. 1997;98:983-991.
0.0
0
100
200
310
Weeks
410
With Permission of E Estey, MD
520
0.8
Idarubicin-AraC
0.6
Fludarabin-AraC
0.2
0.4
Topotecan-AraC
0.0
Probability of Relapse or
Death After CR
1.0
Intensive Chemotherapy
(MDAnderson Experience)
0
100
200
Time (weeks)
300
400
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
Randomization
CCR
• 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
21progression
Overall Survival: Azacitidine vs CCR
ITT Population
Log-Rank p=0.0001
HR = 0.58 [95% CI: 0.43, 0.77]
Deaths: AZA = 82, CCR = 113
Difference: 9.4 months
1.0
Proportion Surviving
0.9
0.8
0.7
50.8%
24.4 months
0.6
0.5
0.4
15 months
26.2%
AZA
0.3
CCR
0.2
0.1
0.0
0
5
10
15
20
25
30
Time (months) from Randomization
22
35
40
Hazard Ratio and 95% CI for Overall Survival
Total - Event / N
ITT Subgroups
ITT
RAEB & RAEB-T: AGE ≥ 65
AGE: < 65
≥ 65
≥ 75
Male
Female
FAB: RAEB
RAEB-T
WHO: RAEB-1
RAEB-2
IPSS: INT-2
High
Cytogenetics: Good
Intermediate
Poor
Karyotype: -7/del (7q)
Cytopenias: 0/1
2/3
BM Blasts: ≥ 5% to < 11%
≥ 11% to < 21%
≥ 21% to < 31%
LDH: ≤ 240 U/I
> 240 U/I
195 / 358
138 / 240
45 / 100
150 / 258
50 / 87
134 / 251
61 / 107
95 / 207
80 / 123
15 / 31
102 / 193
71 / 146
98 / 167
80 / 167
38 / 76
67 / 100
42 / 57
20 / 53
167 / 290
34 / 61
98 / 192
58 / 99
97 / 208
94 / 145
0.125
23
0.250
0.500
Favors Azacitidine
1
2
4
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
Probabilité cumulée
0.9
0.8
87%
(6 cycles)
0.7
0.6
0.5
0.4
50%
(2 cycles)
0.3
Extrêmes : 1-22 cycles
0.2
0.1
0
Temps (cycles) :
0
3
6
9
12
15
18
21
Nombre de cas :
91
34
12
6
3
1
1
1
24
Abs 227 – CO – L R SILVERMAN et al.
Secondary Endpoints:
IWG (2000) CR,PR and HI
Response
Overall (CR+PR)
CR
PR
IWG HI
Major+Minor
AZA
CCR
N=179 N=179
(%)
(%)
P-Value
AZA vs
CCR
29
17
12
12
8
4
0.0001
0.02
0.009
49
29
<0.0001
AZA-001: 2-year OS with azacitidine by best
response (IWG 2000)
1.0
78.4%
71.7%
Proportion of patients surviving
0.8
0.6
HI
PR
CR
0.4
CCR
0.2
0
0
5
10
15
20
25
30
35
40
Time from randomisation (months)
IWG = International Working Group; HI = haematological improvement
PR = partial response; CR = complete response
Adapted from List AF, et al. Oral presentation at
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
222
LDAC
94
Chemo
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
Treatment
K-M OS
Time mos
K-M OS Time
mos
Hazard
Ratio
Logrank P
11.5
24.5
9.6
0.56
0.002
15.3
25.1
9.2
0.58
0.015
15.7
9.4
0.87
0.75
21.1
AZA (N=117)
vs
BSC (N=105)
AZA (N=45)
vs
LDAC (N=49)
AZA (N=17)
vs
Stand Chemo (N=25)
33
AZA-001: OS – azacitidine versus
LDAC
(Brit J Haematol, 2010)
1.0
Azacitidine
Probability of survival
0.9
LDAC
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0
10
20
Time from randomisation (months)
30
40
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
hospital/pt year
27
P<10-4
18
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
hospital/pt year
27
P<10-4
18
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
hospital/pt year
27
P<10-4
18
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
hospital/pt year
27
P<10-4
18
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
HR= 0.47 (95% CI: 0.28–0.79)
Deaths: azacitidine = 24, CCR = 41
Proportion surviving
0.9
0.8
0.7
50.2%
0.6
24.46 months
0.5
0.4
Azacitidine
15.9 months
0.3
0.2
0.1
15.9%
CCR
0
0
Number at risk
AZA
55
CCR
58
5
43
43
10
38
36
15
20
25
30
Time (months) from randomisation
26
22
15
6
10
3
4
0
1
0
35
40
0
0
JCO , in press
Marrow CR Rates
70
% of pts with CR
60
50
(6/11)
P value, P=0.80
40
30
20
10
18
(10/55)
16
(9/58)
(0/27)
(3/20)
0
AZA
CCR
CCR Regimens
Infections, Hospitalizations
Rates of Infections Requiring IV Antibiotics
and Rates of Hospitalization
Rate Per Patient Year
6
P=0.05
5
4,3
4
P=0.003
3,4
3
2
1
0
1,14
0,58
AZA CCR
Infections
Requiring
IV Antibiotics
AZA CCR
Hospitalization
OS according to response
Landmark Analysis
Hematological Improvement
Progression
RC+RP
Stable disease
1
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
– Median OS 17.1 months
– Similar in pts < 80 (p=0.6)
,8
OS
Survie Cum.
