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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Ross et al,The Oncologist, 2007; 12: 1264
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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
Ross et al,The Oncologist, 2007; 12: 1264
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Ross et al,The Oncologist, 2007; 12: 1264
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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
Moyo et al, Ann Hematol 2008; 87: 527
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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
Moyo et al, Ann Hematol 2008; 87: 527
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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%)
Negrin et al, 1996 55 0.2 -5 µg/Kg/d 100 -300 U/Kg/d 8-16 21/44 (48%)
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)
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%)
Negrin et al, 1996 55 0.2 -5 µg/Kg/d 100 -300 U/Kg/d 8-16 21/44 (48%)
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
6 studi 152 pazienti
EPO alfa ad alte dosi60-80 K/settimana
4 studi 196 pazienti
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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Mundle et al, Cancer, 115, 706, 2009
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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Mundle et al, Cancer, 115, 706, 2009
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).
2. 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
• 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).
3. Which patients are candidates forhematopoietic growth factors?
●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.
clinicaloptions.com/oncologyAcute Leukemias and Myelodysplastic Syndromes
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.
clinicaloptions.com/oncologyAcute Leukemias and Myelodysplastic Syndromes
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
clinicaloptions.com/oncologyAcute Leukemias and Myelodysplastic Syndromes
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).
CARENZA MARZIALE IN CORSO DI
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%.
CARENZA MARZIALE IN CORSO DI
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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