Update on the Management of

Immune Thrombocytopenic Purpura (ITP)

Dr Raymond Wong Department of Medicine & Therapeutics Prince of Wales Hospital

Immune Thrombocytopenia (ITP)

• Immune-mediated acquired disease of adults and children

• ITP is characterized by:

• A low platelet count (<100 x 109/L,

transient or persistent)1

• An increased risk of bleeding due to impaired

clotting mechanism2-4

HCV, hepatitis C virus; HIV, human immunodeficiency virus 1. Rodeghiero F, et al. Blood 2009; 113: 2386–93; 2. Stasi R, Provan D. Mayo Clin Proc 2004; 79: 504–22; 3. Chang M, et al. Blood 2003; 102: 887–95; 4. Cooper N, Bussel J. Br J Haematol 2006; 133: 364–74; 5. Terrell D, et al. Am J Hematol 2010; 85: 174–80; 6. Schoonen W, et al. Br J Haematol 2009; 145: 235–44

• The overall incidence of ITP among adults is

estimated at 3.3 per 100,000 person-years5

• Higher incidence in women versus men6

• Male:female ratio increases with age

• Higher incidence at older ages6

Clinical presentation of ITP varies

Dependent on the severity of thrombocytopenia,

the clinical presentation of ITP varies1,2

• Most patients are asymptomatic but may

complain of fatigue and easy bruising

• As platelet counts fall, symptoms become more

severe and may include:

- purpuric skin lesions

- cutaneous bleeding

- epistaxis

- gingival or gastrointestinal bleeding

- haematuria or menorrhagia

• Thromboembolic event risk increased3

Purpura (reddish purple spots)

Petechiae

1 cm 2 cm 3 cm

Actual scale:

1. Stasi R, Provan D. Mayo Clin Proc 2004; 79: 504–22; 2. Cines D, McMillan R. Annu Rev Med

2005; 56: 425–42; 3. Sarpatwari A, et al. Haematologica 2010; 95: 1167–75

4

Current Understanding of

Pathogenesis of ITP

Platelet count after infusion with patient plasma

Antiplatelet antibodies: 19511 Inhibition of megakaryocytes by

plasma from ITP patients: 20042

Immune pathogenesis of Immune Thrombocytopenia (ITP) Evidence that ITP is a B cell disease

1. Harrington WJ et al. J Lab Clin Med 1951;38:1–10; 2. McMillan R et al. Blood 2004;103:1364–1369

Pla

tele

ts (

×1

09/L

)

0

400

600

800

1000

200

1 2 3 1 2 3 4 5 6 7 8 9

Hours Days

Contr

ol m

egakary

ocyte

s (

%)

100

75

50

25

0

Thrombopoietin (TPO) Signaling Pathways

Stem cell

Bilineal progenitor cell

Committed megakaryocyte progenitor cell

Immature megakaryocyte

Mature megakaryocyte

Platelets

TPO

TPO

TPO

TPO

1. Kuter D, et al. Blood 2002; 100: 3456–69; 2. Kaushansky K. N Engl J Med 1998; 339: 746–54; 3. Wolber E, Jelkmann W. News Physiol Sci 2002; 17: 6–10. Figure adapted with permission from Kaushansky K. N Engl J Med 1998; 339: 746–54

TPO regulates the maturation of megakaryocytes,

via signal transduction pathways, into platelet-

producing cells

Thrombopoietin levels are lower than expected in ITP

1. Kosugi S et al. Br J Haematol 2003;93:704–706; 2. Aledort LM et al. Am J Hematol 2004;76:205–213

14

Th

rom

bopoie

tin

leve

l

Normal

12

10

8

6

4

2

0

ITP Aplastic

anemia

No correlation between platelet

count and TPO levels in patients

with ITP1

No significant difference in TPO

levels between patients with ITP

and controls2

ITP is caused by lower production and higher destruction of

platelets

Nugent D et al. Br J Haematol 2009;146:585–596 Ab, antibody

Increased platelet destruction

(spleen)

