Drew Provan

1
Management of immune thrombocytopenic purpura

• Drew Provan
• Barts and The London School of Medicine and
  Dentistry
• Queen Mary, University of London

2
Management of ITP

• Primary (idiopathic) ITP acute and chronic
• BCSH Guidelines for diagnosis treatment in
• Adults
• Children
• Pregnancy
• Refractory ITP
• Novel therapies, ongoing trials collaborations

3
Autoimmune disorders

• Clinical syndromes caused by activation of
• T cells or B cells or both
• In absence of ongoing infection/discernible
  disease
• Organ-specific or non-specific
• ITP
• Organ platelet
• Target platelet glycoproteins
• Cause unknown but involves
• Genetic
• Immunological
• Environmental factors

4
Pathogenesis of ITP

• Poorly understood
• Platelets are coated with autoantibody or immune
  complexes ? RES
• 1st demonstrated by Harrington 1951
• Injected serum from patient with thrombocytopenia
  into himself
• Transient ? in his own platelet count
• Megakaryocytes often ? but may be ?
• Production usually ? or normal
• Problems when platelets
• Antigen never eradicated

Harrington J Lab Clin Med 38, 110 (1951)
5
Acute (post-viral) ITP

• Children adults, peak age 25 yr
• Females Males
• Seasonal (peak incidence Winter/Spring)
• Self-limiting acute severe thrombocytopenia
• Platelets usually
• Occurs within 3 weeks of acute viral infection
  (or immunisation)
• Target platelet glycoprotein (GP) esp.
  GPIIb-IIIa
• Lasts
• Spontaneous remission in 85
• 1015 ? chronic ITP (mirrors adult phenotype)

6
Chronic (adult) ITP

• Insidious onset
• No preceding illness, not seasonal
• Young/middle age adults (1540 yr)
• Commoner in women of child-bearing age
• 6.6 per 100,000
• Platelet glycoproteins GP IIb-IIIa or Ib-IX
• Usually lasts 6 months
• Spontaneous remissions 2
• Problems bruising and mucous membrane bleeding

7
Diagnosis of ITP

• Despite 50 yr investigation no agreed diagnostic
  test
• Eliminate 2 causes
• Clinical diagnosis

8
BCSH Guidelines
Brit J Haem 120, 574-596 (2003)
9
Why the need for UK guidelines for ITP?

• American Society of Hematology Guidelines
  published 1996
• George, JN et al, (1996) Idiopathic
  thrombocytopenic purpura a practice guideline
  developed by explicit methods for the American
  Society of Hematology. Blood, 88, 3-40.
• Shortage of evidence in General Haematology
• UK and US practice varies
• Need for more didactic guidelines for UK
• Investigation (clinical and lab)
• Management
• Adults, children, pregnancy

10
British Committee for Standards in Haematology
Guidelines for the Investigation and Management
of Idiopathic Thrombocytopenic Purpura in
Adults, Children and in Pregnancy

• Dr Drew Provan Prof Adrian Newland
• Barts Royal London Hospital, London
• Dr Mike Murphy Dr Willem Ouwehand
• NBS, Oxford Cambridge
• Dr Derek Norfolk, General Infirmary at Leeds
• Prof Ian Greer, Glasgow Royal Infirmary
• Dr Paula Bolton-Maggs, Alder Hey Childrens
  Hospital, Liverpool Prof John Lilleyman
  Barts Royal London Hospital, London
• Dr Anne May, Consultant Anaesthetist, Leicester
• Mrs Shirley Watson, ITP Support Association

General adult ITP Laboratory investigation Obs
tetric management Paediatric ITP Anaesthetic
guidelines Patient support organisation
11
BCSH guidelines - Adult ITP

• Full clinical history
• Determine type of bleeding (platelet vs.
  coagulopathy)
• Examine patient
• Assess type and severity of bleeding
• Exclude other conditions that might cause
  thrombocytopenia (TTP, CLL, HIV, SLE)
• Laboratory investigations

12
Adult ITP - laboratory investigations

• Repeat FBC
• Examine blood film
• Pseudothrombocytopenia (0.1 adults, use citrate)
• CLL, MDS, megaloblastic anaemia, MAHA
• Autoimmune screen
• Lupus and other autoimmune diseases
• Coagulation screen - not recommended
• Bone marrow?

