SINDROMI MIELODISPLASTICHE: ATTUALITA’ E PROSPETTIVE ... · SINDROMI MIELODISPLASTICHE:...

FATTORI DI CRESCITA

Carlo Finelli

Cosenza, 18 novembre 2011

SINDROMI MIELODISPLASTICHE:ATTUALITA’ E PROSPETTIVE

Terapia delle MDS

HSCT

Miglioramento dell’ematopoiesie della QoL

ESAs (± G-CSF) Lenalidomide Farmaci immunosoppressori Farmaci ipometilanti

Ferrochelazione

MDS a basso rischio

Blocco dell’evoluzione in AML Farmaci ipometilanti Chemioterapia HSCT

MDS ad alto rischio

apoptosi,

differenziaz.

PROGRESSIONE

cellula staminalenormale

early stageMDS

late stage MDS

AML

età,agenti chimiciradiazioni

displasia,citopeniaperiferica

apoptosi

Differenziazione

proliferazione

displasia,citopenia,blasti

MDS: PATOGENESI “MULTISTEP”

alteraz. ciclo cellulare,trascrizione

metilazionegeni oncosopppressori

(da : Nolte, Ann Hematol, 2008)

ANEMIA in MDS• More than 50% of

patients show anemia(Hb < 10 g/dl) atdiagnosis

• More than 90% becomeanemic during the courseof the disease

• More than 80% requirered-cell transfusion

Erythropoietin is Essential for Key Steps inErythropoietin is Essential for Key Steps inErythropoiesisErythropoiesis

Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: BasicPrinciples and Practice. 4th ed. 2005;267-288.

SCF, GM-CSF, IL-3

SCF, IL-1, IL-3, IL-6, IL-11

EPO Dependent EPO Independent

Decreasing EPOReceptor Density

Increasing EPOReceptor Density

Erythropoietin

PluripotentStem Cell

Burst-FormingUnit-ErythroidCells (BFU-E)

Colony-FormingUnit-ErythroidCells (CFU-E)

Reticulocytes RBCsErythro-blasts

Proerythro-blasts

About 8 Days

Iron

In Vitro BFU-E Sensitivityto EPO in MDS

0 500 1000 1500 2000

RA

RARS

RAEB

Normal

Number of BFU-E colonies/10E5 cells

Claessens et al, Blood 2002

I precursori eritroidi in MDShanno una risposta ridotta allostimolo eritropoietinico in vitro.

Serum EPO Levels

0

100

200

300

400

500

600

MDS CMPD CLL MM NHL Solid Tumors

Serum EPO (mIU/mL)

Nowrousian et al, 1996

CORRELAZIONE EPO – Hct

15 20 25 30 35 40

EMATOCRITO (%)

EP

O,

m

U /

L5000

1000

100

10

1

Risposta adeguata

Produzione di Epoinadeguata

O/PRATIO

Cazzola M et al, 1992

MDS

ACTIVITY OF r-EPO IN MDS

STIMULATIONOF NORMAL ORCLONALERYTHROIDPRECURSORS

INHIBITION OFPREMATUREAPOPTOSIS

Merchav 1990; Aoki, 1992,Rigolin et al, 2002 and 2004

Aoki et al, 1992; Tehranchi et al,2003; Rigolin et al, 2004; Stasi et al,2004

Risposta a r-EPO nelle SMD

0-50%

Tutti i pazienti20-25%

Trasfusione-dipendenti10-15%

35 studi pubblicati (1990-2001)condotti su più di 1000 pazienti

“Dosi standard”

Tutti i pazienti Trasfusione-indipendenti Trasfusione-dipendenti

Studio Tassi di risposta Criteri di risposta Tassi di risposta Criteri di risposta Tassi dirisposta

Hellström-Lindberg, 1995 16% (33/205) Aumento

Hb ≥1,5 g/dl 44% (16/36) Hb stabilesenza trasfusioni 10% (16/159)

Rose, 1995 28% (28/100)Aumento

ematocrito ≥6%senza trasfusioninell’ultimo mese

20% (2/10)

Riduzione fabbisognotrasfusionale >50%negli ultimi 3 mesi

o aumento ematocrito≥6% senza trasfusioni

nell’ultimo mese

29% (26/90)

ItalianCooperativeStudy Group,1998

37% (14/38) AumentoHb ≥1,0 g/dl 60% (9/15)

Riduzione fabbisognotrasfusionale ≥50%negli ultimi 2 mesi

22% (5/23)

13% (5/38)a AumentoHb ≥20 g/dl

da 0% (0-15)a 33% (5/15)a

No trasfusioninegli ultimi 2 mesia

da 0% (0/23)a 22% (5/23)a

Terpos, 2002 45% (125/277) Aumento Hb≥1,0 g/dl 18% (38/208)

Riduzione fabbisognotrasfusionale ≥50%

nelle ultime 5 settimane10% (7/69)

27% (76/277)b Aumento Hb≥20 g/dl 29% (61/208) No trasfusioni nelle ultime

6 settimane 28% (19/69)

Risposta al trattamento con epoetinanegli studi più significativi

aRisposta complessiva; il numero di pazienti responsivi non differisce in base allo stato di trasfusione-dipendenza. bRisposta principale.

