Traitement)des)SMD)de)haut1risque)aihemato/AIH/documents... · Garcia R, et al. Poster presentation...
Transcript of Traitement)des)SMD)de)haut1risque)aihemato/AIH/documents... · Garcia R, et al. Poster presentation...
Traitement des SMD de haut-‐risque
Norbert Vey Département d’Hématologie
Plan
• Défini8on du « haut-‐risque » • Traitement de première ligne
– Déméthylants – Chimiothérapie – Greffe
• Traitement de 2ème ligne • Améliorer les traitements
– Nouvelles molécules – Combinaisons en première ligne
Greenberg et al. Blood. 1997;89:2079–2088.
Qu’est-‐ce qu’un haut-‐risque?
Score
PrognosGc variable 0 0.5 1.0 1.5 2.0
BM blast, % <5 5–10 — 11–20 21–30
Karyotype Good Intermediate Poor — —
Cytopenia 0/1 2/3 — — —
Risk category score Median survival
Low 0 60 months
Intermediate-‐1 0.5-‐1.0 36 months
Intermediate-‐2 1.5-‐2.0 18 months
High > 2.0 4 months
Biologie des haut-‐risque
• Par défini8on – Excès de blastes – Anomalies chromosomiques
• Pré-‐leucémiques… par nature • Profil biologique
– Ra8o apoptose/proliféra8on inverse des BR – Plus d’angiogénèse – Plus de méthyla8on – Plus d’anomalies de signalisa8on – Plus d’instabilité génomique
Profil mutaGonnel des HR
Papaemanuil, blood 2013
-‐ Nombre de muta8ons
-‐ Muta8ons de TP53, ASXL1, WT1, FLT3, IDH, DNMT3A, AML1, RAS
↑Réponse immune ↑Apoptose ↑Angiogenèse ↑Hyperméthyla8on ↑Instabilité génomique ↑ nombre de muta8ons
Faible risque (bas/Intermédiaire-‐1 IPSS)
Haut risque MDS (Intermédiaire-‐2/haut IPSS)
LAM secondaire
Blastes
0%
5%
10%
20%
Type de SMD Anomalies biologiques
Objec8f thérapeu8que
Correc8on des cytopénies ↑ Qualité de vie Réponses (↓blastes) ↑survie
Critères de réponse IWG-‐2006
Cheson, Blood 2006
Traitement des SMD-‐HR
• Ara-‐C faibles doses – Années 70 – Faible taux de réponse, pas de bénéfice de survie démontré – Toxicité
Zwierzina, Leuk 2005
11 20 HI-‐N Major 19 10 HI-‐P Major 10 8 HI-‐E Major 25 31 Major+Minor
IWG HI 4 4 PR 8 1 CR 12 5 Overall (CR+PR)
LDAC N=49 (%)
BSC N=105 (%) Response
Chimiothérapie intensive « type LAM »
InducGon de la réponse avec AZA vs ICT
• Taux de réponses chez les pa8ents randomisés dans le bras ICT de l’étude AZA-‐001
Fenaux, Lancet Oncol 2009
AZA n=17
ICT N=25
p-value
CR 5 (29%) 9 (36%) .75
PR 0 1 (4%) 1.0
CR+PR 5 (29%) 10 (40%) 0.53
Résultats: survie globale
0 20 40 60 80 100 120 140 Time (months)
0
20
40
60
80
100
Surv
ival
(%)
Watel BJH 1997
Overall CR rate : 41% CR rate in complex cytogeneGcs : 19%
Grovdal BJH 2010
n=60 CR rate : 40%
Temps (semaines) 0 100 200 300 400
0.0
0.2
0.4
0.6
0.8
1.0
Idarubicine-‐AraC Fludarabine-‐AraC
Topotecane-‐AraC
Survie sa
ns re
chute
Quel protocole de chimiothérapie?
En résumé
• ICT est un traitement de référence pour les SMD-‐HR • Taux de RC de l’ordre de 40% mais survie courte • Intérêt?
– Débulking avant greffe • Problème:
– Faisabilité/tolérance chez >60 ans
Risk of PS alteraGon following ICT
• AML elderly pa8ents receiving ICT (3+7 type regimens) • Pa8ent status a{er achieving CR ?
