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

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)

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)

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

Simplified MDS Risk Score(Kantarjian et al, Cancer 2008)

Association between pre-treatment characteristics and survival

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

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

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

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

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

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

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

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

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

AZACITIDINE VS STANDARD CAREREGIMENS IN high risk MDS: randomised,

open label study

25174945105117

CHTazacitidineLD ARA-CazacitidineBSCazacitidine

Fenaux P et al. Lancet Oncol, 2009

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

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

Thrombopoietin (TPO) involved at all stages

Stimulates platelet productionby promoting:

Proliferation

Survival

Differentiation of megakaryocyte precursorsinto mature megakaryocytes

Platelet release

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

TPO levels are inversely proportional to the plateletcount

increased

normal

thrombocytopenia

[TPO] free

[TPO] total normal

normal

normal platelet count

platelet

TPO

plasma

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

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

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

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

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

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

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

Thrombopoietin Receptor AgonistsTPO mimetics of second generation

Fc carrierdomain

Peptide receptor-binding domain

Romiplostim Eltrombopag

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

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

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

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

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

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

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

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

Efficacy of Eltrombopag in splenectomizedversus nonsplenectomized ITP patients

Lancet, 2011

EltrombopagDurability Platelet Response in Long-term

EXTEND trial

Bussel J et al, ASH 2010

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

Potential risks of thrombopoietic agents

Adverse event Rebound thrombocytopenia

Thrombosis

Increased marrow reticulin

Acceleration of hematologic malignancy

George JN et al. Haematologica, 2008

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)

No increase of the malignant cells nor an expansion of blast cells in any of theexamined BM samples in vitro or in vivo

Increased megakaryocytic differentiation and colony formation of BM-MNCin a concentration-dependent manner

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

Mean platelet count increase

*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

*

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

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

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

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

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.

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

Differences were not statistically significant

small number in each group)

RESULTS

RESULTS

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

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

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