Decreased platelet production

(bone marrow)

Antiplatelet

immunity

(Ab + T cell)

Anti-megakaryocyte

immunity

(Ab + T cell)

Healthy

(normal platelet counts)

ITP effector immunity is primarily comprised of antibodies and T cells

Complex ITP pathophysiology underlies platelet regulation

Adapted from Stasi R et al. Thromb Haemost 2008;99:4–13 IFN, interferon; MHC, major histocompatibility complex;

Tc, cytotoxic T cell; TCR, T cell receptor

Th cell

IL-2 IFN-γ

B cell

Impaired megakaryocyte

maturation

Reduced platelet production

Megakaryocyte

Tc cell

Tc-cell-mediated

platelet

destruction

Platelets

Epitope

spreading

Macrophage

Platelet

phagocytosis

CD80

CD80

CD28

CD28

CD40

CD40

MHC II TCR

CD154

CD154

Platelet autoantibody production

10

Diagnosis of Immune

Thrombocytopenia (ITP)

Guidelines for diagnosis of ITP

• ITP remains a diagnosis of exclusion of other conditions or factors that cause

thrombocytopenia1

• Assessment of the following is needed to diagnose ITP:1

– Patient and family history

– Physical examination

– Complete blood count

– Peripheral blood film

– Other laboratory investigations

• There is no robust clinical or laboratory test that can establish a diagnosis with

accuracy1

• A platelet count <100 x 109/L has been defined as the threshold for diagnosis2

1. Provan D, et al. Blood 2010; 115: 168–86; 2. Rodeghiero F, et al. Blood 2009; 113: 2386–93

Results do not suggest

other aetiologies for

thrombocytopenia1

Diagnostic Approach in Suspected ITP

Basic evaluation Tests of potential utility Tests of unproven benefit

• Patient/family history

• Physical examination

• CBC and reticulocyte count

• Peripheral blood film

• Quantitative

immunoglobulin level

measurement*

• Bone marrow

(in selected patients)

• Blood group (Rh)

• Direct antiglobulin test

• H. pylori**/***; HIV/HCV**

• Glycoprotein-specific

antibody

• Antiphospholipid antibodies

(including anticardiolipin and

lupus anticoagulant)

• Antithyroid antibodies and

thyroid function

• Pregnancy test in women of

childbearing potential

• Antinuclear antibodies***

• PCR for parvovirus and CMV

• TPO

• Reticulated platelets

• PaIgG

• Bleeding time

• Platelet survival study

• Serum complement

*Should be considered in children; recommended in children with persistent or chronic ITP

**Recommended for adult patients regardless of geographic location

***Not recommended in children according to the American Society of Hematology guidelines (2011)1

CBC, complete blood count; CMV, cytomegalovirus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PaIgG, platelet-associated immunoglobulin G; PCR, polymerase chain reaction; Rh, rhesus 1. Neunert C, et al. Blood 2011; 117: 4190207; Table reproduced with permission from Provan D, et al. Blood 2010; 115: 168–86

Diagnosis of ITP

• The diagnosis of ITP remains one of exclusion; known causes of

thrombocytopenia include:

• Lupus erythematosus, infection (HIV, HCV), thrombotic thrombocytopenic purpura

• Hereditary thrombocytopenia: absent radius syndrome,

radio-ulnar synostosis, congenital amegakaryocytic thrombocytopenia, Wiskott-Aldrich

Syndrome, MYH9-associated thrombocytopenia, Bernard-Soulier Syndrome

• Vaccinations and transfusions

• Medication/drugs/diet (e.g. platelet-lowering treatments, alcohol, vitamin deficiency,

quinine from tonic water)

• Liver disease

• Other bone marrow disease/leukemia

HCV, hepatitis C virus; HIV, human immunodeficiency virus Provan D, et al. Blood 2010; 115: 168–86

