Haematology

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 2009Standardisation 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

12. Pathophysiology of ITP Harrington J Lab Clin Med 38, 1–10 (1951) • 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%

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

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 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

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 2010Therapeutic 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

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 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 optionsrecent treatments1 *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.

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

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

29. 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 • Rituxan label information : http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103705s5344lbl.pdf (date accessed: 19 Sep 2011); • 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); • Gottenberg JE et al. Arthritis Rheum. 2010; 62:2625-32.

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

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

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

34. Median Weekly Platelet Count - Romiplostim Romiplostim Placebo Splenectomized 200 150 Median Platelet Count (x109/L) 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 42 21 42 21 42 21 42 21 42 21 42 21 41 21 42 21 41 21 41 20 40 20 39 20 41 20 39 20 40 20 40 20 39 20 40 18 39 19 39 18 40 18 38 19 38 17 39 19 40 Non-splenectomized 200 150 Median Platelet Count (x109/L) 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 41 21 41 21 41 21 41 21 41 21 41 21 40 20 41 18 41 19 40 19 40 19 37 18 40 18 38 18 40 18 38 18 39 18 39 18 38 18 39 18 38 18 36 17 38 16 39 17 39 *Number available for measurement Kuter et al. Lancet 2008;371:395–403

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

36. Reduction in immunoglobulin use Cumulative probability of immunoglobulin use during the 24-week treatment period 1.0 0.9 0.8 Hazard ratio (95% CI) 5.3 (2.6, 11.1), p < 0.001 Placebo Romiplostim 0.7 0.6 Cumulative Probability of Immunoglobulin Treatment 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 Week Patients at risk Placebo Romiplostim 42 83 32 81 22 76 20 71 11 45 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

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-likeagentsPotential 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 agonistlimitations delayed onset action continuous administration ? intermittent unknown long term effects cost pregnancy

40. Approximate costs per course/mnth year IvIg newly diagnosed acute & ‘rescue’ or pre procedure 400mg/kg x 5 £5000 ? or 1g/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. Management of symptomatic ITP splenectomy 1st line Steroids IvIg 2nd line steroids - low dose other immune suppression IvIg splenectomy Rituximab ??TPO agonists splenectomy Rituximab Long term steroids low dose other immune suppression TPO agonists On demand IvIg Steroids TPO agonist

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