IWG Response Criteria in MDS

• Complete Remission:• Partial Remission:

• HematologicImprovements:

<5% BM blasts, No dysplasia;Hgb>11; PMN>1.5, PLT>100KSame as CR; ↓ blasts by 50%

RBC (HI-E): Major: Treatment-indepen. or >2g/dl ↑ in Hgb; Minor:50% ↓ in tx req or 1-2 g/dl ↑ in Hgb.PLT (HI-P): Major: PLT tx indep or ↑by 30K if < than 100K at baseline;Minor: 50% ↑ in PLT count (of at least10K) if baseline <100K.PMN (HI-N): Major: if ANC <1500, a100% ↑ or 500/ µl, ↑ whichevergreater; Minor: if ANC <1500, ANC ↑by 100%, but < than 500/ µl.Cheson BD, et al. Blood 2000.

96:3671-4.

New IWG criteria(Hematological Erythroid Improvement for Hb

< 11 g/dl)Blood 2006

• Hb increase by > 1.5 g/dl

• Reduction of transfusion by an absolutenumber of at least 4 RBC trasfusions/8weeks compared to pre-treatmenttransfusion number in the previous 8weeks (Hb < 9 g/dl)

• Responses must last > 8 weeks

TuttiStudio % di risposta Dose EPO/sett

Musto, 2003 38% (5/13) 40 K

Stasi, 200427% (13/48)

(refrattari a 10 K TIW)40-60 K

Clavio, 2004 55% (6/11) 80 K poi 40 K

Latagliata, 2008 50% (30/60) 80 K poi 40 K

Aloe Spiriti, 2005 68% (86/126) 80 K poi 40 K

Risposta al trattamento con epoetina (40 K)

PREDICTIVE FACTORS OFPREDICTIVE FACTORS OFRESPONSE TO ESA IN MDSRESPONSE TO ESA IN MDS

• ENDOGENOUS EPO < 200-500 mU/ml

• NO/LOW (< 2/MONTH) TRANSFUSION NEED

Comparison of rHuEPO and darbepoetin alfa

• Three N-linked carbohydratechains

• Maximum 14 sialic acids• MW ~ 30,400 daltons• 40% carbohydrate• High receptorial affinity

Newcarbohydrateside chains

Receptor 1

Darbepoetin alfa

Receptor 2 Receptor 1

rHuEPO

Receptor 2

Carbohydrateside chains

• Five N-linked carbohydratechains

• Maximum 22 sialic acids• MW ~ 37,100 daltons• 51% carbohydrate• Low receptorial affinity

MW = molecular weight

1Heatherington A, et al. Proc Am Soc Clin Oncol. 2002;21:256b. Abstract and poster;

2Macdougall I, et al. J Am Soc Nephrol. 1999;10:2392-2395.

DarbepoetinDarbepoetin alfaalfa has a longer half-life than has a longer half-life than rHuEPOrHuEPO::single-dose PK of IV administrationsingle-dose PK of IV administration

100

10

1

0.1

0.010 25 50 75 100

Time post-IV injection (hours)

Mea

n (S

D) b

asel

ine-

corr

ecte

dse

rum

con

cent

ratio

n (n

g/m

L)Darbepoetin alfa (oncology; 0.5 µg/kg, n = 20)*1

Darbepoetin alfa (dialysis; 0.5 µg/kg, n = 11)2

rHuEPO (dialysis; 100 IU/kg, n = 10)2

t1/2 = 25.3 hours

t1/2 = 8.5 hours

t1/2 = 38.8 hours

*Oncology patients received 2.25 µg/kgData shown is normalised for 0.5 µg/kgSD = standard deviation

DARBEPOETIN vsr-EPO dosing

DOSING: 150 µg/sc/w = 30.000 UI r-EPO

300 µg/sc/w = 60.000 UI r-EPO

500 µg/sc/w = 100.000 UI r-EPO

Newcarbohydrateside chains

Predictive factors of response todarbepoetin-alpha (DPO)

in myelodysplastic syndrome (MDS).

EPO, erythropoietin; NS, not significant.

NS2/22 (9%)4/15 (26·6%)Hypoplastic bone marrow

<0·00027/22 (31·8%)14/15 (93·3%)Marrow blasts <5%

<0·0311/22 (50%)13/15 (86·6%)Red blood cell transfusions< 4/month

<0·0036/21 (28·5%)11/13 (84·6%)Serum EPO levels < 200 IU/l

P-valueNon-respondersResponders

Stasi et al, Ann Onc 2005

Musto et al, Br J Haematol2005

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SLinee-guida

Ross et al,The Oncologist, 2007; 12: 1264

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SEven better

response rate with …

• Longer treatments (20 weeks)• Iron supplementation• Lower endogenous EPO levels


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Moyo et al, Ann Hematol 2008; 87: 527

Darbopoetin

r-Epo alfa

No directcomparativestudies

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p<0.001


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SFactors predicting aresponse to r-Hu-Epo

• Serum erythropoietin level lower than 500miu/ml

• FAB class (refractory anaemia or refractoryanaemia with ring sideroblasts)

• Fixed, rather than weight adjusted, dosages


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49-59%after 12-52

wks ***

500 mcg Q2-3 WDarbepoetin206Phase IIGabrilove,2008

69% **300 mcg QWDarbepoetin44Phase IIVillegas,2008

50%40.000 BIWr-HuEpo α60Phase IILatagliata,2008

66%60.000 U/W300 mcg QW

r-Hu-EPO α/βdarbepoetin

271RetrospectivePark, 2008

ERR *Dose/ScheduleType of ESAN. pts.Type of study

More recent trials…

* EER: Erythroid reponse rate; ** 71% after adjunct of G-CSF;*** 26-34% of preiously ESA-treated pts.