Gardin Blood 2007 Pautas JCO 2010
Age No. included
% Induction death
Not eligible for consolidation
98-01 55-70
(med 60) 478 6% 13%
98-02 65+
(med 72) 416 10% 36%*
87/236 pts in CR were not eligible for consolidation randomization: - 53/87 (60%) for “acquired comorbidities”: (severe infection, 28; poor PS, 16; congestive heart failure, 5; renal failure, 2; other, 2)
Chimiothérapie intensive dans la “vraie vie”
Vey N. EBMT, March 2015
50% ICT eligibility rates
40% response rate
20% unfit following ICT
Progression Donor availability
etc…
100 60-70 year-old HR MDS
50 eligible for ICT
20 in response
16 fit for alloSCT
<8 actually transplanted
Une bonne option… pour quelques élus !
PaGent flow.
Estey E et al. Blood 2007;109:1395-‐1400 14/259 (5.4%)
Traitement par agents hypométhylants
Hypermethylated genes in MDS
• P15INK4a (~65%) – cell cycle regula8on • DAPkinase (~47%) – apoptosis • SOCS1 – cytokine regula8on • E-‐cadherin – cell adhesion • Calcitonin – calcium and phosphorus metabolism • Alpha catenin (del 5q)
• ParGcularly in high risk MDS and MDS with “unfavorable” karyotype • Increases during progression
Methylated
Unmethylated
Time (months)
P s
urvi
val
Methylated
Unmethylated
Time (months)
P s
urvi
val
Quesnel et al. Blood 1998;91:2985–90
Survival in pa8ents with MDS according to p15INK4b gene methyla8on status
ara-C
ON
NNNH2
OHO
HO
Decitabine2'-Deoxycytidine
ON
NNH2
OHO
HO
HOO
N
NNH2
OHO
HO
ON
NNH2
OHO
HO
ON
NNNH2
OHO
HOOH OHCytidine 5-azacytidine
Analogues nucléosidiques
Agents Hypométhylants
Déméthylants: mécanisme d’acGon
AzaciGdine Survival Study (AZA-‐001)
AZA 75 mg/m2/d x 7 d q28 d
CCR Randomization
• Best Supportive Care (BSC) only • Low Dose Ara-C (LDAC, 20 mg/m2/d x 14d) • Std Chemo (7+3)
Screening/Central Pathology Review
Investigator CCR Tx Selection
Fenaux et al. Lancet Oncol 2009
Fenaux, Lancet Oncol, 2009
Response rate in AZA-‐001
Fenaux, Lancet Oncol 2009
Overall Survival: AzaciGdine vs CCR ITT PopulaGon
Log-‐Rank p=0.0001 HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113
0 5 10 15 20 25 30 35 40
Time (months) from Randomization
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Prop
ortio
n Su
rviv
ing
CCR AZA
Difference: 9.4 months
24.4 months
15 months
50.8%
26.2%
Fenaux, Lancet Oncol, 2009
– WIJERMANS et al. ASH 2008, Abs 226
Decitabine
100
80
60
40
20
0
0
Supportive care
Survie sans progression
24 18 12 6 30
Médiane (mois) : 6,6 vs 3 HR = 0,68, 65% CI (0,52, 0,88) p=0,004
Mois
10
30
50
70
90
36
100
80
60
Decitabine 40
20
0
0
Supportive care
Survie globale
24 18 12 6 30
Médiane (mois) : 10,1 vs 8,5 HR = 0,88, 95% CI (0,66; 1,17) p=0,38
Mois
10
30
50
70
90
36 42
Etude de phase III de la Décitabine dans les SMD de haut risque (EORTC)
Aza treatment: clinical management
• Dose and regimen? • Date of first disease assessment? • Treatment dura8on for responders? • Can response be predicted? • How to define aza failure • Management of side effects • Should elderly pa8ents be treated with aza?
Haematological improvement obtained with three alternaGve dosing schedules of AZA in MDS
Major haematological improvement in 139 paGents by IWG criteria
* Includes major and minor haematological improvement; patients were counted only once for best response in an improvement category.
Lyons R, et al. Blood. 2007;110 [abstract 819].