Role of Bone Marrow Examination in the diagnosis of ITP

may be informative in patients > 60 years of age, in those with systemic

symptoms or abnormal signs, or in some cases pre-splenectomy

is not necessary irrespective of age in patients presenting with typical ITP

International consensus report on the investigation and management

of primary immune thrombocytopenia

Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, Chong BH, Cines

DB, Gernsheimer TB, Godeau B, Grainger J, Greer I, Hunt BJ, Imbach PA, Lyons G, McMillan R,

Rodeghiero F, Sanz MA, Tarantino M, Watson S, Young J, Kuter DJ. Blood 2010;115:168–186

The American Society of Hematology 2011 evidence-based practice

guideline for immune thrombocytopenia

Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA;

American Society of Hematology. Blood 2011;117:4190–4207

Provan D, et al. Blood 2010; 115: 168–86. Neunert C, et al. Blood 2011; 117: 4190 207;

15

Treatment strategies

for patients with ITP

Factors That Contribute to ITP Management Decisions

• In patients with platelet counts >50 x 109/L treatment is not usually indicated unless the patient has other risk factors (e.g. bleeding or surgery)1

• A platelet count of <30 x 109/L is commonly used as the threshold for treatment in asymptomatic patients

1. Rodeghiero F, et al. Blood 2009; 113: 2386–93; 2. Neunert C, et al. Blood 2011; 117: 4190–207; 3. Provan D, et al. Blood 2010; 115: 168–86

The goal of treatment in chronic ITP is not well defined and depends on balancing efficacy against the adverse effects of a given treatment1

Treatments for ITP: mechanisms of action

Newland A, et al. Immunotherapy (2018) 10(1), 9–25

International Consensus Report (2010):

Guidelines on First-line Treatment Options

IVIg, intravenous immunoglobulin Adapted with permission from Provan D, et al. Blood 2010; 115: 168–86

Clinical situation Therapy option

• Corticosteroids (standard initial treatment)

• Dexamethasone

• Methylprednisolone

• Prednis(ol)one

• Intravenous anti-D (Rho) immunoglobulin

• IVIg

Second-line therapy

Treatment for patients

failing first- and second-line

therapies

First-line therapy (initial treatment for newly diagnosed ITP)

ITP: Corticosteroid Treatment Strategy

Recommended

treatment strategy

Response

rate

Time to

response

Toxicities Duration of

sustained response

Dexamethasone

40 mg daily for

4 days every

2–4 weeks for

1–4 cycles

Up to 90% of

patients

respond

initially

Several days

to several

weeks

Can include: mood swings,

weight gain, anger, fluid

retention insomnia,

Cushingoid faces, dorsal fat,

diabetes, osteoporosis, skin

changes, alopecia,

hypertension, gastrointestinal

distress, ulcers, avascular

necrosis, immunosuppression,

psychosis, cataracts,

opportunistic infections,

adrenal insufficiency,

hypertension, anxiety.

Tolerability decreases with

repeated dosing

50–80%, the latter

with 3–6 cycles

Methylprednisolone

30 mg/kg/day for 7

days

As high as

95%

4.7 days (high

dose)

23% have sustained

platelet count (>50 x

109/L) at 39 months

Prednis(ol)one

0.5–2 mg/kg/day for

2–4 weeks

70–80% of

patients

respond

initially

Several days

to several

weeks

Remains uncertain;

estimated 10 year

disease-free survival

for 13–15%

Adapted with permission from Provan D, et al. Blood 2010; 115: 168–86

ITP: Intravenous Immunoglobulin (IVIg) Therapy

Provan D, et al. Blood 2010; 115: 168–86

Profile

• Have an initial response rate comparable to corticosteroids with a shorter time to response

• Many recipients attain a platelet increase within 24 hours at a dose of 1 g/kg

• In some patients, corticosteroids may enhance the IVIg response

Safety and efficacy

• Associated with higher toxicity than corticosteroids, especially headaches

• There is a need for a prolonged infusion over several hours

• Rare but serious toxicities include renal failure and thrombosis

• Transient response

ITP: Intravenous Anti-D Immunoglobulin

IVIg, intravenous immunoglobulin 1. Provan D, et al. Blood 2010; 115: 168–86; 2. Neunert C, et al. Blood 2011; 117: 4190–207

