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Idiophatic Thrombocytopenic

Purpura: Current Concepts In

Pathophysiology AndManagement

Dr. Roberto StasiS.C. di Oncologia ed Ematologia

Ospedale Regina Apostolorum

Albano Laziale

Italy

Slovenian Society of Hematology

Kranjska Gora, 3-4 October 2008

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Terminology adopted by the IWG on ITP

(Blood, in press)

ITP = Primary Immune Thrombocytopenia

Idiopathic thrombocytopenic purpura no

longer used

We know that ITPO is an autoimmune disorder

Not all patients with ITP have purpura

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ITP: Definition

1. Isolated thrombocytopenia with otherwise

normal CBC and peripheral smear

2.

No other conditions or factors that maycause thrombocytopenia

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Epidemiology: The incidence of ITP in

adults increases with age

Frederiksen and Schmidt. Blood 1999;94(3):909-913

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Role of B cells

Role of T cells

Role of dendrytic cells (?)

ITP: Pathophysiology

Stasi et al, Thromb Haemost 2008; 99: 413

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Harrington et al, J Lab Clin Med 38:1, 1951

1951 plasma

Carl V Moore

Passive transfer of ITP with ITP plasma

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Antibody production

Cytokine secretion (TNF alpha, chemokines)

Antigen presentation

Co-stimulatory signals for T cells

B cells in ITP


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Oligoclonal T cells turn to polyclonal after

rituximab

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Cytokine secretion: (IFN-, IL-2, IL-10)

Co-stimulatory signals for B cells

Co-stimulatory signals for APC cells

Direct antiplatelet T-cell lysis

Preferential usage of TCR VB (oligoclonality)

Loss of appropriate T-cell apoptosis

Direct megakaryocyte damage (?)

Decreased Treg number and fuction

T cells in ITP


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B cell

CD154 CD40CD40 CD154

Macrophage

(APC cell)MHC II

CD28CD80

Th cellTCR

IL-2IFN-

MegakaryocyteTc cell

Epitopespreading

Platelet

phagocytosis

X

XX

Platelet autoantibody production

Impaired megakaryocyte maturation

Reduced platelet production

CD28

CD80

Platelets

Tc cell-mediated

platelet destruction


?

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Mechanism of Thrombocytopenia in ITP

Decreased platelet survival Impaired platelet production

No treatment

Prednisone

Post-splenectomy

No treatment

Prednisone

Post-splenectomy

Normal

range

Normal

range

Radiolabeled autologous platelets Production Platelet count / Platelet survival

Heterologous platelets

are cleared much faster

(minutes-hours)

Most patients have

inappropriately low or

normal rates of platelet

production

Ballem PJ et al. J Clin Invest. 1987;80:33-40

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Antibodies can also damage

megakaryocytes in the bone marrow

Electron micrographs,

showing normal

megakaryocytes (A) versus

the apoptotic damaged

megakaryocytes (B, C)

present in the bone marrowof patients with ITP

McMillan et al. Blood 2004;103:1364-1369

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TPO levels in ITP are not or only mildly

elevated

Kosugi et al. Br J Haematol1996;93:704706

Where it should be

Where it is

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Clinical presentation

Stasi & Provan. Mayo Clin Proc 2004;79:504522

Often diagnosed on the basis of routine labs

if thrombocytopenia is mild.

Signs/symptoms:

Easy bruising

Mucocutaneous bleeding

Life-threatening hemorrhages

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Impact of ITP on quality of life in relation to

other chronic conditions

All scores range from 0 to 100.

Higher scores indicate better

health-related quality of life (HRQoL)

SF-36 scales

0

10

20

30

40

50

60

70

80

90

100

Physical

function

Physical

role

Bodily

pain

General

health

Social

function

Emotional

role

Vitality Mental

health

Healthy Arthritis Diabetes ITP

Adapted from: Bussel J et al. Presented at:

45th ASH Annual Meeting; Dec 69, 2003; San Diego, CA, USA

Data on file, Amgen

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The 3 categories of ITP patients

1. Those who must or should be treated. Active bleeding

OR

Platelet count 30 x 109/L

Stasi & Provan. Mayo Clin Proc 2004;79:504522
http://www.freefoto.com/preview.jsp?id=21-18-72http://www.freefoto.com/preview.jsp?id=21-18-73http://www.freefoto.com/preview.jsp?id=21-18-71

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Management of the bleeding patient

How severe is bleeding?

Life-threatening (eg intracranial

haemorrhage, gastric haemorrhage

[melena]) see Emergency treatment

Not life-threatening

Severe (eg metrorrhagia, unstoppableepistaxis) see Emergency treatment

Mild to moderate (eg petechiae, ecchymoses,

gingival bleeding) see Standard treatment

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Emergency treatment

Intravenous immunoglobulin

1 g/kg, repeated the following day if the platelet

count remains

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If not bleeding, when should we treat

ITP patients?

