Haematology
Jennie Wimperis
Consultant Haematologist
Norfolk and Norwich University Hospital
Norwich
Immunoglobulin use in haematology
2010 database report
Total Grams Infused for Haematology in 2010
Alloimmune thrombocytopenia fetal therapy (treatment to the
mother)
5%
Haemophagocytic
lymphohistiocytosis
1%
Other specified uses
4%
Autoimmune haemolytic
anaemia
4%
Unspecified use
16%
ITP
70%
Total Grams Infused for Haematology Q1 2010
Alloimmune
thrombocytopenia fetal therapy
(treatment to the
mother)
5%
Autoimmune
haemolytic anaemia
5%
Haemophagocytic
lymphohistiocytosis
1%
Other specified uses
2%
Unspecified use
18%
ITP
69%
Total Grams Infused for Haematology Q2 2010
Alloimmune
thrombocytopenia - fetal
therapy (treatment to the
mother)
4%
Autoimmune haemolytic
anaemia
4%
Other specified uses
4%
Unspecified use
15%
ITP
73%
Total Grams Infused for Haematology Q3 2010
Alloimmune
Haemophagocytic
thrombocytopenia - fetal
lymphohistiocytosis
therapy (treatment to the
1%
mother)
4%
Autoimmune
haemolytic anaemia
5%
Autoimmune
(acquired)
haemophilia
1%
Other specified uses
3%
Unspecified use
14%
ITP
72%
Total Grams Infused for Haematology Q4 2010
Autoimmune
haemolytic anaemia
3%
Haemophagocytic
lymphohistiocytosis
1%
Other specified uses
7%
Alloimmune
thrombocytopenia - fetal
therapy (treatment to the
mother)
5%
Unspecified use
16%
ITP
68%
Current treatment of
Immune Thrombocytopenia
•
•
•
•
ITP – Definition and Terminology
therapeutic goals
treatment - place of IvIg in treatment
new treatments ? effect on IvIg use
Current treatment of
Immune Thrombocytopenia
•
•
•
•
ITP – Definition and Terminology
therapeutic goals
treatment - place of IvIg in treatment
new treatments ? effect on IvIg use
International Working Group
Consensus 2009
Standardisation of terminology for ITP
Definition
Acquired immune mediated disorder characterised by isolated
thrombocytopenia
Defined as a platelet count < 100 x 109/L - (versus often used 150)
Terminology
Primary immune thrombocytopenia (replacing term idiopathic)
Secondary immune thrombocytopenia (SLE, drugs etc)
Neonatal Allo Iimmune Thrombocytopenia and Post Transfusional
Purpura , Heparin Induced Thrombocytopenia retained
Rodeghiero et al: Blood 2009, 113, 2386-2393
NAIT neonatal immune thrombocytopenia, PTP post transfusional purpura ,HITT heparin induced
thrombocytopenia
Pathophysiology of ITP
• Platelets are coated with autoantibody or immune
complexes - removed by spleen, liver and elsewhere
• First demonstrated by Harrington 1951
– injected serum from ITP patients into non-ITP volunteers
– transient fall in platelet counts
• Megakaryocytes often increased
but may be decreased
• Production reduced in 40%
Harrington J Lab Clin Med 38, 1–10 (1951)
Presentation of ITP
International Working Group
Consensus 2009
Phases of disease
• Newly diagnosed (replacing acute)
• Persistent
• Chronic
Rodeghiero et al: Blood 2009, 113, 2386-2393
International Working Group
Consensus 2009
Severity of disease
previously correlated with degree of thrombocytopenia
Severe ITP
‘clinically relevant bleeding’ irrespective of platelet count
Refractory
failed splenectomy or relapse thereafter
and have severe ITP or a risk of bleeding
Rodeghiero et al: Blood 2009, 113, 2386-2393
Clinical course of ITP
Childhood
Adult
Spontaneous
remission
Chronic ITP
83%
2%
15%
43%
Complete
recovery
Response to
splenectomy
89+%
64%
71%
66%
What actually are the risks of ITP?
