Cytopenia among CML Patients on Imatinib in Kenya: Types ...
Le Sindromi Mielodisplastiche - Siematologia- dysplasia in one or more cell lineages - peripheral...
Transcript of Le Sindromi Mielodisplastiche - Siematologia- dysplasia in one or more cell lineages - peripheral...
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Le Sindromi MielodisplasticheAspetti biologici e terapia
TERAPIA DELLE MIELODISPLASIE
I Farmaci trombo-mimetici
Convegno Regionale SIE Abruzzo-Molise
7 luglio 2011
Marco RuggeriUO Ematologia, Ospedale San
Bortolo, Vicenza
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Myelodysplastic syndromes
Group of clonal haematopoietic stem cell disorders:
- ineffective haematopoiesis- dysplasia in one or more cell lineages- peripheral cytopenia(s)- variable tendency to progression to AML
Epidemiology- Annual incidence :3-5/100 000; >20/100 000 age>70yrs-Median age: 70 yrs M/F ratio 1.2:1
(WHO,2008)
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Myelodysplastic syndromes (MDS)
-Two classification systems (FAB-1982 and WHO-2008)
- Several prognostic-scoring systems (IPSS,WPSS,Simplified MDS Risk Score)
- Standardized response criteria (International WorkingGroup-IWG)
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Prognostic scoring systems underweightthe clinical importance of severe
thrombocytopenia
---2/30/1Cytopenias
PoorIntermediateGoodKaryotype
21-3011-20-5-10< 5Blast %
2.01.51.00.50
--RegularNoTransfusion*
-PoorIntermediateGoodKaryotype
RAEB-2RAEB-1RCMD;RCMD-RS
RA;RARS;5q-WHO cat.
3210
IPSS
WPSS *= RBC transfusion dependency
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Simplified MDS Risk Score(Kantarjian et al, Cancer 2008)
Association between pre-treatment characteristics and survival
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Prognostic factor PointsECOG performance status >2Age 60-64 >65Platelets (x 109/L) <30 30-49 50-199Hemoglobin <12 g/dLBM blasts, % 5-10 11-29WBC >20x109/LChromosome 7 or complex(<3)abnormalitiesPrior transfusion
2
12
3212
1223
1
Simplified Myelodysplastic Syndrome RiskScore (Kantarjian et al, Cancer 2008)
Score Mediansurvival(months)
0-45-67-8>9
5425146
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FABclassification Total no. Thrombocytopenia* Severe
thrombocytopenia°
AR 577 336(58%) 89(15%)
RARS 175 75(43%) 22(13%)
RAEB 804 574(71%) 137(17%)
RAEB-t 680 525(77%) 150(22%)
CMML 174 95(55%) 17(10%)
2410 1605(67%) 415(17%)
*platelet count <100x109/L°platelet count <20x109/L
Incidence of thrombocytopenia in 2410 MDS patients referred to M.D.Anderson Cancer Center since 1980 (Kantarjian et al, Cancer 2007)
The incidence and impact of thrombocytopenia in MDS
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IPSS group Total no. Thrombocytopenia* Severethrombocytopenia°
Low risk 257 52(20%) 6(2%)
Int-1 risk 603 387(64%) 93(15%)
Int-2 risk 514 371(72%) 83(16%)
High risk 382 316(82%) 95(25%)
SecondaryMDS 507 378(75%) 106(21%)
Prior CHT 76 56(73%) 17(22%)
*platelet count <100x109/L°platelet count <20x109/L
Kantarjian et al, Cancer 2007
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Clinical consequences ofthrombocytopenia
- <10% of MDS patients present initially withserious bleeding
-Hemorrhage was a contributory cause ofdeath: 20%
-Hemorrhage was the only cause of death in10%
Kantarjian et al, Cancer 2007
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IWG response criteria for hematologicimprovement (HI)
Platelet responseHI-P M (Major)For patients with pretreatment PLT count < 100 x 109/L:
an absolute increase of 30 x 109/L or moreFor PLT-transfusion-dependent patients: stabilization of
PLT count AND PLT transfusion independence
HI-P m (Minor)For patients with pretreatment PLT count < 100 x 109/L: a
50% or more increase in PLT count, with a net increasegreater than 10 but less than 30 x 109/L
