Overview of ITP - Haematology Association of Ireland

Overview of ITP
Dr Gary Benson
Director N Ireland Haemophilia Comprehensive Care Centre
and Thrombosis Centre
Belfast City Hospital

Idiopathic (Immune)
Thrombocytopenic Purpura
• Thrombocytopenia in the absence of other
blood cell abnormalities (normal RBC &
WBC, normal blood film)
• No clinically apparent conditions or
medications that can account for
thrombocytopenia

Statistics of ITP
• Incidence of 22 /million/year in one study
• Prevalence greater as often chronic
*Segal et al �100 /million/year
*age-adjusted prevalence 9.5/100,000
*1.9 :1 females / males

Clinical Manifestations
• May be acute or insidious onset
• Mucocutaneous Bleeding
*petechiae, purpura, ecchymosis
*epistaxis, gum bleeding
*menorrhagia
*GI bleed, CNS bleed = RARE

Aetiology of ITP : Children
• Maternal associated
• Often after infection (viral or bacterial)
– Post MMR vaccination
• Theories:
*antibody cross-reactivity
*H. pylori
*bacterial lipopolysaccharides

Aetiology of ITP : Adults
• ?? Auto-antibodies?

Diagnosis (of Exclusion)
• Rule out other causes:
*lab error / PLT clumping
*drug / medication interaction
*infections (HIV, Hepatitis C)
*thyroid / autoimmune disease
*destructive / consumptive processes (TTP/HUS)
*bone marrow disease (leukemias, MDS)

Diagnosis (of Exclusion)
• Rule out other causes:
*lab error / PLT clumping
*drug / medication interaction
*infections (HIV, Hepatitis C)
*thyroid / autoimmune disease
*destructive / consumptive processes (TTP/HUS)
*bone marrow disease (leukemias, MDS)

To Marrow or Not to Marrow?
• Bone marrow aspiration & biopsy if…
• Patient 60 yrs. or older
• Poorly responsive to tx
• Unclear clinical picture

Anti-Platelet Antibody Testing
• NOT recommended by BSH Practice
Guidelines
• Poor positive/negative predictive values,
poor sensitivity with all current testing
methods…
• …and doesn’t change the management!

Management of ITP in Adults
• Emergency vs. Chronic Tx
• Goal = prevention of bleeding, NOT cure!

Management of ITP in Adults
• Emergency vs. Chronic Tx
• Goal = prevention of bleeding, NOT cure!

General Principles of Therapy
• Major bleeding rare if PLT > 10,000
• Goal = get PLT count to safe level to
prevent bleeding…
•…not to specifically cure the ITP!

“Safe” Platelet Counts
• “moderately” t-penic = 30-50,000
• Probably safe if asymptomatic
• Caution with elderly (CNS bleeds)

When Planning Therapy…
• Tailor therapy and decision to treat to the
individual patient
• Weigh bleeding vs. therapy risks

Initial Therapy
• Prednisolone 1 mg/kg/day
*usual response within 2 weeks
• Taper off after PLT response
• Duration of use = controversial

Second-Line Therapy
• IV Immune Globulin (IVIg)
1 gram/kg/day x 2 days
• anti-D – if pt is Rh+
50-75 mcg/kg/day

Treatment Side-Effects
•Steroids
*bone density loss *GI effects
*muscle weakness *weight gain
• IVIG/anti-D
*hypersensitivity *headache
*renal failure *nausea/vomiting
*alloimmune haemolysis

Splenectomy
• Usually reserved for treatment failure
• Consider risk of bleeding, pt lifestyle
• RISKS
*surgical procedure
*loss of immune function � vaccinations

Response Post-Splenectomy
• Usually normalized PLTs within 2 weeks
(often immediately)
• Younger pts do better
• Kojouri et al (Blood 2004) � 65% CR

Data from Fabris, F, et al. Br J Haematol 2001; 112:637.

Chronic Refractory ITP
• Persistent > 3 months
• PLT < 50,000
• Failure to respond to splenectomy

When all else fails…
• Steroids
• IVIg / anti-D
• Rituximab (anti-CD20)
• Cyclophosphamide
• Danazol
• Accessory splenectomy
• H. pylori eradication

Mean SF-36 Scores
ITP and Health-Related QOL
SF-36 Domains and Component Summary Scales
• Patients with ITP have worse QOL than the general
population and patients with common disorders
• ITP QOL is better than CHF or missing or paralyzed limb
McMillan R, et al. Am J Hematol. 2008;83(2):150-154.