• survival
Age <80
Age ≥80
,6
,4
,2
0
0
5
10
15
20
25
Temps
months
30
35
40
4
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
progression free survival
90
Overall survival
90
80
80
70
Médian (months) : 6,6 vs 3
HR = 0,68, 65% CI (0,52, 0,88)
p=0,004
60
50
Médian (mnthss) : 10,1 vs 8,5
HR = 0,88, 95% CI (0,66; 1,17)
p=0,38
70
60
50
40
40
Decitabine
30
Decitabine
30
20
Supportive care
20
Supportive care
10
10
0
0
0
6
12
18
Mois
24
30
36
0
6
12
18
24
30
36
42
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
Cohorte d’ATU (développement)
bajo
Intermedio
alto
1,0
Analisis multivariada
HR 95% CI
p
puntuacion
Performance status
2,0 [1,4-2,9]
<10-4
1
≥ 4 unidades de GR/8 semanas
1,9 [1,4-2,6]
<10-4
1
Presencia de blastos circulantes
2,0 [1,5-2,7]
<10-4
1
<10-4
Citogenetica (IPSS)
Probabilité cumulée de survie
0,8
p<0,0001
Riesgo intermedio
1,4 [0,8-2,3]
1
Desfavorable
3,0 [2,0-4,3]
2
0,6
ATU (n=269)
(N,%)
Survie
médiane
globale
(mois)
(N,%)
Survie
médiane
globale
(mois)
0
30
(11%)
NR
23
(15%)
NR
Intermedio
1-3
191
(71%)
15,0
114
(75%)
21,4
Elevado
4-5
48
(18%)
6,1
15
(10%)
9,3
Grupo, de riesgo
Score
0,4
0,2
bajo
0,0
0
6
12
18
24
30
Mois
36
42
48
54
60
AZA-001 (n=152)
R. Itzykson et al.,Blood , 2011
mutaciones de TET2: factor predictivo
de respuesta a Azacitidina
Résultatos
Todos
TET2 mutado
TET2 non mutado
103
17 (17%)
86 (83%)
7 [1-39]
11 [4-34]
6 [1-39]
0,016
Citogénética desfavorable
(IPSS)
30 (34%)
1 (7%)
29 (39%)
0,01
RC
24 (23%)
7 (41%)
17 (20%)
0,07
RC+ HI
53 (52%)
14 (82%)
39 (45%)
0,007
Pacientes
Ciclos de AZA
p*
 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
GROSSMAN et al. ASH 2010, # 296 – CO

Citometria de flujo?
C. ALHAN et al., ASH 2010, # 441 – CO
V.
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
 ATU française n=369
Population
Âge médian (ans)
69 ans
SMD/LAM
341/224
Blastes médullaires avant AZA
- < 10%
- 10% à 20%
- > 20%
129 (23%)
269 (47%)
167 (30%)
recaida 37%
Cytogénétique
- Favorable
- Intermédiaire
- Haut risque
219 (39%)
138 (24%)
208 (37%)
intolerencia 8%
Traitement de 1ère ligne par AZA
294 (52%)
fracaso:
primario 55%,
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
Médicaments à l’étude
Inconnu
Allogreffe
100
Tratamiento
N=
ORR
OS mediana
(meses)
desconocido
215
NA
3.6
supporte
160
NA
3.3
quimoterapia
84
1/25 et
5/33
7.6
Survie globale
75
50
25
*
**
Nuevas drogas
56
4/39
13.2
Alo TPH
50
17/25
18.3
0
0
365
730
1095
1460
1825
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)
10 (50%)
6 (33%)
Complete response
7 (35%)
4 (25%)
Hematologic improvement
3 (15%)
2 (13%)
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%
2 (10%)
2 (13%)
Overall Response
Grade ≥ 3 Adverse Events
6-Week Mortality
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
Short-chain fatty acids (SCFA)
Butyrate derivatives,
Valproic acid
Hydroxamic acids
Trichostatin A, SAHA (Vorinostat)
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
(mg/kg)
N
CR
CRp
BM
OR
N (%)
Courses to
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 5azacitidine in patients with MDS
5-azacitidine
Vorinostat – cohorts 1-4
Vorinostat – cohorts 5-7
Vorinostat – cohort 8
0
7
14
Day
21
28
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%)
12
(55%)
CR+CRi
*IWG 2000 MDS
IWG 2006 MDS
IWG AML
+Response
Confirmed
by NCI Audit
PR
5 (05%)
HI
5
(23%)
Stable
2
(09%)
NR
2
(09%)