13
Adult ITP - bone marrow

• If picture is that of ITP with no atypical
  features
• Limited value
• Studies show low pick-up rate for other diseases
• Unpleasant and expensive
• But worth doing if
• Atypical features
• Patient 60 years
• Splenectomy being considered
• Poor response to first line therapy

14
Adult ITP - antiplatelet antibodies

• PAIg ? in most patients with ITP (Direct PIFT)
• BUT PAIg often ? in non-immune thrombocytopenias
• Antibodies to specific glycoproteins (GP)
  IIb/IIIa (MAIPA)
• Even less sensitive (50-65)
• But more specific (90) in ITP
• Recommend dont check unless patient considered
  to have
• BM failure immune thrombocytopenia
• ITP refractory to 1st and 2nd line treatment
• Drug-dependent thrombocytopenia

15
Adult ITP - other tests

• Thrombopoietin (TPO) assays
• Normal in ITP
• Not routinely available
• Not recommended
• Reticulated platelets
• Recent interest
• Increased in children with ITP (but not
  leukaemia)
• Not recommended at present (role not clear)

16
Adult ITP - Helicobacter pylori

• Implicated in gastritis, peptic ulcers,
  autoimmune disease
• Italian study 30 refractory ITP patients
• H pylori () in 30 cases
• Rx with triple therapy
• Improvement in platelet count in 92
• CR in 33
• PR in 16
• Breath test or blood test
• Worth checking if refractory

Emilia et al, Blood 97, 812 (2001)
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Adult investigation - summary 1

• Diagnosis of ITP is based on the exclusion of
  other causes of thrombocytopenia
• Further investigations not indicated in the
  routine work-up of patients with suspected ITP if
  the history, examination, blood count and film
  are typical of the diagnosis
• Bone marrow examination is unnecessary in adults
  unless
• Atypical features
• Patient 60 years
• Patient relapses following complete remission
• Splenectomy is being considered

18
Adult investigation - summary 2

• PAIg is ? in both immune and non-immune
  thrombocytopenia
• Therefore has no role in the diagnosis of
  uncomplicated ITP
• Worth determining the presence of H. pylori in
  patients refractory to therapy

19
ITP therapies and natural history

• Minor disorder for most individuals affected
• BUT natural history is variable and unpredictable
• Most patients are in good health
• Tendency to over-treat
• Significant morbidity and mortality associated
  with Rx
• Infective deaths (50)
• Aims should be to offer
• Individualised therapy
• Least toxic Rx
• For shortest period of time
• Maintaining good QoL

Portielje et al, Blood 97, 2549-2554 (2001)
20
Aims of treatment

• What are we trying to achieve?
• Reduce morbidity and mortality
• Prevent bleeding
• Achieve safe platelet count
• Does not need to be normal
• Patients with ITP can tolerate very low platelet
  counts
• cf. leukemia, chemotherapy, aplastic anemia
• Support not given if platelets 10 x 109/L
  (unless bleeding, sepsis, fever)
• Higher risk of bleed in older patients with low
  counts

Guthrie et al, Am J Med Sci 296, 17-21 (1988)
21
Adult ITP - safe platelet counts

• Clinicians, dentists etc want to know safe
  levels
• Dentistry (fillings) ?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

Evidence level IV
22
Adults first line therapy

• Platelets 30 x 109/L
• Observe
• Or treat if
• Bleeding
• Planned procedure likely to induce bleeding

• Platelets
• Observe
• Treat if
• Platelets
• Clinical problems
• Planned procedure
• Prednisolone 1mg/kg/day x 2/52 then ?
• IVIg (effective in 75 but not sustained)

23
Adults second line therapy - drugs

• Decide on need for treatment (may be worse than
  disease)
• High dose steroids
• Dexamethasone
• Methylprednisolone
• High dose IVIg
• IV anti-D
• Danazol
• Azathioprine
• Cyclosporin
• Vincristine, combination chemoRx, dapsone, etc.

No therapeutic modality is truly evidence-based
24
Adults second line therapy - splenectomy

• 2/3 will respond
• Need platelets 30 x 109/L for splenectomy
• Vaccination
• Pneumovax, Hib, Meningococcal C
• 2 weeks pre-op
• Other prophylaxis
• Penicillin 250-500mg bd (or equivalent) ?for life
  ?2 years
• Annual flu vaccine Pneumovax booster 5 yearly
• Can we predict response?