PaGe
nts (%)
4452
575560
67
0
10
20
30
40
50
60
70
80
AZA 5-2-2 AZA 5-2-5 AZA 5
Any haematological improvement* Transfusion independence
n = 46 n = 44 n = 49
Spanish registry: different dosing schedules of azaciGdine in paGents with MDS
A retrospective analysis of three different dosing schedules of azacitidine (75mg/m2/
day) in patients with MDS
Garcia R, et al. Poster presentation at ASH 2009. Abstract 2773
Schedule AZA 5
(n=52)
AZA 5-2-2
(n=46)
AZA 7
(n=46)
Median age (years)
69 68 70
IPSS int-2-/high- risk (%)
42 46 59
Transfusion dependent (%)
100 100 100
Median cycles 6 7 6
Median follow up: 14.3 months (2.4–40.0)
Response
AZA 5
AZA 5-‐2-‐2
AZA 7
10 20 30 40 50 60 70
0
41
68 57
OR (%
)
Grade 3–4 AEs
AZA 5-2-2
0
10
20
30
40
50
60
Neutropenia Anaemia Thrombo-‐ cytopenia
Febrile neutropenia
AZA 5
AZA 7 Pa
tient
s (%
)
50 43
35 42
30 22
29
17 17
8
17
7
In real-‐world clinical prac8ce, the EMEA-‐approved dosing regimen has the best overall efficacy/safety profile
• Dose and regimen? • Date of the first disease assessment? • Treatment dura8on for responders? • Can response be predicted? • How to define aza failure • Management of side effects • Should elderly pa8ents be treated with aza?
• Overall response rate 51% (IWG 2000)
• Median number of cycles (responders) 11,5 et 16,5
• Median 8me from PR/HI to CR : 3,2 mois 1.0
0.8
0.6
0.4
0.2
0
0
91
50% (2 cycles)
12 3
9 6
6
12
3
34
15 1
Range: 1-22 cycles
0.1
0.3
0.5
0.7
0.9
Prob
abili
té c
umul
ée
18 1
21 1
24
Temps (cycles) :
Nombre de cas :
87% (6 cycles)
Time to response (AZA001)
Silverman, Cancer 2010
• Dose and regimen? • Date of first disease assessment? • Treatment dura8on for responders? • Can response be predicted? • How to define aza failure • Management of side effects • Should elderly pa8ents be treated with aza?
0
1
2
3
PR as Best Response Aftera First Response (HI)
CR as Best Response Aftera First Response (HI or PR)
Azacitidine continuation results in improvement of response in 48% of patients
Med
ian
Mon
ths
from
Fi
rst t
o B
est R
espo
nse
(n=21) (n=30)
3.2 months (95% CI: 2.4 – 6.9)
2.3 months (95% CI: 0.3 – 3.0)
Silverman, Cancer 2010
Response duraGon and outcome aper disconGnuaGon
• AZA001 study (Fenaux et al. Lancet Oncol. 2009) – Median of 14 cycles in responders – No plateau in PFS curves
• Dura8on of haematological response (CR+PR+HI): median 13·∙6 months • Median dura8on of CR+PR : 3·∙2 months
• 100% relapse following treatment discon8nua8on at 24 months in 2 studies a{er 2-‐4 months
• Soriano, Blood 110:2302, 2007 • Garcia-‐Manero, Blood 108:3271, 2006
• Dose and regimen? • Date of first disease assessment? • Treatment dura8on for responders? • Can response be predicted? • How to define aza failure • Management of side effects • Should elderly pa8ents be treated with aza?