Cheson BD et al. Blood, 2000
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IWG modified response criteria forhematologic improvement
Platelet response (PLT pre-treatment< 100 x 109/L): Absolute increase of > 30 x 109/L (starting > 20 x 109/L) Increase from < 20 x 109/L to > 20 x 109/L and by at
least 100%
Cheson BD et al. Blood, 2006
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Hematologic Improvement for PLT
11/018Valproic acid
6/0101Arsenic trioxide
14/1729Thalidomide
16/1250Cyclosporine A
40/2768Antithymocyte Ig
0/040EPOr
10/043LenalidomideHI PLT% major/minor*N patientsTreatment
*Cheson BD et al. Blood, 2000
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Hypomethylating agents in MDS
Azacitidine and Decitabine have demonstrateanti-MDS activity1
FDA-EMA approved for MDS 2,3:1. Significant reduction in risk of transformation to AML2. Significant prolongation of survival in patients with
high-risk MDS
1Santini V et al. Ann Intern Med, 2001; 2Silverman LR et al. J Clin Oncol, 2002; 3Kantarjian H et al.Cancer, 2006
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Best response for MDS patients treated withazacitidine
44753518177474740284421Overall
000000000000HIMm
584221880042HINM
352100333200HIPm
16276352212196169HIPM
171184104884342HIEm
403316821222216112110HIEM
114200110021PR
1322830010101712157CR
%N%N%N%N%N%N
AZA SC 169 pts
AZA SC51 pts
Observation41 pts
AZA SC99 pts
AZA SC 70 pts
AZA IV48 pts
8921+9221Pro.9221Pro. 8921Pro. 8421
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AZACITIDINE VS STANDARD CAREREGIMENS IN high risk MDS: randomised,
open label study
25174945105117
CHTazacitidineLD ARA-CazacitidineBSCazacitidine
Fenaux P et al. Lancet Oncol, 2009
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0.8720 (18%)25 (19%)HINM<0.00318/129 (14%)46/141 (33%)HIPM
< 0.000117 (11%)62 (40%)HIEM< 0.000151 (29%)87 (49%)Any improvement
HI0.00947 (4%)21 (12%)PR0.01514 (8%)30 (17%)CR
HR< 0.000110.1 (3.9-19.8)15 (8.8-27.69TTT to AML
0.00411.5 (5.7-)21.1 (10.5-)Overall survival
P valueCCR(179)
Azacitidine(179)
AZACITIDINE VS CONVENTIONAL CARE REGIMENS IN H.R. MDSrandomised, open label study, azacitidine vs conventional care regimens
Fenaux P et al. Lancet Oncol, 2009
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Response and outcome of MDSpatients treated with decitabine
Results of RCT of 3 schedules of low dose decitabine95 patients with MDS high risk
33/68 (49%) patients with PLT pre-treatment < 100 x 109/Lachieved a PLT response (> 100 x 109/L)
4/15 (27%) with PLT pre-treatment < 20 x 109/L 14/31 (45%) with PLT pre-treatment < 50 x 109/L 15/22 (68%) with PLT pre-treatment < 99 x 109/L
One-year survival by platelet count: 86% for responders vs 54 non-responders (p= 0.03)
Steensma DP et al. J Clin Oncol 2009
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Thrombopoietin (TPO) involved at all stages
Stimulates platelet productionby promoting:
Proliferation
Survival
Differentiation of megakaryocyte precursorsinto mature megakaryocytes
Platelet release
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TPO: mechanism of action
Kuter DJ. Blood, 2007
CytoplasmSTAT P
P
RAS/RAF
MAPKK
p42/44
SOS
GRB2
P P
JAK
SHCCell membrane
TPOreceptor
Inactive receptor Active receptor
TPO
Signal Transduction andActivation of Transcription
Increased platelet production
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TPO levels are inversely proportional to the plateletcount
increased
normal
thrombocytopenia
[TPO] free
[TPO] total normal
normal
normal platelet count
platelet
TPO
plasma
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TPO levels are inversely proportional to the plateletcount (not in ITP!)
Nichol JL. In: Kuter DJ et al, eds. Thrombopoiesis and Thrombopoietins: Molecular,Cellular, Preclinical and Clinical. 1996;Mukai Thromb Haemost.