All’analisi univariata e multivariata sono risultati fattori associati alla risposta:

- Indipendenza dalle trasfusioni

- Livelli di EPO sierica

- Citogenetica

- Valori basali di Hb

Modificata da Latagliata R, et al. Acta Haematologica 2008;120:104-107.

Fattori prognostici favorevoli associatialla risposta con EPO

Variabili Hazard ratio (IC 95%) pEtà 1,011 (0,981-1,042) 0,464Sesso maschile 0,792 (0,385-1,628) 0,526Tempo dalla diagnosi 0,995 (0,980-1,010) 0,507Livelli sierici di EPO 0,993 (0,986-1,000) 0,046Hb 1,845 (1,235-2,756) 0,003Citogenetica 0,479 (0,244-0,938) 0,032LDH 1,000 (0,999-1,002) 0,720Ferritina 1,000 (1,000-1,000) 0,845TD 2,876 (1,354-6,070) 0,006

Dall’analisi multivariata:Per ogni 1 g/dl di Hb basale in più, la probabilitàdi risposta cresce del 98% (p = 0,02)

Analisi di regressione di Cox univariata della risposta

Tehranchi, R. et al. Blood 2003;101:1080-1086

EFFETTO ANTI-APOPTOTICO di G-CSF

APOPTOSIS

G-CSFR Expressed on ErythroblastsTehranchi et al, unpublished

Glycophorin A+

CD34+

Day 0 (GpA+) Day 14 (Erythro) Day 14 (GpA+)

G-CSFRDay 0

92%

82% 51% 57%

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Reference No. pts G-CSF dose r-EPO dose

* darbepoetin

Duration

(weeks)

ITT Erythroid response

(complete + partial)

Negrin et al, 1993 24 0.2 -5 µg/Kg/d 100 -300 U/Kg/d 8-16 10/24 (42%)

Hellstrom -Lindberg et al, 1993 22 0.3 -3 µg/Kg/d 60-120 U/Kg/d 12 8/21 (38%)


Hellstrom -Lindberg et al, 1998 50 30 -150 µg/d 5.000 -10.000 U/d 10-12 18/47 (38%)

Remacha et al, 1999 14 1 µg/Kg/t.i.w. 300 U/Kg t.i.w. 8 5/11 (45%)

Himamura et al, l 994 10 400 -1200 µg/sqm/d i.v. 100 -400 U/Kg t.i.w. 10 0/10 (0%)

Musto et al, 1994 12 300 µg/t.i.w. 300 U/Kg t.i.w. 8 0/12 (0%)

Mantovani et al, 2000 33 1.5 µg/Kg/d (adjusted) 200 -400 U/Kg t.i.w 12-36 20/25 (80%)

Musto et al, 2001 27 300 µg/t.i.w 300 U/Kg t.i.w 8 1/25 (4%)

Hellstrom -Lindberg et al, 2003 63 75 -300 !g/t.i.w 10.000 U 5 d/week 12 22/53 (41.5%)

Casadevall et al, , 2004 30 105 µg/t.i.w 20.000 U/t.i.w 12 14/24 (58.3%)

Miller et al, , 2004 35 1 µg/Kg/d 150/300 U/kg d 12 14/35 ( 40%)

Balleari et al, 2006 24 300 µg/w 10.000 U t.i.w. 8-16 15/24 (62,5%)

Bowen et al, 2006

Park et al, 2008

Go tlib et al, 2009

21

132

15

30 -130 µg/ t.i.w

1.5 µg/Kg/d, 75 -300 !g/t.i.w

2.5 !g/kg b.i.w

10.000 -20.000 U t.i.w.