French ATU program: factors influencing outcome on 5-‐aza
Itzykson, Blood 2011
variable Response (%) OR p
Low dose AraC 24/ 46 0,26
[0,10-0,71] 0,009
Normal karyotype 51/ 39 0,4
[0,2-0,7] 0,003
BM blastes > 15% 35/ 50 0,44
[0,26-0,77] 0,004
variable Median OS HR p
ECOG 0-1 vs>2
15,7/ 7,1 2 [1,4-2,9]
<0,0001
karyotype fav/int/unfav 22,4/ 15 /8,8 3 [2-1,3]
<0,0001
Circulating blasts > 15 vs < 15%
9,4/ 19,8 2 [1,5-2,7]
<0,0001
Transfusion dependance > 4 RBCs/8sem vs 0-1
10,3/19,2 1.9 [1,4-2,6]
<0,0001
Survival by prognosGc groups
Itzykson, Blood 2011
ATU cohort (development)
AZA-001 cohort (validation)
0,0
0,2
0,4
0,6
0,8
1,0
0,0
0,2
0,4
0,6
0,8
1,0
0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36
Cum
ulat
ive
prob
abili
ty o
f sur
viva
l
Mois Mois
Cum
ulat
ive
prob
abili
ty o
f sur
viva
l p < 0,0001
p = 0,0027
Low Intermediate high
Low Intermediate high
Gene mutaGons
• Muta8ons TET2 prédisent réponse mais pas OS (Itzykson, Blood 2012, Bejar Blood 2015)
• Impact sur OS de TP53, PTPN11 Bejar, blood 2015
MéthylaGon et prédicGon de la réponse
• Nombreuses études néga8ves – Méthyla8on globale ou régions promotrices
• Iden8fica8on Differen8ally Methylated Regions (DMRs) – Localisées enhancers et
régions régulatrices distales
• Le niveau de méthyla8on des ces DMRs avant trt prédit la réponse (CMML traitées par DAC)
• Dose and regimen? • Date of first disease assessment? • Treatment dura8on for responders? • Can response be predicted? • How to define aza failure? • How to manage side effects? • Should elderly pa8ents be treated with aza?
Critères de réponse IWG2006
Cheson Blood 2006
AZA-‐001: correlaGon response-‐survival
Time from randomisation (months)
Patie
nts
surv
ivin
g (%
)
Adapted from List AF, et al. Oral presentation at ASCO 2008, Chicago, IL, USA
0 5 10 15 20 25 30 35 40 0
20
40
60
80
100
HI
PR
CR
CCR
71.7% 78.4%
26.2%
2-‐year survival rates
French ATU programme: retrospecGve analysis of paGents with higher-‐risk MDS treated with azaciGdine
– survival with respect to response
Response n Median OS (months)
CR or PR 34 17.6*
SD or MR with HI 48 21.8*†
SD or MR without HI 58 10.3*
Progression 36 3.4
*p=0.0003 versus progression †p=0.7 versus CR/PR
A{er 6 months of therapy, pa8ents with SD or MR ± HI, as well as pa8ents with CR or PR, achieved a significant survival benefit versus pa8ents who progressed
Itzykson R, et al. Poster presentation at ASH 2009. Abstract 3820 MR = Marrow Response
Stable disease: a challenging case
• OS of pa8ents with SD is beter than pa8ents with progressive disease
• But no difference between AZA and CCR
Gore et al 2011
Stable disease aper AZA: recommendaGons
• Administer at least 6 cycles before concluding to SD
• 2 excep8ons:
1/ SD with hints of hematologic improvements or clinical improvement
è give 1 to 2 addi8onal cycles
2/ SD with myelosuppression
è stop treatment and re-‐assess a{er wash-‐out
Sekeres Blood 2009, Garcia-Manero JCO 2011
• Dose and regimen? • Date of first disease assessment? • Treatment dura8on for responders? • Can response be predicted? • How to define aza failure • How to manage side effects? • Should elderly pa8ents be treated with aza?
AE frequency decreases with Gme
Cycles 1–2
(n = 175)
Cycles 3–4
(n = 147)
Cycles 4–5
(n = 130)
Cycles 7–8
(n = 107)
Cycles 9–10
(n = 89) % with ≥ 1 AE 94 79 65 65 65
Blood and lymphatic disorders, %
75 54 42 36 36
GI disorders % 62 42 25 27 30 Injection site reactions and general disorders, %
62 44 32 32 28
Santini V, et al. Poster presented at ASH 2008. Abstract 1653.
AE that occurred in ≥ 20% de patients)
Douvali et al. , Leukemia Research 2013, Volume 37:889 -‐ 893
AZA et insuffisance rénale
• Dose and regimen? • Date of first disease assessment? • Treatment dura8on for responders? • Can response be predicted? • How to define aza failure • Management of side effects • Should elderly pa8ents be treated with aza?