25
111In labelled autologous platelet scan (Royal
London)
spleen
liver

• Pattern 5-30 years 30 years
• Splenic 96 remission 91
• Mixed/hepatic 15 response

Najean et al, Brit J Haem 97, 547-550 (1997)
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Failed splenectomy management options

• Simple measures
• Non-selective drug therapies
• Novel or experimental therapies

27
Failed splenectomy Simple measures

• Observation
• Intervene if necessary
• Antifibrinolytic agents/contraceptives
• Look for accessory spleen?
• Found in 12 of patients initially/failing to
  respond
• Removal seldom works
• Helicobacter pylori
• Serology and/or breath tests
• Variable reports of ITP response
  post-eradication

posterior
Emilia et al, Blood 97, 812-814 (2001)
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Options for severe refractory ITP

• 25 adults
• Intermittent IVIg, combination chemoRx
• Recommend
• Rituximab
• Mycophenolate mofetil
• Campath-1H
• BUT treatments with
• Interferon-a
• Protein A columns
• Plasmapheresis
• Liposomal doxorubicin

? ? ?
Not recommended
29
ITP therapy in adults
Fail 1st 2nd Observe Intermittent
IVIg/steroids Combination chemoRx Experimental M
ycophenolate Rituximab Campath
First line Prednisolone IVIg
Second line Observe Dexamethasone Methylprednisolo
ne High dose IVIg Anti-D Dapsone Azathioprine Cycl
osporin Cyclophosphamide Combination
chemoRx Vinca alkaloids
Splenectomy
30
Adults emergency treatment e.g. bleeding

• For rapid elevation of the platelet count in
  extreme emergencies
• Transfusion of random donor platelets is
  appropriate
• When a higher platelet count is required but
  there is less urgency
• IVIg and/or IV methylprednisolone
• and/or IV cyclophosphamide may be useful

31
Outcome hemorrhagic risks

• For adults with severe refractory ITP
• Cerebral hemorrhage 3
• Hemorrhagic death 4
• Risk of intracranial haemorrhage greatest in
• Elderly
• Head trauma
• Patients with bleeding
• Drugs e.g. aspirin, NSAIDs
• Coagulation disorders
• No response to therapy

Portielje et al, Blood 97, 2549-2554 (2001) Lee
Kim Neurol 50, 1160-1163 (1998) George Raskob
Semin Hematol 35 (Suppl 1), 5-8 (1998)
32
Childhood ITP investigations

• FBC and blood film
• Coagulation screen only if suspected
• Meningococcal infection
• Inherited bleeding disorder
• Non-accidental injury
• Antiplatelet antibodies no value
• Helicobacter pylori no evidence in children -
  not recommended
• Bone marrow contentious
• Recommended pre-treatment (e.g. lymphoblastic
  leukaemia)

33
Childhood ITP management

• Most children have acute ITP
• Dramatic presentation but get better without
  treatment
• Classify clinically (i.e. not by platelet count)
• Degree of purpura or bruising does not predict
  bleeding
• 4 may have severe nose or GIT bleeds
• Intracranial haemorrhage
• Low risk (0.3)
• Occurs with or without treatment

34
Childhood ITP if bleeding symptoms

• Prednisolone
• IVIg (pooled)
• High dose methylprednisolone
• Pulsed dexamethasone
• Anti-D (pooled)
• Splenectomy rarely indicated
• Only for severe unremitting chronic ITP
• Specialist referral before splenectomy
• Blood products e.g. platelets only for
  life-threatening bleed

35
Pregnancy ITP

• Consider gestational (5)
• Mild thrombocytopenia (rarely
• Healthy women, otherwise normal blood counts, 3rd
  trimester
• ITP 1-5 cases per 10,000 pregnancies (0.01)
• Blood film
• To exclude spurious thrombocytopenia, red cell
  fragments, other haematological disorders
• Coagulation screen (PT, APTT, fibrinogen,
  D-dimer)
• Liver function tests
• Anticardiolipin antibodies/lupus anticoagulant
• SLE serology

36
Pregnancy management of ITP

• Asymptomatic women,platelets 20 x 109/L
• Do not need treatment until delivery is imminent
• Platelet counts 50 x 109/L
• Safe for normal vaginal delivery
• Platelet counts 80 x 109/L
• Safe for caesarean section, spinal or epidural
  anaesthesia
• In women who need treatment
• Oral corticosteroids and IVIg similar response
  rate to non-pregnant patients.
• No convincing data on the effect of
  corticosteroids or IVIg on the fetal/neonatal
  platelet count

37
Refractory ITP in adults - experimental therapies

• Strategies for raising platelet count
• ? destruction (? antibody by B cells)
• E.g. antibodies against key targets
• ? production (ignore process but make more
  platelets)
• E.g. TPO and TPO-like drugs
• Restore immune tolerance
• Re-set immune system