Profile

• Appropriate for Rhesus D-positive, non-splenectomised ITP patients1,2

• May be an effective alternative to IVIg:1

• It can be infused in a shorter time

• It has a potentially longer response

• May reduce the need for splenectomy

Limitations

• Not recommended for use in patients with autoimmune haemolytic anaemia to avoid exacerbation of haemolysis1,2

• Mild anaemia is expected and may be dose-limiting1

• It has a small donor pool and therefore the potential for limited availability1

ITP: Second-line Therapy

Provan D, et al. Blood 2010; 115: 168–86

Treatment decisions to be individualised based on:

Comorbidities

Patient expectations Compliance

Bleeding history

When first-line therapy fails, it is appropriate to move to second-line therapy in an attempt to gain a sustained increase in platelet count

International Consensus Report (2010):

Guidelines on Second-line Treatment Options

Adapted with permission from Provan D, et al. Blood 2010; 115: 168–86

Clinical situation Therapy option

First-line therapy

• Azathioprine

• Cyclosporin A

• Cyclophosphamide

• Danazol

• Dapsone

• Mycophenolate mofetil

• Rituximab

• Splenectomy

• TPO-R agonists (eltrombopag, romiplostim)

• Vinca alkaloid regimens

Treatment for patients failing first-

and second-line therapies

Second-line therapy

Second-line Immunosuppressive Agents for Adult ITP Patients

Adapted from Provan D, et al. Blood 2010; 115: 168–86

ITP: Rituximab Treatment

Chimeric, monoclonal antibody against B-cell antigen CD201 that

causes a transient elimination of B-cells2

Rituximab is not currently approved for treatment of ITP

The ASH guidelines indicate rituximab as a consideration for patients at

risk of bleeding who have failed one line of therapy such as

corticosteroids, IVIg, or splenectomy3

Initial response was seen in 62.5% of cases with a complete response

in 46.3% of patients*4

The 5-year response rate is approximately 21% for adults5

IVIg, intravenous immunoglobulin

*a complete response was defined as platelet count >150 x 109/L and overall response as a platelet count >50 x 109/L

1. Godeau B, et al. Blood 2008; 112: 999–1004; 2. Stasi R, et al. Thromb Haemost 2008; 99: 4–13; 3. Neunert C, et al. Blood 2011; 117; 4190–207; 4. Arnold D, et al. Ann Intern Med 2007;

146: 25–33; 5. Patel V, et al. Blood 2010; 116: abstract 72

ITP: Splenectomy

Splenectomy:

Is considered the traditional second-line therapy in adults with chronic ITP resistant to first-line treatments1

80% of patients respond to splenectomy with ~66% achieving a lasting response2

Splenectomy complication and mortality rates have been seen to be higher with laparotomy than in laparoscopy2

Criteria for splenectomy:1

Severe thrombocytopenia (platelet count <10 x 109/L)

A high risk of bleeding for platelet counts <30 x 109/L

The requirement of continuous corticosteroid therapy to maintain safe platelet counts

Splenectomy is deferred in most patients for ≥6 months2 but often for >12 months3 after diagnosis

1. Stasi R, et al. Thromb Haemost 2008; 99: 4–13; 2. Provan D, et al. Blood 2010; 115: 168–86; 3. Neunert C, et al. Blood 2011; 117: 4190–207

ITP: Splenectomy

Schwartz J, et al. Am J Hematol 2003;72:94-8; Vianelli N, et al. Haematologica 2005;90:72-7