60.000 U/w – 300 !g /w *

9 !g/kg/week *

8-20

12

6

7/21 (33.3%)

79/132 (58%)

7 /15 (47%)

TOTAL

567

241/523 (46 %),

Clinical trials evaluating the combination of r-EPO and G-CSF in MDS

241/523: 46%

Study design

8 weeks

16 weeks

Off study

Response lost

Continue

Response

Response No Response

rHEPO(10.000 U x 3/w)

Continue

Response

Off study

Response lost

Response

Off study

No Response

HEPO + G-CSF!0.000 u x 3/w

+ 300 microg/w

randomisation

Cross-over

24 weeks

Balleari E et al, Annals Hematology 2006, 85:174-80

EPO+ G-CSF IS BETTER THAN EPO ALONE IN LOW-RISK MDS: RESULTS FROM A SINGLE CENTER RANDOMISED STUDY

0

10

20

30

40

50

60

70

80

8 weeks 16 weeks

rHEpo

rHEpo + G-CSF

Erythroid response

p= 0.03

EB- DIMI 2006

Balleari E et al, Annals Hematology 2006, 85:174-80

0

10

20

30

40

50

60

70

80

90

transfusion-

dependents

no-transfusion

dependents

rHEpo

rHEpo + G-CSF

Response rates according to transfusion-dependence

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Reference No. pts G-CSF dose r-EPO dose

* darbepoetin

Duration

(weeks)

ITT Erythroid response

(complete + partial)


Hellstrom -Lindberg et al, 1993 22 0.3 -3 µg/Kg/d 60-120 U/Kg/d 12 8/21 (38%)


Hellstrom -Lindberg et al, 1998 50 30 -150 µg/d 5.000 -10.000 U/d 10-12 18/47 (38%)

Remacha et al, 1999 14 1 µg/Kg/t.i.w. 300 U/Kg t.i.w. 8 5/11 (45%)

Himamura et al, l 994 10 400 -1200 µg/sqm/d i.v. 100 -400 U/Kg t.i.w. 10 0/10 (0%)

Musto et al, 1994 12 300 µg/t.i.w. 300 U/Kg t.i.w. 8 0/12 (0%)

Mantovani et al, 2000 33 1.5 µg/Kg/d (adjusted) 200 -400 U/Kg t.i.w 12-36 20/25 (80%)

Musto et al, 2001 27 300 µg/t.i.w 300 U/Kg t.i.w 8 1/25 (4%)

Hellstrom -Lindberg et al, 2003 63 75 -300 !g/t.i.w 10.000 U 5 d/week 12 22/53 (41.5%)

Casadevall et al, , 2004 30 105 µg/t.i.w 20.000 U/t.i.w 12 14/24 (58.3%)

Miller et al, , 2004 35 1 µg/Kg/d 150/300 U/kg d 12 14/35 ( 40%)

Balleari et al, 2006 24 300 µg/w 10.000 U t.i.w. 8-16 15/24 (62,5%)

Bowen et al, 2006

Park et al, 2008

Go tlib et al, 2009

21

132

15

30 -130 µg/ t.i.w

1.5 µg/Kg/d, 75 -300 !g/t.i.w

2.5 !g/kg b.i.w

10.000 -20.000 U t.i.w.

60.000 U/w – 300 !g /w *

9 !g/kg/week *

8-20

12

6

7/21 (33.3%)

79/132 (58%)

7 /15 (47%)

TOTAL

567

241/523 (46 %),

Clinical trials evaluating the combination of r-EPO and G-CSF in MDS

241/523: 46%

Responses with r-EPO alone:

Alpha or Beta r-EPO: 38.4-68.3%

Darbo: 40.5-71%

Is there a real role for the association with G-CSF?

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SA validated decision model for treatment of the anemia in MDS with G-CSF + EPO

Predictive value of model: p < 0.001

Variable value score value score

Transf. need < 2 U/m 0 ≥ 2 U/m 1

Serum-epo < 500 U/l 0 ≥ 500 U/l 1

Total score 0: 74% OR, score 1: 23% OR, score 2: 7% ORCR = normalised HbPR = stopped transfusion need or increase > 1.5 g/dlOR = overall responseBetter response in RARS

Hellstrom-Lindberg et al, Br J Haematol 2003

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Mundle et al, Cancer, 115, 706, 2009

Modificata da Mundle S, et al. Cancer 2009;115:706-715.

Metanalisi di studi con EPO alfa: risposta eritroide

Analisi della risposta eritroidestratificata per dosaggio diEPO alfa

• Metanalisi di 15 studi

• Pazienti esaminati: 741

La risposta a EPO alfa

• Migliora con l’aumento della dose

• Non migliora con l’aggiunta di G-CSF

Dosaggio EPO N. studi N. pazientiEPO alfa dose std30-40 K/settimana

5 studi 393 pazienti

EPO alfa + G-/GM-CSF30-40 K/settimana


EPO alfa ad alte dosi60-80 K/settimana


Ris

post

a er

itroi

de

p<0,001

CSF

0

20%

40%

60%

80%

EPO std. EPO std. + G-/GM-CSF EPO alte dosi

RE globale RE maggiore

n.s.49,0%

27,2%

50,6%

30,5%

64,5%

44,9%p=0,007

Modificata da Mundle S, et al. Cancer 2009;115:706-715.

Risposta eritroide nei pazienti trasfusione - dipendenti

Analisi della risposta eritroidenei pazienti trasfusione-dipendenti, stratificata perdosaggio di EPO alfa

• Metanalisi di 12 studi

• Pazienti esaminati: 307

DosaggioRispostaeritroideglobale

Diventanoindipendenti

da trasfusioni

EPO monoterapia 41,6% 28,8%

p = 0,643 p = 0,705

EPO + G-/GM-CSF 36,4% 24,8%

Dosaggio EPO N. studi N. pazienti

EPO alfa mono6 studi

(4 ad alte dosi+ 2 a dose std)

192 pazienti

EPO alfa +G-/GM-CSF 6 studi 115 pazientiR

ispo

sta

eritr

oide

0

20%

40%

60%

Solo EPO EPO std. + G-/GM-CSF

RE globale Indipendenza da trasfusioni

41,6%

28,8%

36,4%

24,8%

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Vs High EPO p < .001 (p < .01 for Major ER)

Vs High EPO p < .007 (p < .01 for Major ER)

p n.s.