38
Refractory ITP in adults - experimental therapies

• Antibody therapies
• Rituximab (anti-CD20)
• Campath-1H (anti-CD52)
• Anti-CD40 ligand (anti-CD154)
• Antiprolif immunosupp. Mycophenolate mofetil
• Co-stimulatory blockade CTLA-4-Ig
• Thrombopoietin and TPO-like drugs
• Helicobacter pylori
• Stem cell transplantation

39
Rituximab (anti-CD20)

• Genetically engineered human/mouse chimeric
  anti-CD20
• Developed as treatment for B-NHL
• IgG1 k murine L and H chain variable region
  sequences
• human C region
• Binds to CD20 on B cells
• Induces lysis
• Induction of apoptosis
• Evolving role for autoimmune disease

40
Rituximab (anti-CD20)

• Stasi (2001)
• 25 patients with chronic refractory ITP
• Treated if platelets symptoms
• 2-5 prior treatments (8 had failed splenectomy)
• After 4 courses (375/m2 weekly x 4)
• 5 CR (platelets 100 x 109/L)
• 5 PR (platelets 50-100 x 109/L)
• 3 minor response (platelets
• Peak response up to 4 weeks of treatment
• 28 had responses lasting 6 months
• Sustained in 7 patients (6 months)

Stasi et al, Blood 98, 952-957 (2001)
41
Rituximab (anti-CD20)

• Appears effective in chronic refractory ITP
• 72 response rate
• Mild predictable side-effects, easily controlled
• Is it sustained?
• 28 lasting CR
• 136 weeks
• Long-term?

42
Campath-1H

• Genetically engineered antibody
• Target antigen
• CD52, panlymphocyte, monocytes
• Humanized IgG
• Developed for B cell neoplasms e.g. CLL
• Used in small numbers of patients with
• RA, Wegeners, vasculitis
• Contraindications
• Bleeding
• Infection

43
Campath-1H

• 21 patients with autoimmune cytopenias
• AIHA, ITP, autoimmune neutropenia
• Test dose (1mg) then 10mg/day x 10 days
• Response in 15 of 21 (71)
• Best responses in AIN
• Responses in ITP, but relapse rate high
• Side-effects

Willis et al, Brit J Haem 114, 891-898 (2001)
44
Anti-CD40 ligand (IDEC-131)
B cell /APC
CD4 T cell
Protection from apoptosis
Proliferation IL-2 production
Antibody Production
APC function

• CD40/CD40L signal is essential for T and B cell
  activation
• Effective (though number treated small)
• Thrombotic complications ? trial stopped

45
Mycophenolate mofetil (MMF)

• Antiproliferative immunosuppressive
• Licensed for prevention of rejection (solid organ
  Tx BMT)
• 10 patients (4 AIHA 6 ITP, 4 splenectomized)
• 6 ITP patients
• Age 39-84
• 500mg bd - ? to 1 gram bd after 2 weeks
• 2 x CR
• 3 x PR
• 1 x no response
• Time to maximal platelet count 1-6 months
• Overall response in 9 of 10 patients
• Need more studies with larger numbers

Howard et al, Brit J Haem 117, 712-715 (2002)
46
T cell co-stimulatory blockade CTLA-4-Ig
Cytotoxic T Lymphocyte Antigen-4 on T
cells Natural OFF switch for T cells Prevents
them from being permanently ON Attenuates
immune response Previous psoriasis
study Current ITP study (RLH) Polymorphisms ?
autoimmune disease susceptibility
47
Selective therapy CTLA-4-Ig
Block second signal
Fc receptors
X
Y
Y
Y
Y
Antigen-presenting T cell B
cell Antibody cell
Y
Y
Y
Y
Coats the platelets
48
Other experimental strategies

• TPO-like agents (RLH)
• Stem cell transplantation
• Toxic
• High rate of complications in ITP

49
Future studies

• We need
• Larger natural history laboratory studies
• UK ITP Registries (Royal London Alder Hey)
• Intercontinental Childhood ITP Study Group
  Registry III
• EHA Platelet Working Group
• Therapeutic trials
• Royal London Hospital, other centres
• Aiming for targeted and specific drugs with ?
  toxicities

a.b.provan_at_qmul.ac.uk
50
Conclusions 1

• Despite advances diagnosis of ITP remains one of
  exclusion
• Tendency to over-investigate and over-treat
• Treat clinical problems rather than counts
• Severe refractory ITP problematic
• But tolerate low counts well
• Most bleeds occur when platelets
• Through collaborations registries
• Accumulate natural history data ? guide decisions
• Rational use of available therapies
• Continue to explore novel (targeted) therapies

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