ITP: Splenectomy

Standard second-line therapy for ITP1,2

Timing of

treatment

• Generally considered from 6 months after failure of primary treatment1,2

Efficacy • Initial haemostatic response in 70–80% of patients1,2

• 15–25% of patients relapse within 10 years1

• Success rate of ~66% with a sustained complete response1,3

Safety/

tolerability

• Splenectomy is associated with significant morbidity and a risk of overwhelming

and fatal Streptococcus pneumoniae infection2

• Complications of splenectomy can include infections, long-term relapse, prolonged

hospitalisation and risk of death1,2

• Risk of serious post-splenectomy infection is greater in patients >65 years of age1

• There may be a lower mortality rate with laparoscopic splenectomy1,3

• Occasionally, patients may fail to respond to splenectomy because of the failure to

remove an accessory spleen3

1. Provan D, et al. Blood 2010; 115: 168–86; 2. Neunert C, et al. Blood 2011; 117: 4190–207; 3. Stasi R, et al. Thromb Haemost 2008; 99: 4–13

TPO-R Agonists

• A novel therapeutic class of agents for chronic adult ITP which stimulate platelet

production:

• Bind and activate the TPO-R, helping to balance platelet production against

destruction1

• Agents include TPO peptide agonists (e.g. [romiplostim]) and TPO non-peptide

agonists (e.g. [eltrombopag])

Figure not to scale

Kuter D. Blood 2007; 109: 4607–16

Licensed TPO-RAs

Bussel JB et al. N Engl J Med 2006;355:1672–1681; Bussel JB et al. N Engl J Med 2007;357:2237–2247; Kuter DJ. Semin Hematol 2010;47:243–248

Small molecule, non-peptide

Does not compete with TPO for binding to TPO-R

Orally bioavailable, once-daily dosing

Low immunogenic potential

Advised not to take 2 hours before or 4 hours after a high-calcium meal or products containing polyvalent cations

Eltrombopag

TPO

Eltrombopag

Thrombopoiesis-stimulating peptibody

Structurally unrelated to TPO

Two dipeptides linked to the Fc fragment of an IgG1, administered subcutaneously once a week

Recycled via FcRn

Romiplostim

Fc Carrier Domain

TPO-RA

Peptides

RAISE Study Design

Cheng G et al. Blood. 2008;112(11):400.

Randomise

2:1

Phase III, randomised, double-blind, placebo-controlled study

N=135

N=62

Screening

6-month treatment period Adult, chronic ITP

patients,

<30 x 109/L

50 mg Eltrombopag + SoC

Placebo + SoC

• Randomized patients were stratified by splenectomy status, concomitant

maintenance ITP therapy, baseline platelet count ≤15,000/µL

• Eltrombopag dose adjustments were allowed (between 25–75 mg)

• Reduction of concomitant medication and use of rescue treatments were allowed

RAISE: Sustained Increase in Median Platelet Count versus Placebo

During Treatment with Eltrombopag

Median platelet counts rose from 16 x 109/L to ~36 x 109/L after 1 week in the eltrombopag group

Cheng G, et al. Lancet 2011; 377: 393-402. Erratum: Lancet 2011; 377: 382

59

131

60

134

58

128

58

129

120

On treatment

20

140

60

0

61

135

Eltrombopag

Placebo

40

100

59

128

59

123

43

96

46

101

44

95

43

91

53

110

54

110

55

118

58

119

Placebo

Eltrombopag Number of

patients

80

Post-

treatment

0 1 5 6 2 4 10 14 18 22 26 1 2 4 3 Study week

RAISE: Eltrombopag Reduces Clinically Significant Bleeding versus

Placebo

Over 6 months’ treatment, the odds of bleeding and clinically significant bleeding with eltrombopag were respectively 76% and 65% less compared with placebo (OR 0.24, 95% CI 0.16, 0.38; p<0.0001 and OR 0.35, 95% CI 0.19, 0.64; p=0.0008)

World Health Organization Bleeding Scale: Grade 2, mild blood loss; Grade 3, gross blood loss; Grade 4, debilitating blood loss CI, confidence interval; OR, odds ratio Cheng G, et al. Lancet 2011; 377: 393-402. Erratum: Lancet 2011; 377: 382