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In all studies taken together, a univariate metaregression analysis revealed thatgreater proportions of patients who had RA or RARS (p < .001) and lower sEPOlevels (p < .001) were associated with significantly higher ER rates.

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SOther combinations…

• ATRA: Stasi, Blood 2002; Itzykson,Leukemia 2009

• 13-cis retinoic acid + Vit D: Ferrero, Br JHaematol 2009

• Thalidomide: Steurer , Br J Haematol;2003; Musto, Leuk Res 2006

• Lenalidomide: ECOG 2905 trial

On-going or still preliminary or relevantside-effects: currently not recommended

Modificata da Ferrero D, et al. Br J Haematol 2009;144:342-349.

Risposta eritroide nei pazienti trasfusione-dipendenti

Trattamento: EPO + acido 13 cis-retinoico + Vit. D3

• MDS con Hb <10 g/dl

• Blasti midollari <10%

• Trasfusione-dipendenti: 70%

Studio in aperto su 63 pazienti

Risposte eritroidi secondo i criteri dell’International Working Group (Cheson et al., 2000)Sottogruppo di pazienti Numero di pazienti Risposte maggiori Risposte minori Risposte totali p*

Tutti 63 29 (46%) 12 (19%) 41 (65%)

Non-RAEB* 47 24 (51%) 9 (19%) 33 (70%) 0,224

RAEB-1 16 5 (31%) 3 (19%) 8 (50%)

Trasfusione-dipendenti 44 23 (52%) 5 (11%) 28 (63%) 0,780

Non trasfusi 19 6 (31%) 7 (37%) 13 (68%)

Le risposte sono elevate anche nei pazienti trasfusione - dipendentise a EPO si aggiungono agenti differenzianti

RAEB, anemia refrattaria con eccesso di blasti. *Risposte totali valutate con il test esatto di Fisher.

The largest study on ESA in MDS

• 433 MDS patients with low/int-1 IPSS, Hb < 10 g/dl,serum EPO < 500 miu/ml, compared with IPSS cohort

• Weekly dose of r-EPO alpha or beta (60.000 U) orDarbepoetin (300 mcg), +/- G-CSF (wbc < 10.000/mmc)

• 50% response according to IWG 2006 criteria (medianduration of response of 20 months, range 3-74)

• 72% of 54 relapses without disease progression

• Factor associated with response at multivariate analysis:Epo level < 200 miu/ml, no tranfusion need

Park et al, Blood 2008; 111: 574-82

No impact of other potentialpredictive factors for response

• Multilineage dysplasia: (63% responders vs61% non-responders (p 0.52)

• Interval between diagnosis and r-EPOtreatment (p 0.13)

• r-EPO or Darbo alone (66%) vs r-EPO orDarbo + G-CSF (58%) (p 0.17)

• RARS/RCMD-RS: r-EPO or Darbo alone (62%)vs r-EPO or Darbo + G-CSF (64%): (p 0.8)

Park et al, Blood 2008; 111: 574-82

Reasons for loss of response toEPO in MDS

• Clinical observations of responders• – Marrow progression / AML 18-28%• – Often no evidence of disease progression

• Development of functional iron deficiency• Pure red cell aplasia• – Very rare

• Theoretical basis• – Exhaustion of the normal erythroid progenitor pool• – No evidence of receptor down-regulation

Jädersten et al, Blood 2005, Park et al, Blood 2007 , Piron et al, Blood 2001

Interval between diagnosis and onset of ESA:< 6 months: blue curve; ≥ 6 months: red curve

Early introduction of ESAs may delay onsetof transfusion need

• 112 de novo MDS with Hb <10 g/l and no previous transfusions• Retrospective analysis from previous ESA studies• 63% erythroid response (IWG 2006) at 12 weeks• Predictors of response in multivariate analysis;• – Hb >9 g/dl• – S-Epo <100 U/l• – time from diagnosis to start of ESA <6 months

• Time to onset of transfusion dependency• – 80 months in pts with <6 months to ESA vs 35 months in pts• with C> 6 months to ESA (p=0.007)

Park et al (GFM) Leuk Res 2010

Do Growth Factors Improve Survival in MDS

Study Analysis No.