10000
1000
100
10
eTP
O L
evel
(pg/
mL)
Normale AA ITP
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Proposed feedback mechanism: TPO levels are inverselyrelated to the combined platelet and megakaryocyte
mass, because these cells bind and degrade TPO
In steady state conditions, plasma concentrations of platelet-bound TPO and free TPO are fixed
When platelet and megakaryocyte mass decrease, free TPOincreases
In ITP there is usually increased megakaryocyte mass andaccelerated removal of TPO by the increased plateletturnover
Free TPO is not sufficiently increased to compensate forthrombocytopenia
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Thrombopoietic growth factors1994: purification and cloning human TPO
“FIRST GENERATION” TPO: -Recombinant human thrombopoietins
rhTPOPEG-rHuMGDF
- Recombinant TPO fusion proteinsPromegapoietin (TPO/IL3 fusion protein)
rhTPO and PEG-rhMGDF studied in several thrombocytopenicdisorders
1998: clinical trials stopped for auto Ab against PEG-rhMGDF and endogenous TPO in some patients→ no development ofrhTPO
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CIT and rTPO: evidences from clinical studies(with first-generation TPO agents)
DecreaseTCP grade 3/4
CarboGynecologicCancer
12Ann Inter Med2000
Increaserecovery PLT
DoxoIfosfamide
Sarcoma12Ann Inter Med1997
Rh-TPO
DecreaseTCP grade 3/4
CTXAdvancecancer
68JCO 2000
ReductionPLTtransfusion
Carbopl.Paclitaxel
Lung cancer3010 (plac.)
ASCO meet.1998
Increaserecovery PLTcount
Carbopl.CTX
Advancedcancer
3110 (plac.)
Blood 1997
Increaserecovery andnadir PLTcount
Carbopl.Paclitaxel
Lung cancer4112(plac.)
NEJM 1997PEG-TPO
OutcomeCHTDiseaseN°ptsRef.TPO
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In non-myeloablative treatments a dose-dependent increase in platelet count havebeen demonstrated in several RCT
Efficacy is observed when a population of MKCis available to respond to TPO
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CIT and rTPO: evidences from clinical studies(with first-generation TPO agents)
No differenceIda, ARACAML28Blood 1998Rh-TPO
No differenceDauno, ARACAML2411 (plac.)
Blood 2000
No differenceDauno,ARAC, VP16
AML3812 (plac.)
Blood 1994PEG-TPO
OutcomeCHTDiseaseN°ptsRef.TPO
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In a myeloablative setting:
Moderate increase in peak platelet production Reduction in time to full platelet recovery No improvement in time to recovery to a platelet
count > 20 x 109/L No reduction in the need for platelet transfusions
No clinical activity in absence of target cells
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Thrombopoietin Receptor AgonistsTPO mimetics of second generation
Fc carrierdomain
Peptide receptor-binding domain
Romiplostim Eltrombopag
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Romiplostim: mechanism of action
PP
CytoplasmSTAT
RAS/RAF
MAPKK
p42/44
SOS
GRB2
P P
JAK
SHCCell membrane
thrombopoietinreceptor
inactive receptor active receptor
Signal Transduction andActivation of Transcription
Increased platelet production
Romiplostim
AKT1
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Eltrombopag: mechanism of action
PP
CytoplasmSTAT
RAS/RAF
MAPKK
p42/44
SOS
GRB2
P P
JAK
SHCCell membrane
thrombopoietinreceptor
inactive receptor active receptor
Eltrombopag
Signal Transduction andActivation of Transcription
Increased platelet production
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Romiplostim in Chronic ITP: Phase III study
TotalN= 125
Splenectomy(n = 63)
Non-splenectomized(n = 62)
Placebo(n = 21)
Romiplostim (n = 42)
Placebo(n = 21)
Romiplostim(n = 41)
Kuter D et al, Lancet 2008
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Placebo Romiplostim
0
38
(p = 0.0013)
Perc
ent
0
20
40
60
80
100
5
61
(P < 0.0001)
Splenectomizedn=21
Nonsplenectomizedn=42
0
79
0
20
40
60
80
100
(p < 0.0001)
Perc
ent
14
88
(p < 0.0001)
Splenectomizedn=21
Nonsplenectomizedn=41
OverallResponse
DurableResponse
Kuter D et al, Lancet 2008
Romiplostim – Efficacy: Platelets> 50,000/109L
2x baseline
>6 of last 8 weeks
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P = 0.017
(N = 41) (N = 84)
0
10
20
30
40
50
60
70
Placebo AMG 531
Perc
enta
ge o
f Pat
ient
s
Grade 2
Grade 3-5
Grade 1
Grade 1
Grade 2
Grade 3-5
34%
16%
Gernsheimer T et al, J Thromb Haemostas 2010
