Adult Chronic ITP

Adult Chronic ITP

2016. 06. 25 Jun Ho Jang

Samsung Medical Center (SMC)

Bleeding

Primary hemostasis

Secondary hemostasis

M/72

WBC 4800/uL, Hgb 13.2 g/dL, platelet 7,000/uL

No drug or food history

이 환자에서 가장 처음 R/O 하여야 할 질환은?

1) Hematologic malignancy

2) Myelodysplastic syndrome (MDS) 3) Pseudothrombocytopenia

4) Immune thrombocytopenia (ITP)

5) Thrombotic thrombocytopenic purpura (TTP)

Pseudothrombocytopenia

• Immune-mediated acquired disease of adults and children

• ITP is characterised by:

– A low platelet count

(<100 x 10⁹/L, transient or persistent)¹ – An increased risk of bleeding due to

impaired clotting mechanism^24

• Currently no definitive diagnostic criteria exist for primary ITP

– Considered a diagnosis of exclusion – Thrombocytopenia may occur

secondary to other conditions such as lupus, leukaemia, HIV, HCV⁵

Normal platelet count

Thrombocytopenia

Platelets

Red blood cells

Red blood cells

ITP

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. Cines D, Blanchette V. N Engl J Med 2002; 346: 9951008

Terminology

• An IWG evaluated terminology, definitions and outcomes in ITP in 2008 and recommended:

– New terminology: ITP =

Primary Immune ThrombocytoPenia Old terminology: ITP =

Idiopathic thrombocytopenic purpura

IWG, International Working Group

Rodeghiero F, et al. Blood 2009; 113: 2386–93

Demographics of ITP: 19902005

Female Male 20

15

10

5

0 <18 18–24 25–34 35–44 45–54 55–59 60–64

Age group, years Mean annual incidence (per 100,000 person-years)

65–74 75–84 85–100 Total

Reproduced with permission from Schoonen W, et al. Br J Haematol 2009; 145: 235-44

Natural History

Chronic illness

Most patients attain CR or PR; however, the response is rarely sustained

(Sailer et al. Haematologica 2006;91:1042) (Pamuk et al. Ann Hematol 2002:81:436)

114 pts with PLT < 20,000/L N=321

Pd (10yr DFS 13%) Splenectomy

Natural History

(Nogaard et al. Blood 2011;117:3514)

Danish population-based cohort study

407 chronic ITP Pts Vs. 4,069 control cohort

Parameters Adjusted RR (95% CI)

Hospital contact involving infection 1-year: 4.5 (3.3-6.1)

Hospitalized ICH 5-year: 3.2 (1.2-9.0)

Hospitalized hemorrhage other than ICH 5-year: 4.4 (2.3-8.3)

Mortality 5-year: 2.3 (1.8-3.0)

There is a complex ITP pathophysiology that underlies platelet destruction

Y Y

Y Y Y

Y Y

B-cell

CD154 CD40 CD40 CD154

Macrophage

(APC cell) ^{MHC II}

CD28 CD80

Th-cell

TCR

IL-2 IFN-γ

Tc-cell

Epitope spreading

Platelet phagocytosis

X X X

Platelet auto-antibody production

CD28 CD80

Platelets

Tc-cell-mediated platelet destruction

Treg

APC, antigen-presenting cell; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; Tc, cytotoxic T-cell;

TCR, T-cell receptor; Th, helper T-cell; Treg, regulatory T-cell

Adapted with permission from Stasi R, et al. Thromb Haemost 2008; 99: 4–13

ITP involves diverse autoimmune mechanisms

• Although the exact pathology behind ITP remains unclear, recent advances have indicated two broad routes

Increased platelet destruction¹

Decreased platelet production²

1. Cooper N, et al. Br J Haematol 2006; 133: 364–74; 2. Gernsheimer T. Eur J Haematol Suppl 2008; 80: 3–8; 3. Provan D, et al. Blood 2010; 115: 168–86

“Concepts… have shifted from the traditional view of increased platelet destruction mediated by auto-antibodies to more complex mechanisms where both impaired platelet

production and T-cell-mediated effects play a role.”³

Antibody-mediated platelet destruction

• Antibody-coated platelets undergo accelerated clearance by

macrophages¹

• Increased antibody levels in ITP, primarily involving:

– IgG antibodies – Fcγ receptors

– Glycoproteins IIb/IIIa, Ib/IX, Ia/IIa²

• Clearance via the liver/spleen¹

• No longer considered the only mechanism for thrombocytopenia in ITP³

– B-/T-cell regulation and impaired platelet production

Macrophage

Platelet internalised and degraded

Platelet Glycoproteins IIb/IIIa Fcγ

receptor

Antibody

IgG, Immunoglobulin G

1. Cooper N, et al. Br J Haematol 2006; 133: 364–74; 2. Cines D, Blanchette V. N Engl J Med 2002; 346: 995–1008;

3. Provan D, et al. Blood 2010 115: 168–86; Figure adapted with permission from Cines D, Blanchette V. N Engl J Med 2002; 346: 995–1008

Suppression of megakaryocyte production in ITP plasma dilutions

• Compared with healthy controls, plasma from patients with ITP has been shown to inhibit megakaryocyte proliferation in vitro

– CD34⁺ cells isolated from patient plasma – CD34⁺ cells then stimulated in vitro

with TPO to induce development of megakaryocytes

– Healthy controls set 100% level of megakaryocyte differentiation – Plasma auto-antibodies from adult

ITP patients substantially reduce in vitro megakaryocyte production

100 75 50 25

% megakaryocyte production (measured against healthy control) 0

2.0 4.0 8.0 16.0

ITP plasma dilution

McMillan R, et al. Blood 2004; 103: 136469; Figure adapted with permission from McMillan R, et al. Blood 2004; 103: 136469

TPO

• TPO is a potent endogenous

haematopoietic growth factor that plays an integral role in platelet production^1–3

– Produced primarily in the liver at constitutive rate¹

– Influences proliferation/differentiation of megakaryocytes²

• Drives platelet production via TPO-R³

• Decline in platelet mass causes increase in TPO levels to maintain platelet levels

– TPO levels remain elevated during persistent thrombocytopenia¹

Stem cell

Bilineal progenitor cell

Committed megakaryocyte progenitor cell

Immature megakaryocyte

Mature megakaryocyte

Platelets

TPO

TPO

TPO

TPO

TPO-R, TPO receptor

1. Kuter D, Begley C. 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 signalling pathways

• TPO regulates the maturation of megakaryocytes, via signal transduction pathways, into platelet-producing cells

TPO-R

Cell membrane

NUCLEUS TPO

JAK

RAS/RAF

MAPK/ERK STAT

P13K

AKT SHC

GRB2 SOS

Kaushansky K. J Clin Invest 2005; 115: 333947

TPO and platelet levels in ITP

• TPO levels typically rise in response to low platelet levels and stimulate platelet production

• In patients with ITP, TPO levels remain inappropriately low despite a low platelet count and platelet production is suboptimal

250 200 150 100 50

0 Amegakaryocytic ITP

thrombocytopenia Healthy

donors

Platelet counts Serum TPO levels

25 20 15 10 5 0

Platelet count (x103 /µL) Serum TPO (femtomoles/mL)

Mukai H, et al. Thromb Haemost 1996; 76: 675–8; Figure reproduced with permission from Mukai H, et al. Thromb Haemost 1996; 76: 675–8

Understanding the complex ITP pathophysiology can help to identify new therapeutic targets

Y Y

Y Y Y

Y Y

B-cell

CD154 CD40 CD40 CD154

Macrophage

(APC cell) ^{MHC II}

CD28 CD80

Th-cell

TCR

IL-2 IFN-γ

Megakaryocyte Tc-cell

Epitope spreading

Platelet phagocytosis

X X X

Platelet auto-antibody production

Impaired megakaryocyte maturation Reduced platelet production

CD28 CD80

Platelets

Tc-cell-mediated platelet destruction

Treg

APC, antigen-presenting cell; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; Tc, cytotoxic T-cell;

TCR, T-cell receptor; Th, helper T-cell; Treg, regulatory T-cell

Adapted with permission from Stasi R, et al. Thromb Haemost 2008; 99: 4–13

SIGNS AND SYMPTOMS OF ITP

Clinical presentation of ITP varies

• Dependent on the severity of thrombocytopenia, the clinical presentation of ITP varies

– 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)

1 cm 2 cm 3 cm

Actual scale:

Petechiae

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

Severe clinical features

• At very low platelet levels (<10 x 10

/L) severe purpuric lesions and potentially fatal intracranial haemorrhages can occur

Petechiae

Ecchymoses Purpura

Cines D, et al. Annu Rev Med 2005; 56: 425–42 Skull

Large haemorrhage within the cerebellum

Distortion of cerebellum Intracranial

Hemorrhage Healthy

Brain

Cerebrum

Brainstem

Cerebellum

Platelet < 10,000/uL 환자에서 severe bleeding이 1년내 발생할 확률은?