% EDOResponse;

Median (mos) Benefit from GF

•Golshayan Medline; 162studies 2592 39%

2-yr PFS 69% vs 57%2-yr Surv 78% vs 68%

•Park French EPOvs IPSS 284

40-50%; 20-24 mos

5-yr surv 64% vs 39%

•Jadersten Sweden vsPavia 358 39%; 23 mos

↑ Survival by MVA inlower risk, Tx ≤ 2PC/mo

•Greenberg EPO + GCSFvs SC 110 36% Median 3.1 vs 2.6 yr

(NS)

BJH 137:125, 2007. Blood 111:574, 2008. JCO 26:3607, 2008. Blood 114:2393, 2009

r-Epo and Survival in MDS

Park et al, Blood 2008Jadersten et al, J Clin Oncol 2008

Modificata da Park S, et al. Blood 2008;111:574-582.

EPO: sopravvivenza

• All’analisi multivariata il trattamento conr-EPO è associato in modo indipendentea una migliore sopravvivenzaHR: 0,43 [IC 95% 0,25-0,72]

• Il vantaggio in termini di sopravvivenzaè riservato ai pazienti che rispondonoa EPO

Francia IMRAW

Anni dalla diagnosi o di trattamentocon r-EPO

00

20

40

60

100

80

Sopr

avvi

venz

a gl

obal

e (%

)

2 4 5 6 7 8 9 10

Anni dalla diagnosi o di trattamentocon r-EPO

00

20

40

60

100

80

Sopr

avvi

venz

a gl

obal

e (%

)

1 2 3 5 6 7 8 10

90

70

50

30

10

31

90

70

50

30

10

94

Risposta a EPONessuna risposta a EPO IMRAW

Rispostaa EPO

p <0,001

Modificata da Jädersten M, et al. J Clin Oncol 2008;26:3607-3613.

EPO + G-CSF: sopravvivenza

All’analisi multivariata il trattamento con EPO + G-CSF è associato a:• Migliore sopravvivenza globale HR: 0,61 [0,44-0,83] p = 0,002• Minor rischio di morte non leucemica HR: 0,66 [0,44-0,99] p = 0,042

Tempo (anni)

00

0,2

0,4

0,6

1,0

0,8

Prob

abili

tà d

i sop

ravv

iven

za

2 4 6 8 10 12 14 16

Trattati con EPO-G Non trattati

Pz trattati conEPO + G-CSF

per 12-18 mesi (n = 121)

Pz NON trattati (n = 237)

HR = 0,61(IC 95% 0,44-0,83)p = 0,002

Modificata da Jädersten M, et al. J Clin Oncol 2008;26:3607-3613.

EPO + G-CSF: progressione AML

Tempo (anni)

00

0,2

0,4

0,6

1,0

0,8

Prob

abili

tà d

i lib

ertà

da

AM

L

2 4 6 8 10 12 14 16

Trattati con EPO-G Non trattati

Pz trattati conEPO + G-CSF

per 12-18 mesi (n = 121)

Pz NON trattati (n = 237)

HR = 0,89(IC 95% 0,52-1,52)p = 0,66

Nessun effetto del trattamento sull’evoluzione leucemicaHR: 0,89 [0,52-1,52] p = 0,66

EPO + GCSF May Improve Survival inMDS with Low RBC Tx Needs

• Comparison of Nordic studies (EPO;n121) to Pavia (no EPO; n=237)

• Erythroid response 39%• Median response duration 23 mos• MVA: survival better with EPO if Tx

needs < 2 URBCs/mo (HR 0.61; p=0.002); no effect if higher Tx needs (p=0.36)

Jadersten. JCO 26:3607, 2008.

Epo and G-CSF in low risk MDS

Jadersten. JCO 26:3607, 2008

< 2 U RBC/month ≥ 2 U RBC/month

Studio prospettico: EPO ± G-CSF

Modificata da Greenberg PL, et al. Blood 2009;114:2393-2400.

SopravvivenzaLa sopravvivenza media è analoganei 2 bracci di trattamento:• SC: 2,6 anni EPO: 3,1 anni p = 0,28• Sopravvivenza globale HR: 0,77 (IC 95% 0,48-1,24)

Progressione• Non vi è alcuna differenza significativa tra i 2 gruppi• All’analisi multivariata il trattamento con EPO

non ha alcun effetto sulla trasformazione leucemica(p = 0,58)

Nei pazienti trattati con EPO la sopravvivenza è statisticamentemigliore nei responder rispetto ai non responder:3,7 anni vs 1,7 anni (p = 0,018)

Trattamento di supporto EPO 150 µ/Kg/d Sopravvivenza globale con trattamento

Prob

abili

tà 0,8

1,00,9

0,7

0,0

Mese

0,60,50,40,30,20,1

Prob

abili

tà 0,8

1,0

Log Rank Test p=0,28

0,9

0,7

0,0120

Mese

0,60,50,40,30,20,1

1101009080706050403020100

57 48 9 31,0Tr. supporto

53 38 15 37,0EPO

Totale Insuccesso CNSR MedianaTrattamento

57 6 51 -Tr. supporto

53 4 49 -EPO

Totale Insuccesso CNSR MedianaTrattamento

Tempo alla trasformazione leucemicacon trattamento

1201101009080706050403020100

Log Rank Test p=0,83

La selezione dei pazienti migliora l’esitodella terapia con EPO

15% di rispostePazienti SMD non selezionati• Tutti i sottotipi WHO/FAB

>60% di rispostePazienti SMD selezionati per• Diagnosi recente

• Trasfusione-indipendenza

• EPO <200 U/l (<500 U/l)

