1. Haematology Jennie Wimperis Consultant Haematologist Norfolk and Norwich University Hospital

2. Norwich

3. Immunoglobulin use in haematology 2010 database report

4. Total Grams Infused for Haematology in 2010

5. Total Grams Infused for Haematology Q1 2010

6. Total Grams Infused for Haematology Q2 2010

7. Total Grams Infused for Haematology Q3 2010

8. Total Grams Infused for Haematology Q4 2010

9. Current treatment of Immune Thrombocytopenia ITP – Definition and Terminology therapeutic goals treatment - place of IvIg in treatment new treatments ? effect on IvIg use

10. Current treatment of Immune Thrombocytopenia ITP – Definition and Terminology therapeutic goals treatment - place of IvIg in treatment new treatments ? effect on IvIg use

11. 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 10 9 /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

12. 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)

13. Presentation of ITP

14. International Working Group Consensus 2009 Phases of disease Newly diagnosed (replacing acute) Persistent Chronic Rodeghiero et al: Blood 2009, 113, 2386-2393

15. 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

16. Clinical course of ITP ChildhoodAdult Spontaneous remission 83%2% Chronic ITP 15%43% Complete recovery 89+%64% Response to splenectomy 71%66%

17. 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 events 1 For those with long-standing, severe refractory ITP 2 – Cerebral haemorrhage3% – Haemorrhagic death4% – Mortality of chronic disease/treatment5% 1. Mathias S et al. Curr Med Res & Opinion 2009;25:375–383; 2. George JN & Raskob GE. Semin Hematol 1998;35:5–8

18. Current treatment of Immune Thrombocytopenia ITP – Definition and Terminology therapeutic goals treatment - place of IvIg in treatment new treatments ? effect on IvIg use

19. 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 >20–30x10 9 /L Platelet >50 x10 9 /L Platelet >80 x10 9 /L Provan D et al. Blood 2010;15:168–186

20. 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

21. Indications for treatment of ITP symptomatic on demand – bleeding, trauma, pre procedure

23. Current treatment of Immune Thrombocytopenia ITP – Definition and Terminology therapeutic goals treatment - place of IvIg in treatment new treatments ? effect on IvIg use

24. 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

25. Current treatment of Immune Thrombocytopenia ITP – Definition and Terminology therapeutic goals treatment - place of IvIg in treatment new treatments ? effect on IvIg use

26. Recommendations overview of medical management options recent treatments 1 1 New International Consensus Guidelines Provan, Stasi, Newland et al Blood 2010; 115; 168-186. 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 CyclophosphamideDanazolDapsone Mycophenolate mofetil RituximabSplenectomy Thrombopoietin-receptor agonists** Vinca alkaloids Treatment for refractory ITP patients (patients failing first- and second- line 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 *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

27. Rituximab anti CD20 humanised McAb – B cells weekly doses – 375 mg/m2 x 4 – fixed dose 100mg x 4

28. 25% † 56% * 100%100% 57%* 38% * 32% † 32% † 31% † 25% † 21% † Total Initial Response 1 Year 2 Years 5 Years Children Adults * Derived from published reports † Long-term follow up data acquired in this study Response to Rituximab in Children and Adults with ITP Patel VL, et al. ASH 2010 Abstract 72 Median response 10.5 months

29. Rituximab is associated with an increased risk of adverse events Black box warning applied to FDA label 1 and special warning to EMEA label 2 for – risk of infusion reactions – mucocutaneous reactions – increased risk of PML Risk of hepatitis B reactivation 1 Risk of severe infections – French AIR registry: 5.0 severe infections/ 100 patients/year 3 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. PML, progressive multifocal leukoencephalopathy

30. Thrombopoietin-receptor agonists Stimulates platelet production by promoting Proliferation Survival Differentiation of megakaryocyte precursors into mature megakaryocytes Platelet release May prime platelets for activation

31. Adapted from: Nichol JL. Stem Cells. 1998;16(suppl 2): 165–175. Why should exogenous thrombopoietin be effective in ITP?

32. Thrombopoeitin receptor agonists Nonpeptide Mimetics - Eltrombopag (Revolade), AKR 501 Peptide Mimetics - Romiplostim (N-plate), PEG TPOmp

33. Incidence of Overall Platelet Response Overall Platelet Response (%) (p <.0001) 0 14 7 79 88 83 0 20 40 60 80 100 SplenectomizedNon-splenectomizedTotal PlaceboRomiplostim Kuter et al. Lancet 2008;371:395–403

34. Median Weekly Platelet Count - Romiplostim Non-splenectomized 200 Placebo* Romiplostim* 150 100 50 0 12345678910111213141516171819202122232425 Study Week 2141214121412141214121412140204118411940194019371840183818401838183918391838183918381836173816391739Placebo*Romiplostim* Median Platelet Count (x10 9 /L) 200 150 100 50 0 123456789111213141516171819202122232425 Study Week 2142214221422142214221422141214221412141204020392041203920402040203920401839193918401838193817391940 Median Platelet Count (x10 9 /L) Splenectomized 10RomiplostimPlacebo *Number available for measurement Kuter et al. Lancet 2008;371:395–403

35. Placebo (n=41) Romiplostim (n=84) Severity grades according to MedDRA 9.0 definition 42% reduction 12 7 Grade ≥ 3 0 5 10 15 20 25 30 35 40 Percentage 59% reduction 34 14 Grade ≥ 2 Lyons et al. ASH 2007; poster Patients with bleeding events

36. Reduction in immunoglobulin use Cumulative probability of immunoglobulin use during the 24-week treatment period 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 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Hazard ratio (95% CI) 5.3 (2.6, 11.1), p < 0.001 Week Cumulative Probability of Immunoglobulin Treatment Patients at risk Placebo Romiplostim 32814283227620711145 024681012141618202224 PlaceboRomiplostim

37. 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

38. 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

39. TPO agonist limitations delayed onset action continuous administration – ? intermittent unknown long term effects cost pregnancy

40. Approximate costs per course/mnthyear IvIg newly diagnosed acute & ‘rescue’ or pre procedure 400mg/kg x 5£5000 ? or1g/kg x 2 Rituximab persistent & chronic 375 mg/m2 x 4£1000£1000 100mg x 4£6000£6000 TPO receptor agonists prersistent & chronic Romiplostim £1700-£3400£20,000-£40,000 Eltrombopag (50mg)£2000£24000

41. 1 st line SteroidsIvIg 2 nd line steroids - low dose other immune suppression IvIgsplenectomyRituximab ??TPO agonists splenectomy splenectomyRituximab Long term steroids low dose other immune suppression TPO agonists On demand IvIgSteroids TPO agonist Management of symptomatic ITP

42. Total Grams Infused for ITP NICE recommended romiplostim for the treatment of patients with severe, chronic ITP on 27/04/2011 ?

43. Second edition update

44. Clarification: Immune thrombocytopenia Immune thrombocytopenia (newly diagnosed) Immune thrombocytopenia (persistent) Immune thrombocytopenia (chronic – on demand)* Immune thrombocytopenia (chronic) * For bleeding, trauma or pre-procedure

45. Clarification: Immune thrombocytopenia Database update will reflect intended advice and updated terminology for immune thrombocytopenia

46. Thank you