1) 0.1~1%

2) 5~10%

3) 20%

4) 50%

5) 70% 이상

Differential 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/leukaemia

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

Bone marrow examination In patients >60 years with atypical features,

or pre-splenectomy

As well as bone marrow aspirate and biopsy, flow cytometry and cytogenetic testing should

be considered

Recent changes from previous guidelines

Quantitative immunoglobulin levels

To exclude immune deficiency syndrome, or if intravenous immunoglobulin treatment

is to be considered

HIV, HCV and H. pylori Routinely tested in adults

Regardless of local prevalence

& risk factors

HCV, hepatitis C virus; HIV, human immunodeficiency virus

1. George J, et al. Blood 1996; 88: 3–40; 2. Guidelines for the investigation and management of ITP. Br J Haematology 2003; 120: 57496

Guidelines/Recommendations for ITP

ASH guidelines

British Society for Haematology guidelines

(Br J Haematol 2003;120:574)

Dutch guidelines

International Working Group report on nomenclature &

response evaluation

International consensus report on investigation &

management

ASH guidelines

ASH guidelines : methodology (Neunert et al)

● Creation of focused clinical questions based on 1996 guidelines

● Embase and MedLine searches 1996–2009

● Rigorous evidence selection: focus on systematic reviews and RCTs

● Grading of recommendations and evidence level

● External panel assessment

Neunert C, et al. Blood 2011;117:4190–207 RCT=randomised controlled trial

ASH 2011 evidence-based practice guideline for ITP

Goals of Therapy

Maintain a hemostatic platelet count (≥ 20,000-30,000/L) for most patients.

Minimize treatment-related toxicity.

Predicated on 3 assumptions

The platelet count is a reliable surrogate marker of bleeding risk.

Medical intervention does not alter the natural history or ITP.

The burden of disease is adequately captured by bleeding and drug toxicity.

Is the platelet count a reliable

surrogate marker of bleeding risk?

(Lacy & Penner. Semin Thromb Haemost 1977;3:160) (Cohen et al. Arch Int Med 2000;12:160) 1,817 pts with PLT < 30,000/L

0.0162-0.0389 cases per adult patient-year

< 40 40-60 >60 Age groups (Yrs)

Events per Patient-Year

Criteria for assessing response to ITP Tx

(International Working Group)

(Blood 2009;113:2386)

Criteria for assessing response to ITP Tx

(International Working Group)

(Blood 2009;113:2386)

ITP치료에 있어서 1950년대 부터 1

line therapy로 자리 잡은 치료는?

1) Prednisolone 2) Rituximab 3) Splenectomy

4) TPO receptor agonist

5) Vincristine

Splenectomy: first-line, gold standard procedure

Steroids were introduced

Splenectomy: second-line treatment of choice

Early 1990s Treatment of ITP

1950s

First-line Second-line TPO mimetics B-cell targeted treatment

Immunosuppressive/cytotoxic/other agents

Corticosteroids IVIg

IVAnti-D

Splenectomy Romiplostim Eltrombopag

Rituximab Azathioprine, Cyclophosphamide, Cyclosporin A, Danazol, Dapsone, Mycophenolate Mofetil, Vinca alkaloids

Stasi R, et al. Ann Hematol 2010;89:1185-95.

1 ^st line therapy

Agent Dose Initial

response

Time to response Prednisolone^ASH 0.5-2 mg/kg/d (for 2-4 wks) 70-80% Several days

to wks Methylprednisolone 30 mg/kg/d (for 7d?) As high

as 95% 4.7 d vs. 8.4 d Dexamethasone

40 mg/d for 4 d

every 2-4 wks for 1-4 cycles

Up to 90% Several days to wks

IVIg 0.4 g/kg/d for 5 d or

1 g/kg/d for 1-2 d Up to 80% Many in 24 h;

typically 2-4 d

Anti-Rh(D) 50-75 g/kg Up to 80% 4-5 d

International Consensus Report (Blood 2010;115:168)

First Line Steroids IVIg Anti-D

If fail first- and second-line Rx options with sufficient data TPO-R agonists

Rx options with minimal data and potential for considerable toxicity

Campath-1H

Combination of 1st and 2nd line Rxs Combination chemotherapy

Haemopoietic stem cell transplantation Second Line

Azathioprine

Cyclophosphamide Cyclosporin A

Danazol Dapsone

Mycophenolate mofetil Rituximab

Splenectomy TPO-R agonists*

Vinca alkaloids

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

*Licensed for second-line use where there is a contraindication for splenectomy (EMA) This slide contains information about drugs that may not be licensed for

certain indications as listed

Corticosteroid therapy

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

Profile

• Standard initial treatment due to high initial response rate

• Have the potential to reduce bleeding independent of the patient’s platelet count rise by a direct effect on blood vessels

Adverse effects

• Adverse effects rapidly become apparent and create significant complications

• Over time, the detrimental effects of corticosteroids can often outweight their benefits

스테로이드 합병증

여드름

쿠싱증후군 고혈압

당뇨

골다공증

Intravenous immunoglobulin (IVIg)

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

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

만성적으로 스테로이드에 dependent한 ITP환자에서 IVIg를 사용하였다. 일주일 후 환자의 혈소판은

7,000/uL에서 40,000/uL으로 상승하였다. 환자는 2주 후

출혈과 함께 다시 혈소판이 3,000/uL까지 하락하였다. 이때 고려해야할 치료는?