• Citogenetica normale

• Sottotipo morfologico: anemiarefrattaria

Prolungare il periodo di trattamentoa 24 settimane/Aggiungere G-CSF

LIN

EE-G

UID

A S

IE, S

IES,

GIT

MO

PER

IL M

ANAG

EMEN

T D

ELLE

MD

SBody of evidence

• Three meta-analyses including randomised (few)and phase II, single arm trials (level 1+)

• One large retrospective study and threeprospective, phase II trials (level 2++)

LIN

EE-G

UID

A S

IE, S

IES,

GIT

MO

PER

IL M

ANAG

EMEN

T D

ELLE

MD

S

• Patients with low-INT1 IPSS risk disease,haemoglobin levels lower than 10 g/dl, and serumerythropoietin levels <500 mIU/ml should beconsidered for ESAs, i.e. erythropoietin alpha,erythropoietin beta or darbepoetin (grade B).

• Fixed, rather than weight-adjusted, weeklysubcutaneous doses of 60–80,000U oferythropoietin (once-a-week or subdivided in twodoses) (grade A) or 300mcg darbepoetin (once-a-week) should be used (grade B) for at least 12weeks, possibly more than 20 (grade B).

1. Which patients are candidates forhematopoietic growth factors?

LIN

EE-G

UID

A S

IE, S

IES,

GIT

MO

PER

IL M

ANAG

EMEN

T D

ELLE

MD

S

• During ESAs treatment iron supplementationshould be considered for patients with atransferrin saturation lower than 20% (gradeD).

• If the patients respond to ESAs treatment, anattempt should be done to reduce the dose (orthe frequency of administrations) to the lowesteffective schedule able to the maintainhaemoglobin level between 10 and 12 g/dl(grade D).


LIN

EE-G

UID

A S

IE, S

IES,

GIT

MO

PER

IL M

ANAG

EMEN

T D

ELLE

MD

S

• The combination of ESAs and G-CSF should beconsidered only for not heavily (less than 2U permonth) red-cell transfusion-dependent patientswith serum erythropoietin levels <500 mIU/mland not responding to ESAs alone (grade C).

• Daily use of G-CSF to modify disease course isnot recommended (grade B).

• The use of G-CSF in severely neutropenicpatients with documented infection is notrecommended routinely, but must be decided ona case-to-case basis (grade D).


●Romiplostim 2 peptide chains with 4 TPO-R-binding sites

“Peptibody” (Amgen) (no sequence homology with TPO)

+ IgG-Fc-Fragment

Clinical trial in MDS:* - platelet ≤ 50 x109/L, best supportive care only

(n = 44) - 300, 700, 1000 or 1500 µg weekly for 4 weeks- platelet ↑ to 60, 73, 38, and 58 x109/L, resp.

– a durable platelet response for 8 consecutive weeks independent of platelettransfusions was achieved by 19 patients (46%)

– treatment was well tolerated, 2 patients progressed to AML during the trial

●Eltrombopag oral, no peptide, TPO receptor agonist

“Small molecule” (GSK)

MDS: stimulation ofplatelet production

* Kantarjian H, et al. J Clin Oncol. 2010;28:437-44.

clinicaloptions.com/oncologyAcute Leukemias and Myelodysplastic Syndromes

Extension Study of Romiplostim inThrombocytopenic MDS Patients Long-term follow-up extension study of open-label phase I/II

trial 28 patients; median age: 71.5 yrs (range: 63.0-76.6)

– Mean baseline platelet count: 31 x 109/L

– Bleeding events within last 12 mos: 36%

– Responded to treatment during previous study: 86%

Platelet responses achieved in 82% of patients– Responses lasting ≥ 8 wks: 61%

– Responses in patients with baseline platelets < 20 x 109/L: 67%

– Median response duration: 30 wks

– Responded by Wk 3: 54%Fenaux P, et al. ASH 2009. Abstract 2765.


Extension Study of Romiplostim inThrombocytopenic MDS Patients No patients developed antibodies to romiplostim or TPO

No reported bone marrow fibrosis

Bleeding in 64%

– ≥ 1 significant bleeding event: 21%

– Platelet transfusions: 29%

Adverse events mostly mild to moderate

– Epistaxis (36%), arthralgia (29%), anemia (21%), cough(21%), nasopharyngitis (18%), dizziness (14%), fatigue(14%), gingival bleeding (14%), hematoma (14%), andpruritus (14%)

Fenaux P, et al. ASH 2009. Abstract 2765.


Phase II Study of Romiplostim PlusLenalidomide in Lower Risk MDS Patients

Lyons RM, et al. ASH 2009. Abstract 1770.

Patients with IPSSlow- or intermediate-

1–risk MDS

(N = 39)

Romiplostim 500 µg subcutaneously once wkly + Lenalidomide 10 mg/day

(n = 14)

Romiplostim 750 µg subcutaneously once wkly + Lenalidomide 10 mg/day

(n = 13)

Placebo + Lenalidomide 10 mg/day

(n = 12)

*Patients who completed treatment could continue on an optional open-label romiplostim extensionperiod; findings of extension period not reported here.