Romiplostim – Reduction in bleeding
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Romiplostim - DurabilityPlatelet Response in Long-term Extension Study
Bussel J et al, Blood 2009
Study Week
Per
cent
0102030405060708090
100
41 8 16 24 32 40 48 56 64 72 80 88 96 104 112120 128 136 144
Platelet Counts ≥ 50 x 109/L and Double the Baseline Value
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ITP patients,<30,000/µL
Standard of care+
50 mg eltrombopag
Standard of care+
Placebo
N=135
N=62
Randomize
2:1
Screening
6-month treatment period
• RAISE is a phase III, randomized, double-blind, placebo-controlled study ofeltrombopag treatment for 6 months
• Randomized patients were stratified by splenectomy status, concomitantmaintenance ITP therapy, baseline platelet count ≤15 x 109/L
• Eltrombopag dose adjustments were allowed (between 25–75 mg)• Reduction of concomitant medication and use of rescue treatments were allowed
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Odds of response: 8 times greatercompared to placebo
On therapy! Post therapy
BL 1 2 3 4 5 6 10 14 18 22 26 1 2 4
Odds ratio [99% CI] = 8.2 [3.59–18.73]; P<0.001
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Efficacy of Eltrombopag in splenectomizedversus nonsplenectomized ITP patients
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Lancet, 2011
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EltrombopagDurability Platelet Response in Long-term
EXTEND trial
Bussel J et al, ASH 2010
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INDICATIONS (EMA, AIFA): Adult patients with ITP, after
splenectomy failure, refractory to othertreatments (e.g. steroids or IVIg)
Adult patients, as second-line therapyand contraindication to splenectomy
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Potential risks of thrombopoietic agents
Adverse event Rebound thrombocytopenia
Thrombosis
Increased marrow reticulin
Acceleration of hematologic malignancy
George JN et al. Haematologica, 2008
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Does TPO mimetic drug potentially stimulatemalignant hematopoiesis in patients with AMLor MDS?
Is TPO mimetic drug effective in stimulatingmegakaryopoiesis in these patients?
BM cells(BM-MNC) of 10 pts (5 primary AML, 3 AML secondary to MDS, 2primary MDS) and 5 healthy controls exposed to different concentrationof Eltrombopag (0,1-30 mcg/ml)
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No increase of the malignant cells nor an expansion of blast cells in any of theexamined BM samples in vitro or in vivo
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Increased megakaryocytic differentiation and colony formation of BM-MNCin a concentration-dependent manner
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Safety and Efficacy of Romiplostim in Patients With Lower-Risk Myelodysplastic Syndrome and Thrombocytopenia
Kantarjian H et al, J Clin Oncol 2009
MDS low or INT-1 risk, PLT count < 50 x 109/L receiving onlysupportive care
Phase I/II, multicenter open label sequential – cohort, doseescalation study (4 sequential cohort: 300, 700, 1.000, 1.500 µgRomiplostim, once weekly; 4 week treatment phase, than 1 yearextension phase)
Efficay: IWG 2000 e 2006; durable PLT response: HI-P for > 8consecutive weeks (only for patients entered the extensionphase)
Safety: NCI Common toxicity Criteria for Adverse Events (version3.0); progression to AML was not considered an adverse event
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Mean platelet count increase
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*Osteonecrosis; blast cell count increase; anemia; neutropenia; thrombocytopenia
4 deaths: 1 cerebral hemorrhage; 1 sudden death after fall; 1 for general physical deterioration; 1 afterhospitalization for multiple small hemorrhages
*
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Adverse events of interest
1 thrombotic event (catheter related) 24 patients with BM biopsy pre- and
end-of-treatment: reticuline gradeincrease in 7, unchanged in 10,decreased in 7
No ab anti TPO
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Increase Blast cell/progressionto AML
4 (9%) blast cell increase: Count at baseline 0% with 700 µg RMP, 5% with 1.000; 5% and
3% with 1.500 Increase more than 20% Decrease within 5 weeks of RMP withdrawal to 8%, 6%, 7%,