Eltrombopag

Placebo

EXTEND Study Design

Eltrombopag eXTENded Dosing (EXTEND) is an open-label safety and efficacy study of long-term treatment of adult patients with chronic ITP who had previously completed a eltrombopag olamine study1,2

eltrombopag olamine dosing period

Stage 1: eltrombopag olamine dosing initiation (≥100 x 109/L*)

Stage 2†: Minimizing ITP medications (≥50 x 109/L)

Stage 3: Optimizing eltrombopag olamine dosing (≥50 x 109/L)

Stage 4: Maintenance dosing

Dose modulated to platelet count

Start 50 mg

Screening

Patients

enrolled

N=301

The bars for each stage in the figure represent the period during which a cohort of patients were recruited to that phase of the study, and not the time over which a patient might take eltrombopag olamine *≥50 x 109/L in patients not receiving concomitant ITP medications at baseline †Only required for patients receiving concomitant ITP medications at baseline 1. Saleh et al. Blood 2011; 118: Abstract 3296; 2. Saleh et al. Poster presented at the 53rd Annual Meeting of the American Society of Hematology, Dec, 2011

EXTEND: Exposure

• Mean average daily dose

• 50.2 (range, 1–75) mg/day

• Overall median duration of exposure

• 2.4 years (range, 2 days to 8.8 years)

• 103 patients received rescue therapy

• 62% of patients were receiving

eltrombopag 50 or 75 mg at the end of the

study

Last recorded dose of eltrombopag, n (%)

N=302

Dose, mg

0 39 (12.9)

>0 to <25 26 (8.6)

25 43 (14.2)

>25 to <50 6 (2.0)

50 70 (23.2)

75 118 (39.1)

Wong R, et al. Blood 2017

EXTEND Study: Long-term Eltrombopag in patients with ITP

276/302 (91.4%) achieved platelet counts ≥30×109/L without rescue treatment

259/302 (85.8%) achieved platelet counts ≥50×109/L without rescue treatment

IQR, interquartile range aPlatelet count data were collected throughout the study as part of the complete blood count, weekly during the first 4 weeks, and at any dose change (eltrombopag or concomitant ITP medication). If a patient continued on a stable dose during any stage of the study for >4 weeks, platelets were assessed every ≥4 weeks; bFewer than 15 patients had platelet counts at each assessment after Week 250.

Wong R, et al. Blood 2017

Number taking concomitant medication at baseline

101/302 (33%)

Permanently stopped one or more concomitant ITP medications

34/101 (34%)

Reduced or permanently stopped ≥1 concomitant ITP medications without requiring rescue therapy

39/101 (39%)

Sustained reduction of at least 24 weeks

37/39 (95%)

EXTEND: Proportion of Patients Able to Permanently Stop or

Reduce Concomitant ITP Medications Taken at Baseline

Wong R, et al. Blood 2017

EXTEND: Incidence of Bleeding (WHO Bleeding Scale)

Wong R, et al. Blood 2017

Spleen tyrosine kinase (Syk) inhibition

Fosamatinib

An oral SYK

inhibitor, was

developed for the

treatment of

patients with ITP

and other additional

autoimmune

disorders

Newland A, et al. Immunotherapy (2018) 10(1), 9–25

Fosamatinib in the treatment of ITP

2 randomized study of fosamatinib versus placebo in ITP

Bussell J, et al. Am J Hematology 2018 [Epub ahead of print]

Advances in the Management of ITP

Concepts about the mechanisms of ITP have shifted from the traditional

view of platelet destruction mediated by antibodies, to a much more

complex situation where impaired platelet production has emerged as

playing a significant role.

Immunosuppressive therapy continue to be the mainstay of initial

therapy.

Patients who do not go into early remission (persistent ITP) should use

steroid-sparing agents.

Thrombopoietin receptor agonists (TPO-RAs) have been demonstrated

to be very effective in a high percentage of even refractory patients with

ITP. They are generally well-tolerated with good safety profile.

Thank you