1) Prednisolone 사용을 고려한다.

2) IVIg 재사용을 고려한다.

3) Splenectomy를 고려한다

4) 다른 종류의 IVIg를 사용을 고려한다.

5) 혈소판 수혈 등의 보조적 요법만 사용한다.

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

Splenectomy

Lunch debate in EHA 2009

Splenectomy

Side effects Incidence

Surgical Mortality 1.0% (open)

0.2% (laparoscopy) Serious infection Mortality 0.73/1,000 pts x yr Vascular

(VTE, PAT, Atherosclerosis)

?

H. pylori Eradication

(Blood 2009;113:1231) Ab to CagA cross-reacts

with an epitope on GP IIIa (Br J Haematol 2004;124:91)

Rituximab

Median time to response: 4-6wks Median response duration: 10.5mos

Response to retreatment in pts with initial CR

Low-dose rituximab (100mg): similar response, longer TTR

(Arnold et al. Ann Int Med 2007; Godeau et al. Blood 2008)

환자는 spelenectomy 후 혈소판 수치가 60,000 ~ 80,000/uL 유지하다가 1년 후 다시 출혈 경향과 함께 혈소판 수치가 5,000/uL으로 다시 감소하였다. 이때 고려할 수 있는

치료는?

1) Prednisolone을 다시 사용한다.

2) IVIg를 다시 사용한다.

3) TPO RA는 사용한다.

4) 혈소판 수혈 등의 보조적 요법만 사용한다.

5) Chemotherapy를 고려한다.

TPO signalling pathways

• TPO regulates the maturation of megakaryocytes, via signal transduction pathways, into platelet-producing cells

TPO-R

Cell membrane

NUCLEUS TPO

JAK

RAS/RAF

MAPK/ERK STAT

P13K

AKT SHC

GRB2 SOS

Text and figure adapted from: Kaushansky K. J Clin Invest 2005; 115: 333947

TPO-R agonists

Revolade

• TPO non-peptide agonist:¹

– May have an effect additive to TPO

• Stimulates growth and differentiation of

megakaryocytes and increases platelet production³ – activates the TPO-R in a manner that is similar to but different from recombinant human TPO

Romiplostim

• TPO-peptide agonist¹

• Stimulates megakaryopoiesis in the same manner as endogenous TPO¹

– Structurally unrelated to TPO¹

– Competes with TPO for binding to TPO-R²

• Stimulates growth and

differentiation of megakaryocytes and increases platelet production³ – binds to same site on the human TPO-R as endogenous TPO¹

EMA has approved TPO-R agonists for adult chronic ITP if splenectomy has failed or is contraindicated EMA, European Medicines Agency

1. Kuter D. Blood 2007; 109: 4607–16; 2. Broudy V, Lin N, Cytokine 2004; 25: 52–60; 3. EMA. Revolade Summary of Product Characteristics. Available from:

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001110/WC500089964.pdf [Accessed 2011]

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. Nplate^® [romiplostim]) and TPO non-peptide agonists (e.g. Revolade [eltrombopag])¹

Figure not to scale

Kuter D. Blood 2007; 109: 4607–16 TPO-R

romiplostim

Cell membrane

TPO Revolade

Improved QoL for ITP patients treated with TPO-R Agonist

1. George JN et al., British Journal of Hematology, 2009 Feb ; 144(3) 409-15

Long-term romiplostim study:

dosing and platelet count

Kuter D, et al. Br J Haematol 2013; 161: 411–23

Potential Role of TPO-R Agonist

• Management of refractory disease and bleeding

attributable to low platelet counts is a key problem in both adults and children

.

• Thrombopoietin-receptor agonists offer a new

therapeutic option to improve the patient’s quality of life, although they have not been shown to cure the disease

.

1. Nurden AT et al., Lancet 2009 May 2;373(9674): 1562-9

Impact of patient age & activity level

ITP치료에 있어서 혈소판의 목표는?

1) > 20,000/uL

2) > 30,000/uL

3) > 50,000/uL

4) >100,000/uL

5) > 150,000/uL

Thank you for your attention