• Disease impact varies from patient to patient from minor
symptoms, such as an increased tendency to bruise, anaemia,
or mucosal bleeding, to severe, even fatal bleeding events1
• For those with long-standing, severe refractory ITP2
– Cerebral haemorrhage
3%
– Haemorrhagic death
4%
– Mortality of chronic disease/treatment
5%
1. Mathias S et al. Curr Med Res & Opinion 2009;25:375–383;
2. George JN & Raskob GE. Semin Hematol 1998;35:5–8
Current treatment of
Immune Thrombocytopenia
•
•
•
•
ITP – Definition and Terminology
therapeutic goals
treatment - place of IvIg in treatment
new treatments ? effect on IvIg use
International Working Group
Consensus 2010
Therapeutic Goals
• provide a safe platelet count i.e. one that prevents bleeding rather than
to normal levels
• treatment should always be tailored to the individual –
treatment may be worse than disease
• factors which contribute to management decisions include:
–
–
–
–
–
–
–
bleeding
other medical problems
activity and lifestyle
tolerance of side effects
planned procedure
patient preferences/concerns
platelet counts
Platelet >20–30x109/L
Platelet >80 x109/L
Platelet >50 x109/L
Provan D et al. Blood 2010;15:168–186
Treatment of ITP
• platelets are coated with autoantibody or immune
complexes - immune suppression/immune modulation
• removed by spleen, liver and elsewhere - splenectomy
• megakaryocytes often increased but may be decreased production reduced in 40% - stimulation of megakaryocytes
Short course – cure or prolonged remission
Continuous or repeated administrations
Indications for treatment of
ITP
symptomatic
symptomatic
on demand – bleeding, trauma, pre procedure
Current treatment of
Immune Thrombocytopenia
•
•
•
•
ITP – Definition and Terminology
therapeutic goals
treatment - place of IvIg in treatment
new treatments ? effect on IvIg use
Treatment of ITP with IvIg
Newly diagnosed symptomatic ITP
Persistent (3-12 months) or Chronic (>12 months)
on demand – bleeding/trauma/pre procedure
Long term chronic refractory
Dose
– 400mg/kg x 5
– 1g/kg 2 days
Current treatment of
Immune Thrombocytopenia
•
•
•
•
ITP – Definition and Terminology
therapeutic goals
treatment - place of IvIg in treatment
new treatments ? effect on IvIg use
Recommendations
overview of medical management options
recent treatments1
Clinical situation
Therapy option
First line (initial treatment
for newly diagnosed ITP)
Corticosteroids: dexamethasone, methylprednisolone,
prednisolone
Intravenous immunoglobulin
(Anti-D)
Second line*
Azathioprine
Cyclosporin A
Cyclophosphamide
Danazol
Dapsone
Treatment for refractory
ITP patients (patients
failing first- and secondline therapies)
Category A: treatment options with sufficient data
Thrombopoietin-receptor agonists**
Category B: treatment options with minimal data and
considered to have potential for considerable toxicity
Campath-1H
Combination of first- and second-line therapies
Combination chemotherapy
Haemopoietic stem cell transplantation
Mycophenolate mofetil
Rituximab
Splenectomy
Thrombopoietin-receptor
agonists**
Vinca alkaloids
*Treatment options are listed alphabetically and thus do not indicate a oreferred treatment option.
**The EU license for splenectomised adults with ITP who are refractory to other treatments or in non-splenectomised patients
where surgery is contraindicated
1 New International Consensus Guidelines Provan, Stasi, Newland et al Blood 2010; 115; 168-186.
Rituximab
• anti CD20 humanised McAb – B cells
• weekly doses
– 375 mg/m2 x 4
– fixed dose 100mg x 4
Response to Rituximab
in Children and Adults with ITP
Total
100%
100%
Initial
Response
57%*
56% *
1 Year
38% *
32% †
2 Years
31% †
25% †
5 Years
21% †
25% †
Median response 10.5 months
Children
* Derived from published reports
† Long-term follow up data acquired in this study
Patel VL, et al. ASH 2010 Abstract 72
Adults
Rituximab is associated with an increased
risk of adverse events
• Black box warning applied to FDA label1 and special
warning to EMEA label2 for
– risk of infusion reactions
– mucocutaneous reactions
– increased risk of PML
• Risk of hepatitis B reactivation1
• Risk of severe infections
– French AIR registry: 5.0 severe infections/
100 patients/year3
PML, progressive multifocal leukoencephalopathy
1. Rituxan label information :
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103705s5344lbl.pdf
(date accessed: 19 Sep 2011);
2. Rituximab SmPC 2011: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000165/WC500025821.pdf (date accessed: 19 Sep 2011);
3. Gottenberg JE et al. Arthritis Rheum. 2010; 62:2625-32.
Thrombopoietin-receptor agonists
Stimulates platelet production by promoting
• Proliferation
• Survival
• Differentiation of megakaryocyte precursors into
mature megakaryocytes
• Platelet release
May prime platelets for activation
Why should exogenous thrombopoietin be
effective in ITP?
Adapted from: Nichol JL. Stem Cells. 1998;16(suppl 2): 165–175.