Follow-up*

Four 28-day cycles


Phase II Study of Romiplostim PlusLenalidomide in Lower-Risk MDS Patients Preliminary data suggest potential association of romiplostim with

– Reduced incidence of thrombocytopenic events– Increased platelet counts– Reduced lenalidomide dose reductions/delays– Higher MDS response rates

Lyons RM, et al. ASH 2009. Abstract 1770.

Outcome, % Romiplostim 500 µg(n = 14)

Romiplostim 750 µg(n = 13)

Placebo(n = 12)

Clinically significantthrombocytopenia event

29 54 67

Platelet transfusion 7 31 25

Lenalidomide dose reduction/delay 36 15 42

ORR 36 15 8

CR 14 15 8

PR 21 0 0

Eltrombopag for the treatment ofthrombocytopenia due to low- and

intermediate risk MDS

Associazione QOL-ONE

di ricerca sulla qualità di vita in ematologia

II INVESTIGATOR MEETING

The Fox at Excel Hotel – LONDON

June 11, 2011

EQoL-MDS

Study design and population

• Adult MDS patients with thrombocytopenia• IPSS low or int-1

EQoLMDS

Fase II, multicentre, prospective, randomized, single blind

PLT count <30 Gi/L within the 4 weeks prior to randomization.

Subjects must be ineligible or relapsed or refractory to receive othertreatment options and must be ineligible to receive intensivechemotherapy or autologous/allogeneic stem cell transplantation.

Subjects must have PLT count and PLT transfusion data availableover a period of 8 weeks prior to randomization.

During the 2 months prior to randomization, subjects must have abaseline BM examination incl cytomorphology and cytogenetics.Histopathology should be performed.

ESAs or G-CSF in subjects with severe neutropenia and recurrentinfections are allowed during the study as per accepted standards.

ECOG Performance Status 0-3

Adequate baseline organ function defined by the criteria below:total bilirubin (except for Gilbert’s Syndrome) ≤ 1.5xULNALT and AST ≤ 3xULN; creatinine ≤ 2xULNalbumin must not be below the lower limit of normal by more than 20%.

Inclusion criteria:

•Anevaluationofthecostsofspecificdrugs(r-HuEPO,azacytidine,decitabine,lenalidomide)andtheirsequentialuseinthelower-riskIPSS(lowandintermediate-1)subgroupsbasedontheNCCNguidelines

•Resultsestimateanaverageannualcostforpotentiallyanemia-alteringdrugsof$63,577perpatient,rangingfrom$26,000to$95,000,dependingonthespecifictherapies.

•Inpatientsforwhomthetherapiesfail,annualcostsforironchelationplusredbloodcelltransfusionsareestimatedtoaverage$41,412

•Theeconomicimpactofdrugtherapyshouldbeweighedagainstthepatient'spotentialforimprovementinclinicaloutcomes,qualityoflife,andtransfusionrequirements.

GreenbergPLetal,JNatlComprCancNetw.2008Oct;6(9):942-53.

Costs of potentially anemia-altering drugs in MDS

1. Health Interventions(“intervento giusto al paziente giusto”)2. Timing(“al momento giusto e per la durata

giusta”)

Appropriatezzaprofessionale

Appropriatezzaorganizzativa

Appropriatezza

3. Setting(“nel posto giusto”)4. Professional(“dal professionista giusto”)

CARENZA MARZIALE IN CORSO DI

TERAPIA CON rHuEPO

• L'incremento dell'eritropoiesi può consumare i

depositi marziali e portare ad una carenza

marziale "assoluta" (ferritina serica <15 µg/l).• Il rapido ! dell'eritropoiesi, pur con depositi

marziali normali o !, può portare ad un

insufficiente apporto di ferro al midollo eritroide

(insufficiente quantità di ferro rapidamente

scambiabile nel S.R.E.?) (carenza marziale

funzionale, o relativa).


TERAPIA CON rHuEPO

Nella carenza marziale "funzionale" o "relativa" la

ferritinemia è normale, la sideremia scende a <60 µ

g/dl, la saturazione transferrinica a <20%, e la % di

emazie ipocromiche (i.e. GR con MCHC <28 g/dl)

(valutata con contaglobuli automatico) sale da

<2.5% (valore normale) a >10%.


TERAPIA CON rHuEPO

Se, in corso di terapia con rHuEPO (specie nella

fase iniziale), si osserva una mancata risposta

terapeutica (o una risposta transitoria), e una

carenza marziale (assoluta o relativa), la risposta

può essere ripristinata da una terapia marziale (100 -

200 mg/die per os, o, specie se c'è infiammazione,

100 mg i.v. 2 -3 volte/7 gg).

EPO NELLE MDS IN ITALIA

• Indicazione terapeutica: AR, AS, RAEB• Criteri di esclusione: AREB-T• Criteri d’inclusione: anemia sintomatica e

anemia trasfusione-dipendente

• No darbo, no associazione con G-CSF• Gazzetta Ufficiale della Repubblica

Italiana• n.58 10-3-2000, Nota 648

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