Too Early
1
IE for response
3
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:
• MDS by FAB of any age
• AML age > 60
• No good-risk AML
• No prior high-dose
chemotherapy
• No prior decitabine > 1
cycle or azacitidine > 2
cycles
R
A
N
D
O
M
I
Z
E
Decitabine 20 mg/m2 IV/1 h daily days 1-5 q 4 weeks
Decitabine 20 mg/m2 IV/1 h daily days 1-5 q 4 weeks
Valproic acid 50 mg/kg/day p.o. days 1-7 q 4 weeks
Issa et al. ASH 2008, Abstract 228
Ensayo fase II de AZA ± Entinostat
Supervivencia Global
Respuesta (IWG 2000)
1.00
0.80
Bras A
Bras B
AZA seule
AZA + Entinostat
RC
12%
7%
RP
9%
7%
HI (3 lineas)
10%
10%
0.20
HI (1 o 2 linaes)
12%
19%
0. 0
Ausencia de respuesta
57%
56%
Suivi 17 mois
0.60
0.40
p=0.15
0
Traitement
10
20
Mois
Total10
30
40
Décès
Censure
Médiane
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)
Aim
Azacitidine +
lenalidomide in
six dose regimens
Objectives:
safety,
MTD,
DLTs,
efficacy
Patients (n=18)
RAEB-1 = 21% RAEB2 = 53% CMML = 5%
Int-1 = 16%
Int-2 = 47%
High = 32%
Only one patient with
chromosome 5q
deletion
Regimen
1
2
5mg days 1–14
75mg/m2
days 1–5
5mg days 1–21
3
10mg days 1–21
4
5mg days 1–14
5
6
MTD = maximum tolerated dose; DLT = dose-limiting toxicity
Azacitidine schedule
Lenalidomide
schedule
50mg/m2
days 1–5, 8–12
5mg days 1–21
10mg days 1–21
Sekeres MA, et al. Oral presentation at ASH 2008
Blood 2008;112:[abstract 221]
RR (% evaluable patients, n=17)
Azacitidine plus lenalidomide in patients
with higher-risk MDS: efficacy
•
Cohort
ORR = 71%
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
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
RR = response rate; ORR = overall RR; SD = stable disease
Sekeres MA, et al. Oral presentation at ASH 2008
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
R
IDARUBICIN
6 cycles
5 AZACYTIDINE
75 mg/m2 x 7 jours
REVLIMID
5 AZACYTIDINE
75 mg/m2 x 7 jours
Sekeres et al. ‘07
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
isolated del
5q
Single
cytogenetic
additional
s
abn
>1
n
CR
%
9
6
67%
11
1
9%
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
- DNR 45 mg/m² x1
- ARAC 60 mg/m²x 10
- Lénalidomide 10 mg x 14
Lénalidomide
10 mg x 14/mois
- DNR 60 mg/m² x1
- ARAC 60 mg/m²x 10
- Lénalidomide 10 mg x 14
Lénalidomide
10 mg x 14/mois
1ère cohorte
- DNR 45 mg/m² x3
- ARAC 200 mg/m²x7
- Lénalidomide 10 mg x 21
2ème cohorte
- DNR 60 mg/m² x3
- ARAC 200 mg/m²x7
- Lénalidomide 10 mg x 21
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
RC:
global : 63%
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
poor performance status
Supportive care
(Rec. D)
<75 yrs
<65 yrs
Good performance status
No suitable stem cell
donor
Available stem cell
donor
<10% BM
blasts
Hypomethylating
agents
(Rec. B)
Hypomethylating
agents
OR
AML-like CT
(Rec. B)
Allo-SCT
(Rec. B)
>10% BM
blasts
Poor risk
cytogenetics
No poor risk
cytogenetics
Hypomethylating
agents
AML-like
CT
Allo-SCT
(Rec. B)
Allo-SCT
(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
13)
Claude Gardin
Lionel Ades
Fatiha Chermat
Raphael Itzykson
Sylvain Thépot
Hajer Chehimi
Eng Mong Mer
Zehaira Hebibi
Charikleia Kelaidi
Blandine Bève
Pierre Fenaux
•
•
•
•
•
•
•
INSERM U 848
Simone Bohrer
Thorsten Braun
Lionel Ades
Marie Sebert
Pierre Fenaux
Guido Kroemer
Hematology and cytogenetics lab
Avicenne/paris 13
•Fanny Baran
•Virginie Eclache
•Florence Cymbalista