Disease considerations

Patient considerations

Treatment considerations

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Lacey & Penner. Semin Thromb Hemost 1977;3:160174

0 = No bleeding

1 = Minimal bleeding after trauma

2 = Spontaneous but self-limited

bleeding

3 = Spontaneous bleeding requir ing

special attention

4 = Severe life-threatening bleeding

Disease considerations:

platelet count and bleeding in ITP

1401201008060402010 50

1

2

3

4

0

Ble

edingmanifestation

Platelet count x 10

3

/L

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Disease considerations:

natural history of chronic ITP in adults

Variable and unpredictable

Spontaneous remissions ~5-10%1

85% of patients achieve a platelet count

>30 x 109/L without any treatment2

Overall mortality risk relative to the general

population 4.2 in those with chronic severe ITP2

1. Stasi et al.Am J Med 1995;98:4364422. Portielje et al. Blood 2001;97:25492554

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Patient considerations

Risk of fatal haemorrhage greatest in older patients:1

0.4% per year in patients 60 years Energetic lifestyles require safer platelet counts

Platelet >2030 x 109/L Platelet >50 x 109/L Platelet >80 x 109/L

Cohen et al. Arch Intern Med 2000;160:16301638

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Only a few treatments are truly evidence based and

approved by EMEA

Long-term side effects for new agents are not

currently known

Treatment of ITP may be more dangerous than the

disease itself:1

6 patients out of 152 died

2 died from haemorrhage

4 died from infections probably treatment related

1. Portielje et al. Blood 2001;97:25492554

Treatment considerations

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Recommendation for safe platelet counts in

adults

Dentistry 10 x 109/L

Extractions 30 x 109/L

Regional dental block 30 x 109/L

Minor surgery 50 x 109/L

Major surgery 80 x 109/L

Obstetrics: Vaginal delivery 50 x 109/L

Caesarean section 80 x 109/L

BCSH Guidelines. Br J Haematol 2003;120:574596

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First-line therapy in newly-diagnosed ITP

Corticosteroids

Prednisone 12 mg/kg/day OR ~70%, sustained

responses ~15%1

High-dose dexamethasone 40 mg/day for 4 days ~85% OR, sustained responses >50%2

Early management for those unresponsive to steroids

IVIg 0.51 g/kg/day for 1 or 2 days OR ~80%(recommended for patients with critical bleeding)1

IV anti-D 5075 g/kg for 1 day OR ~70%1

1. Stasi et al. Thromb Haemost 2008;99:4132. Cheng et al. N Engl J Med 2003;349:831836

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Splenectomy in ITP

Indicated in case of:1

Severe thrombocytopenia (Plt

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Stasi et al, Am J Med 1995

Thrombocytopenia-free survival after

splenectomy

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Defining chronic refractory ITP

Stasi et al. Thromb Haemost 2008;99:413

The patient has failed to

respond to splenectomy

AND

The platelet count is

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Long-term outcomes in adults with chronic

ITP after splenectomy failure

105 patients with refractory ITP; median

follow-up 110 months

30% patients remained unresponsive

to treatment

16% died of ITP (bleeding, 11 patients; therapy

complications, 6 patients)

14% died of unrelated causes

McMillan & Durette. Blood 2004;104:956960

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Challenges facing clinicians in deciding on

treatments for chronic and refractory ITP

Treatment recommendations derive largely from

uncontrolled cohort studies and expert opinion

Criteria to define platelet count outcomes are not

standardized across studies making their results

difficult to compare

Important clinical outcomes, such as bleeding and

quality of life, are rarely reported in cl inical studies

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Management options in chronic refractory ITP

Simple measures

Interventional measures*

*Many of which are utilised in an off-label setting

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Simple measures

Look for accessory spleen1

Found in 12% of patients failing to respond

Look for H. pylori at presentation2

Variable reports of ITP response

post-eradication2

Tranexamic acid

Widely used (no robust evidence) Oral contraceptives

In young women

1. Stasi et al. Thromb Haemost 2008;99:4132. Stasi & Provan. Mayo Clin Proc 2004;79:504522

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Interventional measures: non-selective

therapies*

Oral/IV dexamethasone

IV methylprednisolone

Danazol

Dapsone

Azathioprine

Vinca alkaloids

IV cyclophosphamide

Cyclosporine

Combination chemotherapy Interferon-

Mycophenolate Mofetil

Osteoporosis, psychosis etc

Diabetes, fluid retention

Weight gain, hirsutism, LFTs abnormal

Haemolysis

Immunosuppression, LFTs abnormal

Neuropathy

Leukaemia, cytopenia, teratogenic

Nephrotoxic, immunosuppression

Leukaemia, myelosuppression Thrombocytopenia

Nausea, diarrhoea

BUT: No real evidence of which/when to use or in which order1

LFTs, liver function tests;Staph, staphylococcal 1. Stasi & Provan. Mayo Clin Proc 2004;79:504522*Many of which are utilised in an off-label setting

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Interventional measures: targeted therapies

Thrombopoietin receptor stimulators

Syk inhibitors

R788 (tamatinib fosdium)

Antibody therapies

Campath-1H (anti-CD52)

Anti-CD40 ligand (anti-CD154)

GMA161 (anti-CD16)

Rituximab

Staphylococcal protein A (PRYX-100)

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Rituximab systematic review: Efficacy