5-‐azacyGdine in elderly MDS paGents (AZA-‐001) • Sub-‐analysis of 87 pa8ents >75 years in AZA-‐001 trial • AZA : 38 pa8ents, CCR 49 pa8ents • 70% BSC arm selected by inves8gator • Median age 78 years
SeymourJF, et al. CritRevOncol/Hematol(2010), doi:10.1016/j.critrevonc.2010.04.005
8% early deaths < 90 days 29% early withdrawal 20% infec8ons (first 2 cycles)
5-‐azacyGdine French ATU program: responses in paGents > 80 ans
Overall response rates not different from that of pa8ents < 80 years (34 vs 39%) p=0,6
Itzykson R, et al. Poster presenta8on at ASH 2009. Abstract 1773
7 4
16
34
0
10
20
30
40
50
OR CR PR SD with HI
Patie
nts
(%)
MR
7
Response n/N (%) Erythroid HI (HI-E) 12/38 (32)
Transfusion Independency 7/19 (37) Platelet HI (HI-P) 9/37 (24)
Neutrophil HI (HI-N) 7/15 (47)
Overall HI 19/41 (46)
0
0.2
0
OS
Time (months)
0.4
5 10 15 20 25 30 35 40
0.6
0.8
1
Age > 80 years Age < 80 years
En résumé
• Respecter les doses / intervalles • Administrer > 6 cycles avant de conclure • Les HI sont des réponses! • Con8nuer jusqu’à progression • Pas de limites d’âge mais adapter le management aux
comorbidités • Pas d’effets secondaires nécessitant a priori l’arrêt du trt • Soins de supports « intensifs » au cours des premiers cycles
Traitements de 2ème ligne des SMD-‐HR
Survival aper HMA failure
29% 15%
Prébet et al JCO 2011
AZA
Jabbour et al Cancer 2010
DAC
Effect of treatment opGons aper AZA failure (n=350)
1: Overall response rate 2: intensive chemotherapy
Type of salvage N= ORR1 Median OS (months)
Unknown 215 NA 3.6 Supportive Care 160 NA 3.3
Cytotoxic therapy 84 1/25 and
5/332 7.6
Investigational therapy 56 4/39 13.2
Allogeneic Transplantation 50 17/25 18.3
* **
RecommandaGons de traitement de 2ème ligne
• Avec projet de greffe – <10% blastes: allo upfront – >10% blastes et sujets « fits » : induc8on type LAM
• Autres – Essai thérapeu8que – Soins de support
Nouvelles drogues pour les SMD-‐HR
Agents hypométhylants
• SGI-‐110: prodrogue de la decitabine • Deméthyla8on plus efficace • 37% CR dans AML unfit • Actuellement
– Phase 3 MDS échec AZA – Phase 3 AML unfit
Inhibiteurs d’HDAC
Study HDACi + combina8on drug
Phase of study N
Pa8ent Popula8on
Response summary
Soriano Blood 2007 77
Valproate 5-‐aza + ATRA
Phase I/II
53 49 AML 4 MDS
OS N/A ORR 42% 2% CR, 5% CRi
Raffoux Oncotarget 101
Valproate 5-‐aza + ATRA
65 55 AML 10 MDS
OS 12.4 months ORR 26% 21% CR 5% PR
Issa Cancer 2015 85 Valproic acid Decitabine
Phase II RAND
149 62 AML 87 MDS
12 months ORR 55% CR+CRi 34%
Gore Cancer Research 2006 83
Sodium phenylbutyrate 5-‐aza Phase I
29 15 AML 2nd MDS 3 Relapsed AML 13 MDS
OS N/A ORR 38% CR+CRi 17%
Silverman ASH2013 [92]
Vorinostat 5-‐aza 55 or 75mg/m² d1-‐7
Phase I-‐II
20 6 AML 14 MDS
OS 21 months ORR 72% CR+CRi 42%
Prébet JCO 2014 102 En8nostat 5-‐aza (50 d1-‐10) Phase II RAND