Pathophysiology of ITP
AP
O
TC
Cines DB, Blanchette VS. N Engl J Med. 2002;346:995-1008.
P
D
AP Autoantibody
Production
O
D
P
TC
Platelet
Opsonization
Platelet
Destruction
Platelet
Production
T-Cell–Mediated
Cytotoxicity

Mechanism-Based Approaches to
Treatment
• Inhibit phagocyte-mediated clearance of Ab-coated platelets
– Steroids
– Splenectomy
– Anti-D
– IVIG
• Decrease antibody production
– Rituximab
– Steroids
– Azathioprine and other immunosuppressants (eg, cyclophosphamide,
cyclosporine, mycophenolate mofetil)
• Impair T and B cell interactions
– Steroids
– Rituximab
– Other immunosuppressants
• Enhance platelet production
– Thrombopoietic agents
– Interleukin 11

Platelet Count (x 10 3 /µl)
Thrombopoietin Levels in ITP
250
200
150
100
50
0
Healthy
Donors
Mukai HY, et al. Thromb Haemost. 1996;76:675-678.
ITP AMT*
*Amegakaryocytic thrombocytopenia
25
20
15
10
5
0
Serum TPO (fmoles/ml)

Romiplostim Trials – Platelet Count
Kuter DJ, et al. Lancet. 2008;371:395-403.

Durable Responses in Romiplostim
Durable Platelet Response (%)
80
70
60
50
40
30
20
10
0
0.0
38.1
Splenectomized
(P = 0.0013)
Trials
Durable Response: Weekly platelet count ≥ 50,000 on 6
of last 8 weeks of study; no rescue meds allowed
Kuter DJ, et al. Lancet. 2008;371:395-403.
4.8
61.0
Nonsplenectomized
(P = 0.0001)
2.4
49.4
Total
(P = 0.0001)
Placebo
AMG-531

Mean (SE) Platelet
Count x 109 /L
Mean (SD) Dose (µg/kg)
300
250
200
150
100
50
0
10
8
6
4
2
0
Mean Platelet Count and
Romiplostim
Dose Over 204 Weeks
Study Week
1 4 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200
n = 212 183 160 146 136 123 118 112 108 103 99 96 86 70 62 58 48 34 26 21 22 21 17 14 12 6
n is the number of patients with available platelet counts, excluding those who received rescue
medications. Platelet counts within 8 weeks after receiving any rescue medications were
excluded.
Kuter DJ, et al. Blood. 2008;112:Abstract 402.

Median Platelet Count (x1,000/µL)
Eltrombopag and Median Platelet
Cheng G, et al. Blood. 2008;112:Abstract 400.
Counts:
RAISE
• Phase III clinical trial
• 26 weeks plus observation

Eltrombopag Enhances Platelet Count
and Ability to Initiate Interferon Therapy
Patients With ≥ 100,000
Platelets /µL at 4 Weeks
P ≤ 0.001 for each group vs Pbo
McHutchison J, et al. N Engl J Med. 2007;357:2227-2236.
Patients Entering Antiviral Phase

Emergency Treatment of Adult ITP
• IVIG (1.0 g/kg/d for 2–3 days) and/or
• Methylprednisolone (1.0 g/d x 3d)
• ± Platelet transfusion
•±Factor VIIa
Cines DB, McMillan R. Annu Rev Med. 2005;56:425-442.

Initial Treatment of Adult ITP
Platelet count: > 25–30,000/µl
• No treatment
Platelet count: < 25–30,000/µl
• Immunization
• Splenectomy
• Rituximab
• TPO agonist
Platelet count: < 25–30,000/µl
Adapted from Cines DB, McMillan R. Annu Rev Med. 2005;56:425-442.
• Prednisolone (1 mg/kg/d PO) or
• Periodic Anti-D (50–75 µg/kg IV as needed) or
• Dexamethasone (40 mg/day x 4 days/month)
Stable platelet count > 25–30,000/µl
• No therapy

Treatment of Patients Failing
Platelet count: < 25–30,000/µl
First-line Therapy
• Rituximab
• TPO agonist
• Prednisone
• Danazol/pred
Splenectomy
Second-line Therapy
• Azathioprine
•Oral
cyclophosphamide
• Mycophenolate
mofetil
• Cyclosporine
Adapted from Cines DB, McMillan R. Annu Rev Med. 2005;56:425-442.
Third-line Therapy
• High-dose
cyclophosphamide
• Combination
chemotherapy
• Stem-cell transplantation

Wrapping it up…
• ITP is often a chronic disease in adults
• Multiple therapies may be needed over
time
• Goal = prevention of complications
• Therapy needs to be tailored to the
individual patient