Thrombopoeitin receptor agonists
Nonpeptide Mimetics
- Eltrombopag (Revolade), AKR 501
Peptide Mimetics
- Romiplostim (N-plate), PEG TPOmp
Incidence of Overall Platelet Response
Placebo
Romiplostim
100
Overall Platelet Response (%)
88
83
79
80
60
40
14
20
7
0
0
(p < .0001)
(p < .0001)
(p < .0001)
Splenectomized
Non-splenectomized
Total
Kuter et al. Lancet 2008;371:395–403
Median Platelet Count (x109/L)
Median Weekly Platelet Count - Romiplostim
200
Romiplostim
Placebo
Splenectomized
150
100
50
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Study Week
Median Platelet Count (x109/L)
Placebo*
Romiplostim*
200
21 21 21 21 21 21 21 21 21 21 20 20 20 20 20 20 20 20 18 19 18 18 19 17 19
42 42 42 42 42 42 41 42 41 41 40 39 41 39 40 40 39 40 39 39 40 38 38 39 40
Non-splenectomized
150
100
50
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Study Week
Placebo*
Romiplostim*
21 21 21 21 21 21 21 20 18 19 19 19 18 18 18 18 18 18 18 18 18 18 17 16 17
41 41 41 41 41 41 40 41 41 40 40 37 40 38 40 38 39 39 38 39 38 36 38 39 39
*Number available for measurement
Kuter et al. Lancet 2008;371:395–403
Patients with bleeding
events
59% reduction
Placebo (n=41)
40
35
Romiplostim (n=84)
34
Percentage
30
42% reduction
25
20
14
15
12
10
7
5
0
Grade ≥ 2
Severity grades according to MedDRA 9.0 definition
Lyons et al. ASH 2007; poster
Grade ≥ 3
Reduction in immunoglobulin use
Cumulative probability of immunoglobulin use during
the 24-week treatment period
1.0
Cumulative Probability of
Immunoglobulin Treatment
0.9
0.8
Hazard ratio (95% CI)
5.3 (2.6, 11.1), p < 0.001
0.7
Placebo
Romiplostim
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
Patients at risk
Placebo
Romiplostim
2
4
6
8
10
12
14
16
18
20
22
24
Week
42
83
32
81
22
76
Cumulative probability of immunoglobulin use in 24 weeks
0.51 (SE: 0.08) for placebo; 0.13 (SE: 0.04) for romiplostim
Pullarkat et al. ASH 2007; poster
20
71
11
45
NICE Guidance (TA 221) on Romiplostim
April 2011
1.1 Recommended for the treatment of adults with chronic ITP:
– whose condition is refractory to standard active treatments
and rescue therapies or
– who have severe disease and a high risk of bleeding that
needs frequent courses of rescue therapies
and
– if the manufacturer makes romiplostim available within the
discount agreed as part of the patient access scheme
1.2 Only a haematologist should start and supervise treatment
with romiplostim
Thrombopoietin-like agents
Potential Adverse events
•
•
•
•
•
•
•
•
•
headache, nausea, vomiting, fatigue, arthralgia
thrombocytosis
thrombosis – venous or arterial (risk factor)
rebound thrombocytopenia on cessation
hepatotoxicity (Eltrombopag)
increased bone marrow fibrosis (reticulin/collagen)
autoantibody formation
reduced threshold for platelet activation
risk of stimulating tumour/leukaemia growth
TPO agonist
limitations
• delayed onset action
• continuous administration
– ? intermittent
• unknown long term effects
• cost
• pregnancy
Approximate costs
per course/mnth
IvIg
newly diagnosed acute & ‘rescue’ or pre procedure
400mg/kg x 5
£5000
or 1g/kg x 2
year
?
Rituximab persistent & chronic
375 mg/m2 x 4
£1000
100mg x 4
£6000
£1000
£6000
TPO receptor agonists prersistent & chronic
Romiplostim
£1700-£3400
Eltrombopag (50mg)
£2000
£20,000-£40,000
£24000
Management of symptomatic ITP
splenectomy
1st line
steroids - low dose
splenectomy
Steroids
other immune suppression
Rituximab
IvIg
IvIg
Long term
2nd line
splenectomy
steroids low dose
Rituximab
other immune suppression
??TPO agonists
TPO agonists
On demand
IvIg
Steroids
TPO agonist
Total Grams Infused for ITP
60000
NICE recommended romiplostim for the treatment of
patients with severe, chronic ITP on 27/04/2011
grams of immunoglobulin
50000
40000
30000
?
20000
10000
0
Q1 2010
Q2 2010
Q3 2010
Q4 2010
ITP
Q1 2011
Q2 2011
Second edition update
Clarification:
Immune thrombocytopenia
Immune thrombocytopenia (newly diagnosed)
Immune thrombocytopenia (persistent)
Immune thrombocytopenia (chronic – on demand)*
Immune thrombocytopenia (chronic)
* For bleeding, trauma or pre-procedure
Clarification:
Immune thrombocytopenia
Database update
will reflect intended
advice and updated
terminology for
immune
thrombocytopenia
Thank you