ITP

Dr Robert BirdDirector of Haematology

Princess Alexandra HospitalBrisbane

About ITP

“Purpura haemorhagica occurs at every period of life, and chiefly affects persons of a weak and delicate habit. Women and boys appear to be most liable to it: in the latter, the haemorrhage usually takes place from the nose”

Willan R. On Cutaneous Diseases. London: J Johnson; 1808.

Historical perspective

“A sedentary mode of life, poor diet, impure air, and anxiety of mind, are the usual exciting causes of this disease”

“In the treatment of this disease, we should recommend moderate exercise in the open air, a generous diet, and the free use of wine…”

Chronic ITP incidence 3.3/100000/yr in USA/UK Australia ~825 new cases per year of ITP lasting > 1 year

Incidence & severity increase with age

Younger Women, Older men

Prevalence of ITP 0.02% in UK in Australia = 5000 people have ITP

40% never require treatment

33% adults respond to first line treatment of newly diagnosed ITP & don’t need treatment thereafter

67% need further treatment for ongoing, refractory or relapsed disease

ITP

NIHR HSC ID6116 www.hsc.nihr.ac.uk

http://www.hsc.nihr.ac.uk

gender difference varies dependent on age

Schoonen WM et al. Br J Haematol 2009;145;235–244

UK-based General Practice Research Database of 1145 patients with ITPIncidence: 3.9/100,000Overall average incidence:

Women: 4.4 (95% CI: 4.1–4.7)Men: 3.4 (95% CI: 3.1–3.7) Females

Males

Age range (years)18–24 85–10075–8465–7460–6455–5945–5435–4425–34 Total

0

2

4

6

8

12

10

Under 18

Mea

n an

nual

inci

denc

e(p

er 1

00,0

00 p

erso

n-ye

ars)

Men: bimodal incidence with peaks:age under 18 years age and between

75 and 84 years

What causes ITP?

1916 splenectomy shown to effective treatment for ITP

1920’s women with severe thrombocytopenia sometimes had babies with severe thrombocytopenia

1960 Harrington Hollingsworth experiment

Harrington–Hollingsworth Experiment

Harrington WJ et al. J Lab Clin Med 1951;38:1–10;Harrington WJ et al. Ann Intern Med 1953;38:433–69

Date: 22/10/1950

Chart1

Pre

15 min

1 hr

2 hr

1 day

2 days

3 days

4 days

5 days

6 days

7 days

8 days

Platelet Count

Platelet Count

800

400

125

25

0

15

35

117

260

320

675

1100

Sheet1

Pre15 min1 hr2 hr1 day2 days3 days4 days5 days6 days7 days8 days

Platelet Count80040012525015351172603206751100

How is ITP diagnosed? With most autoimmune diseases, if people have the

features of a disease & the antibody causing the disease is detected (serology) -> diagnosis is confirmed

But not in ITP….

ITP is a diagnosis of exclusion – making sure other diseases which can cause low platelets are “ruled out”

Not everyone with low platelets count has ITP

Family history of low platelets, deafness, kidney failure without clear causes

Failure to respond to usual treatment for ITP

No previous record of normal platelet count

Could be hereditary thrombocytopenia “familial thrombocytopathy”

Important to diagnose Avoid steroids, splenectomy Some genetic mutations can increase risk of leukaemia

Genetic testing available if familial thrombocytopathy suspected

Until 1990 Not a skin disease, something that responded to

removing the spleen (must be circulating factor)

Circulating factor that could Cross the placenta from mother to baby Be transmitted to others by transfusion of blood, resulting

in temporary ITP

Treatment aimed at: dampening immune system (steroids other

immunosuppression) stopping platelet destruction in spleen (splenectomy, ivIg)

How are platelets made? Platelets are made from large cells in the bone marrow –

megakaryocytes

Megakaryocytes are controlled by a hormone made in the liver (& maybe lungs) – thrombopoietin (TPO)

The liver makes TPO at a constant rate

TPO binds to platelets & megakaryocytes

High platelet count, more TPO bound, less gets to stimulate megakaryocytes, less platelets made

Low platelet count, less TPO bound, more gets to stimulate megakaryocytes, more platelets made

Romiplostim (Nplate) & Eltrombopag (Revolade) are drugs that do the same job as TPO & are called TPO receptor agonists (TPORAs)

TPO is produced in the liver1,2

Unbound TPO drives megakaryocytes to

make platelets1

Circulating Platelets

TPO binds to platelets

A single megakaryocyte can generate 2,000–3,000 platelets2

Aged and dead platelets are removed by tissue-fixed macrophages in the spleen and liver1

Platelets have a short lifespan of about 5–9 days

Liver

Spleen

Bone marrow

Thrombopoietin (TPO) is produced continuously in the liver and binds to a receptor found on platelets and megakaryocytes1

ITP: Immune thrombocytopenia | TPO: Thrombopoietin. 1. Kaushansky K. NEJM 2006;354:2034–2045. 2. Long MW, Hoffman R. Thrombocytopoiesis. In: Hoffman R et al., eds. Haematology: Basic Principles and Practice. 2005;303–320. Adapted from Long MW, Hoffman R. Thrombocytopoiesis. In: Hoffman R et al., eds. Haematology: Basic Principles and Practice. 2005.

