Traitement)des)SMD)de)haut1risque)aihemato/AIH/documents... · 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)

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


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


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


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

Documents

Traitement)des)SMD)de)haut1risque)aihemato/AIH/documents... · 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)