10%
2 (5%) of AML progression1 baseline RA, IPSS 0.5, 4% blasts; after 17 wks of 300 µg RMP a
chloroma was diagnosed; no treatment: after excision and RMPwithdrawal 1% BM blasts and no recurrence of lesion
1 baseline RC with ML dysplasia, IPSS 0, 4 % blasts; after 55 wksof 1.000 µg RMP 24% BM blasts
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Randomized Phase II study evaluating the efficacy andsafety of romiplostim treatment of patients with low or
intermediate risk MDS receiving Lenalodomide
39 MDS patientstreated withLenalidomide(10 mg/day for28-day-cycle)12 placebo14 RMP 500 µg13 RMP 750 µg
x 4 cycles
Lyons RM et al. ASH 2009
000Deaths
01 (8)0Treatment-Related Serious Adverse Events
4 (31)5 (39)6 (55)Serious Adverse Events
13 (100)13 (100)10 (91)Any Adverse Event
N=13N=13N=11Adverse events, n (%)
1/11 (9)3/9 (33)1/10 (10) del(5q) not Detected*
1/2 (50)2/4 (50)0/1 (0) del(5q) Detected*
2 (15)5 (36)1 (8)Overall MDS Responsec
2 (15)5 (36)5 (42)Lenalidomide Dose Reduction/Delayb
4 (31)1 (7)3 (25)Platelet Transfusion
7 (54)4 (29)8 (67)Clinically Significant Thrombocytopenic Event
Efficacy Endpoints, n (%)
001 (8)> 1.0
3 (23)2 (14)3 (25)1.0
5 (39)7 (50)3 (25) 0.5
5 (39)4 (29)4 (33)0
IPSS Score*
8 (62)8 (57)6 (50)≥ 50 x 109/L
5 (39)5 (36)5 (42)< 50 x 109/L
Platelets*
N=13N=14N=12Baseline Demographics, n (%)
750 µg500 µg
RomiplostimPlacebo
Treatmenta
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Efficacy and safety of romiplostim in patients with low orintermediate risk MDS receiving Decitabine
29 MDS patientstreated withDecitabine14 placebo15 RMP 750 µg
x 4 cycles
Greenberg et al. ASH 2009
1 (9%)48239112 (20%)90155194
2 (18%)78245113 (30%)74153103
2 (15%)52181136 (50%)1958122
6 (40%)1353158 (57%)1340141
PLTtransfusion
PLT nadirPLT countday 1
NPLT transfusionPLT nadirPLTcountday 1
NDecitabine cycle
RomiplostimN= 15
PlaceboN= 14
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Phase 2, multicenter, randomized, placebo-controlled study
A treatment phase followed by a 6-monthextension phase.
Azacitidine: 75 mg/m2 subcutaneously dailyfor the first 7 days of each 28-day cycle x 4
Romiplostim 500 µg,750 µg, or placebosubcutaneously weekly starting on day 1 ofthe first azacitidine cycle.
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Primary efficacy endpoint :-incidence of clinically significant thrombocytopenic events
(platelet count < 50 x 109/L or platelet transfusion)
Secondary efficacy endpoints:-incidence of platelet transfusions-frequency and number of units transfused-incidence of azacitidine dose reduction, or delay resulting from thrombocytopenia-response rate at the end of azacitidine treatment
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Differences were not statistically significant
small number in each group)
RESULTS
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RESULTS
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RESULTS
Azacitidine dose was delayed becausethrombocytopenia in:-1 placebo-2 RMP 500 µg-1 RMP 750 µg
Azacitidine response rate was:- 15% placebo- 8% RMP 500 µg- 14% RMP 750 µg
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AML progression
Three cases of AML progression occurred, 1 in theplacebo group and 2 in the romiplostim 500 mcg
The placebo patient was 84 years old, diagnosed 33months before entering the study (RAEB1); IPSSscore: 1.5; entry platelet count of 19 x 109/L.Progression to AML after 15 weeks
The first romiplostim patient was 74 years old,diagnosed 31 months before receivingromiplostim,(RAEB1); IPSS score: 1.0 at baseline;platelet count of 33 x 109/L at study entry.Progression to AML after 11 weeks
The second romiplostim patient was 78 years old,diagnosed 1 month before receiving romiplostim(RAEB1); IPSS score: 2.0; platelet count of 6 x109/L. Progression to AML after 18 weeks
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Conclusions
TPO mimetics could be a potentialtherapeutic option of patients with MDS andthrombocytopenia
Data exploring clinical use of Romiplostim inlow risk MDS alone or in combination withhypoMeth are available
Eltrombopag is being studied in MDS Some concerns exist about the risk of AML
progression and risk of bone marrow fibrosis Actually, MDS patients should be treated with
these agents only in the context of clinicaltrials