149 52 AML 97 MDS
OS 13 months ORR 44% CR+CRi 14%
Tan Blood Cancer J 2014 89
Panobinostat 5-‐aza
Phase I/II
39 29 AML 10 MDS
AML OS 8 months ORR 31% MDS OS 16 months ORR 50%
RIGOSERTIB
• Mul8 Hit Kinase inhibitor – Not binding in ATP pocket – PLK-‐1 pathway inhibitor – PI3 Kinase inhibitor
• Inhibits ac8va8on of an8 apoptop8c proteins such as MCL-‐1 • IV and oral formula8on • High risk MDS AZA failure
– ORR**= 23% (9/39) – OS= 9 months
• Toxicity – Urinary symptoms
Greenberg ASH 2011
RIGOSERTIB phase III vs BSC MDS Aza failure
Garci-‐Mannero ASH 2014
SAPACITABINE
• Oral analog of deoxyci8dine
• Phase I MDS and AML
• Toxicity: fa8gue / GI (DLT AML) / myelotoxicity (DLT Solid
Tumor)
• 13 responders / 47 pa8ents (28%, 4CR, 2 CRp, 7 CRi)
• Combo decitabine phase 3 ongoing
Kantarjian JCO 2011 Kantarjian Lanc Oncol 2012
GFM AZA LDE
• Oral SMO inhibitor LDE 225
• Pts with AZA failure w/o BM progression
• Phase I/II trial: Addi8on de LDE 225 to AZA
• Opening Q1 2014
AZA LDE 225
9 3 7 28 J1
X6
DEFERASIROX+ vitamine D
• 17 pts (vs 13 BSC)
• AML-‐MRC or sAML
previously treated with AZA
• No objec8ve response
• OS 10 ms vs 4 ms (BSC)
• Ongoing phase 1-‐2 GFM
study
Paubelle PLosOne 2013
Lenalidomide aper AZA failure
PaGent # demographics
Disease status before AZA CytogeneGcs
IPSS before AZA
AZA treatment$ AZA Failure
LEN schedule and response$
LEN duraGon and failure
Overall Survival (months)
1 M, 63y RAEB-‐2, EPO resistant Dele8on 11 Int-‐2 75*7d, HI
12 cycles, PD 5*21d, NR 2 cycles, TOX 20
2 M, 78y RARS, EPO resistant Trisomy 8 Int-‐1 75*5d, HI 10 cycles,
PD 5*21d, HI 6 cycles, loss
of HI 22+
3 F, 72y RA, EPO resistant Dele8on 5q complex K. Int-‐1 75*7d, NR 7 cycles, SD 5*21d, CR
10 cycles ongoing 16+
4 M, 49y RARS, EPO resistant Dele8on Y Int-‐1 75*5d, NR 6 cycles, SD 10*21d, NR 6 cycles, SD 17& 5 F, 71y RARS, EPO resistant Normal Int-‐1 75*5d, NR 6 cycles, SD 5*21d, NR 1 cycle, SD 4 6 M, 78y RARS, EPO resistant Dele8on 20q Int-‐1 75*5d, NR 9 cycles, SD 5*21d, NR 3 cycles, SD 22
7 F, 62y AML (RAEB-‐T), relapsed a{er Allogeneic HSCT
Dele8on 5q NA 75*7d + DLI, PR 6 cycles, PD 10*21d, CR 3 cycles, PD 7
8 M, 77y RAEB-‐2, EPO resistant
Dele8on 5q complex K. Int-‐2 75*7d, HI
12 cycles, PD 10*21d, NR 2 cycles, TOX 5+
9 F, 69y RAEB-‐2, EPO resistant
Dele8on 5q, complex K. Int-‐2 75*7d, NR 8 cycles, SD 10*21d, CR
12 cycles, ongoing 14+
10 F, 71y RAEB-‐2, EPO resistant
Dele8on 5q Inversion 3 High 75*5d, CR 5 cycles, PD 10*21d, NR 3 cycles, SD 5
Prebet leukemia Lymphoma 2012
Conclusions
• Azaci8dine représente le standard de traitement de 1ère ligne des SMD-‐HR
• Résultats insuffisants – Combinaisons en 1ère ligne – Étude AZA +
• Place pour chimio intensive chez sujets jeunes avec projet de greffe
• De nombreuses molécules en développement