Normaln = 96

Aplasticanaemia

ITPn = 45

0

100

200

300

400

0

250

500

750

1,000

1,250

1,500

1,750Mean platelet count (× 109/L)Maximal endogenous thrombopoietin (eTPO) level (pg/mL)

Pla

tele

t C

ount

(×1

09/L

)eT

PO

Level (pg/m

L)

Adapted from: Nichol. Stem Cells. 1998;16(Suppl 2):165–175.

Relative Thrombopoietin

Deficiency in ITP

n = 23

ITP is caused by increased platelet destruction and reduced production of platelets1

Traditionally, therapies for ITP focused on reducing platelet destruction

Romiplostim/Eltrombopag act by increasing platelet production1

Some patients will need combined treatment for best response

ITP: Immune (idiopathic) thrombocytopenic purpura.1. Provan D. Eur J Haematol Suppl. 2009;71:8–12.

Increased platelet destruction

(spleen)

Decreased platelet production (bone

marrow)

Healthy (normal platelet counts)Anti-platelet immunity

Anti-megakaryocyte immunity

Adapted from Provan 2009.1

ITP is a variable disorder Experience suggests that there is a spread

Platelet underproduction Splenic destruction

Romiplostim immunosuppression

Eltrombopag Splenectomy

Danazol

•Some patients will respond poorly to single agent TPO agonists, but might respond well with the addition of low dose steroid

Why do we treat ITP?

ITP: Immune (idiopathic) thrombocytopenic purpura.1. Cines DB, Blanchette VS. N Engl J Med 2002;346:995–1008. 2. Oral E, et al. Arch Gynecol Obstet 2002;266:72–74.

33

ITP is a chronic disease with potentially serious consequences1,2

When does ITP need treatment? Bleeding picture

Platelet Count

Age

Other risk factors

Platelet count and bleeding in ITP

Lacey JV, et al., Semin Thromb Hemost. 1977 Jan;3(3):160-74.

ITP: Serious and Fatal Bleeding Events in Relation to Age

Adapted from: Cohen YC. et al., Arch Intern Med. 2000 Jun 12;160(11):1630-8..

Age group (Years)

% P

redic

ted 5

-yea

r ble

edin

g ri

sk

n = 571 n = 240 n = 183

0

10

20

30

4050

60

70

80

90

100

< 40 40–60 > 60

Fatal bleed

Major non-fatal bleed

17 studies1817 patientsPlts

Morbidity & Mortality in Chronic ITP – pre-TPORA era

Long term study of 152 consecutive patients with newly diagnosed ITP from Leiden UMC.

Mean follow up 10.5 years

Patients with Plt>30 x109/l requiring no treatment have equal long term mortality to general population

Patients with Plt>30 x109/l requiring maintenance treatment have mildly increased mortality (not statistically significant) cf general population, but higher hospital admission rate (due to ITP).

Patients with Plt

Initial treatment - steroidsSteroid drug Expected

responseSide effects Long term

response

Dexamethasone40mg/d for 4d every 2-4 weeks x 4-6 cycles

~90%/days to weeks

Many!Vary with dose & length of course.

50-80% (?)

Methylprednisolone30mg/kg/d for 7d

~95%/(4.7d vs 8.4d, HDMP vs pred)

23%

Prednis(o)lone0.5-2mg/kg/d for 2-4 weeks

70-80%/days to weeks

13-15%

How long to continue high dose steroid?