Arnold DM et al. Ann Intern Med. 2007;146:25-33

46,3

24,0

62,5

0,0

10,0

20,0

30,0

40,0

50,0

60,0

70,0

80,0

150 x 10E9/L 50-150 x 10E9/L >50 x 10E9/L

Pooledestimateforr

esponse(%)

19 reports for efficacy (n = 313)

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Rituximab in chronic ITP

No RCT. Long-term CR in 1520% of cases

Adverse events mild, but no long-term safety data

(>10 year data)

Deaths reported in 2.9% of ITP cases treated with

rituximab, but they could not be attr ibuted to the

study drug

Valuable option for patients at high risk for

splenectomy and for those not willing to undergo

surgery

Cooper et al. Curr Opin Hematol 2007;14:642646

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Autologous haematopoietic stem cell

transplantation

Only one phase I/II study reported

14 patients:

5 with Evans syndrome

6 durable complete responses (942 months)

2 durable partial responses No transplant-related death

Huhn et al. Blood 2003;101:7177

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Thrombopoietin receptor stimulators

Stimulate platelet production

Bind to and activate TPO-receptors (Mpl)

BUT no sequence homology to TPO

For two agents, romiplost im and eltrombopag, Phase

III studies are complete

Long-term side effects under investigation

Romiplostim approved by FDA

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P

P

P

JAK2 JAK2

TPO

TPO-R

CRH-1

LATENT STAT

MONOMERS

Recruitment and

phosphorilation

P P

JAK2 JAK2

TPO-R TPO-R

P

P P

P P

TPO

Dimerization

Into nucleus: binds DNA

and activates

transcription

SHCGRB2

SOSRAS/RAF

MAPK

P42/44

Cell membraneCRH-2

Histidine 499

TPO acts through c-Mpl (TPO-receptor)

Stasi et al. Drugs 2008

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No sequence similarity to natural TPO

Therefore, does not elicit anti-TPO antibodies

Romiplostim (nPLate)

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Romiplostim in Chronic ITP

Randomized,

double-blind,

Phase 3 trial

(n = 125)

Splenectomy

(n = 63)

Non-splenectomized

(n = 62)

Placebo

(n = 21)

Romiplostim 1 mcg/kg

SQ q wk, target

Plt 50200x109/L

(n = 42)

Placebo

(n = 21)

Romiplosti m 1 mcg/kg

SQ q wk, target

Plt 50200x109/L

(n = 41)

Weekly, s.c. romiplostim in slowly escalating doses (1 g/kg up to15 g/kg) for 24 weeks

Dose adjusted to achieve a platelet count of 50,000-200,000

Inclusion criteria: Age 18; ITP with platelet count

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Target platelet count 50,000-200,000

SEMSplenectomised

Non-splenectomised

Kuter et al. Lancet. 2008;371:395-403

Dose Adjustments

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Range = middle 2 quart ilesSplenectomised

Non-splenectomised

Platelet Counts


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Definition of durable response rate

Platelets 50,000/L forat least 6 of the last 8

weeks of treatment

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Romiplostim efficacy


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Placebo Romiplostim

Severe or life-

threatening

bleeding

5/41 (12%) 6/84 (7%)

Thrombosis 1 1 popliteal art.

thrombosis

1 CVA

Death 1 ICH

1 PE

1 ICH after

starting aspirin to

treat thrombosis

Increased bone

marrow reticulin

1 (reversible)

Adverse Events


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Eltrombopagc-Mpl

Kuter DJ. Blood 2007;109:4607

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Eltrombopag for Chronic ITP

Randomized

Double-blind

Phase 2 Trial

(n = 118)

Placebo

(n = 29)

Eltrombopag30 mg PO

once daily

(n = 30)

Eltrombopag50 mg PO

once daily

(n = 30)

Eltrombopag75 mg PO

once daily

(n = 28)

Bussel et al. N Engl J Med. 2007;357:2237-2247

Primary end point: Platelet count 50,000/mcl by day 43

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Platelet count 50,000/mcl

by day 43Bleeding

Eltrombopag efficacy

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Eltrombopag was effective regardless of concurrent

ITP therapy, splenectomy or baseline platelet count


Response to eltrombopag by randomization strata

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Adverse Events

Mild-moderate headache in all groups including placebo (10-20%)

One 66-yo with COPD and NSCLC died of sepsis after receiving50 mg eltrombopag for 21 days

No thrombosis reported

Conclusions

Eltrombopag 50-75 mg PO QD is effective for short-term

treatment of chronic ITP (50,000 platelets in ~80% of patients)

The drug is well tolerated

Significant improvement in bleeding symptoms and quality of life

were not well documented in this study

Would a higher dose increase the response rate to 100%?


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*

*

*

Long-term Safety and Efficacy of

Thrombopoietic Agents are Unknown

Kuter DJ. Blood 2007;109:4607

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ITP: Conclusions

Both B-cells and T-cell are deranged

Thrombocytopenia is due both to increased platelet

destruction and impaired platelet production

High-dose DXM probably better than PDN as front-

line therapy

Great efficacy of new thrombopoietic agents in

chronic ITP, but long-term safety data are lacking

Documents

Stasi R j08