George JN et al. Blood 1996;88:3–40

ivIgivIg0.4g/kg/d for 3-5 days or 1g/kg/d for 1-2 days

Up to 80%, 50% achieve CR/2-4 days in responders

Infusion reactions, anaphylaxis in IgA deficiency, aseptic meningitis, headache

Usually platelet count returns to baseline in 2-4 weeks

• Current ivIg used in Australia: • Intragam, flebogamma, privigen

Paul Kaznelson (Prague), 1916ITP is due to increased destruction of platelets by the spleen like in haemolytic anemiaAs a medical student, he persuaded his tutor (Prof Schloffer) to perform a splenectomy on a woman with ITP and platelet counts rose from 2 × 109/L up to 500 × 109/L

SPLENECTOMY - 1916

Schloffer

Kaznelson

Review: Stasi R & Newland AC. Br J Haematol 2011;153:437–50

http://en.wikipedia.org/wiki/File:Paul_Kaznelson_1950.jpg

TPORAs Romiplostim (Nplate) & Eltrombopag (Revolade) in

Australia

PBS requirements ITP still needs treatment after (failed) splenectomy OR splenectomy cannot be performed due to medical

reasons (not refusal)

TPORAs Romiplostim Weekly injection under skin Works in 80% people sometimes adding a low dose steroid (e.g. prednisolone

2.5mg/d) can considerably boost effect Many side effects listed on the product information are

probably due to steroid withdrawal Long term safety excellent No increased cancer risk Risk of blood clots probably due to ITP rather than

romiplostim

TPORAs Eltrombopag Tablet taken daily Very important to follow instructions on taking tablet with

meal times & supplements etc** Works in 80% people sometimes adding a low dose steroid (e.g. prednisolone

2.5mg/d) can considerably boost effect Many side effects listed on the product information are

probably due to steroid withdrawal Long term safety excellent No increased cancer risk Risk of blood clots probably due to ITP rather than

Eltrombopag

Rituximab (mabthera) Antibody treatment given through iv drip every week for 4 weeks

Not paid for by PBS

Used in treating blood cancers (lymphoma)

Dose used in ITP is lower & cheaper than in lymphoma

About 60% response rate, 30% long term response rate

Who is most likely to benefit? Secondary ITP – linked to other autoimmune diseases

No benefit in adding rituximab to initial treatment in newly diagnosed ITP

Mycofenolate mofetil Specialist experience, no trials

Twice daily tablet

Allows lower dose steroid to be used

May have long term benefit in some people

Less side effects than azathioprine

Hou M et al. Eur J Haematol 2003 ;70(6):353-7

dapsone Commonly used in less developed countries – big study

in Brazil

Once daily tablet

Works in about 50% people after about 3 weeks

Causes red cell breakdown (haemolysis)

Rapid relapse after stopping treatment

Not commonly used in Australia

Godeau B, Durand JM, Roudot-Thoraval F, et al. (1997). "Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases". Br. J. Haematol. 97 (2): 336–9.

danazol Anabolic steroid with decreased virilising effects –

can work in aplastic anaemia

Daily tablet

response rates up to 50%

Risks of liver tumours

Virilising

Schreiber AD et al NEJM 1987; 316:503-8, Maloisel F et al Am J Med 2004 116(9):590-4, Yeon AA et al An Intern Med 1987; 107(2);177-81

Azathioprine Daily tablet

Some people have a genetic condition that results in azathioprine being much more toxic than usual

Steroid sparing agent

Bouroncle BA NEJM 1966; 275:630-5

H pylori eradication Bug found in the stomach

Linked to ulcers

Treated with antibiotics

Treatment of H pylori in Japanese patients with ITP has been shown to cure ITP

Experience in treating H pylori as a cause of ITP in Australia has been very disappointing

Stasi R, Sarpatwari A, Segal JB, Osborn J, Evangelista ML, Cooper N, Provan D, Newland A, Amadori S, Bussel JB (2009)". Blood 113 (6): 1231–40.

Long term data on romiplostim- Massachussetts General & PAH

databases 2008-2014423

43

12

Summary ITP is an autoimmune disorder

No simple diagnostic test

In most adults long term disease

Effective treatments

Some patients will not need long term treatment

Risk of steroid exposure

New treatment trials in specialist centres around Australia

Slide Number 1 ITPgender difference varies dependent on ageSlide Number 5What causes ITP?Harrington–Hollingsworth �ExperimentHow is ITP diagnosed?Not everyone with low platelets count has ITPUntil 1990How are platelets made?TPO is produced in the liver1,2Mechanism –�Relative Thrombopoietin Deficiency in ITPITP is caused by increased platelet destruction and reduced production of platelets1ITP is a variable disorder Why do we treat ITP?When does ITP need treatment?Platelet count and bleeding in ITPITP: Serious and Fatal Bleeding Events in Relation to AgeMorbidity & Mortality in Chronic ITP – pre-TPORA eraInitial treatment - steroidsHow long to continue high dose steroid?ivIgSlide Number 24Slide Number 25TPORAsTPORAsTPORAsRituximab (mabthera)Mycofenolate mofetildapsonedanazolAzathioprineH pylori eradicationLong term data on romiplostim�- Massachussetts General & PAH databases 2008-2014Summary