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

Total Grams Infused for Haematology Q1 2010

Total Grams Infused for Haematology Q2 2010

Total Grams Infused for Haematology Q3 2010

Total Grams Infused for Haematology Q4 2010

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 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, 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,

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,

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

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 >20–30x10 9 /L Platelet >50 x10 9 /L Platelet >80 x10 9 /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 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 treatments 1 1 New International Consensus Guidelines Provan, Stasi, Newland et al Blood 2010; 115; 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

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

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

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 : (date accessed: 19 Sep 2011); 2.Rituximab SmPC 2011: _Product_Information/human/000165/WC pdf (date accessed: 19 Sep 2011); 3.Gottenberg JE et al. Arthritis Rheum. 2010; 62: PML, progressive multifocal leukoencephalopathy

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

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

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

Incidence of Overall Platelet Response Overall Platelet Response (%) (p <.0001) SplenectomizedNon-splenectomizedTotal PlaceboRomiplostim Kuter et al. Lancet 2008;371:395–403

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

Placebo (n=41) Romiplostim (n=84) Severity grades according to MedDRA 9.0 definition 42% reduction 12 7 Grade ≥ Percentage 59% reduction Grade ≥ 2 Lyons et al. ASH 2007; poster Patients with bleeding events

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 Hazard ratio (95% CI) 5.3 (2.6, 11.1), p < Week Cumulative Probability of Immunoglobulin Treatment Patients at risk Placebo Romiplostim PlaceboRomiplostim

NICE Guidance (TA 221) on Romiplostim April 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/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£ mg x 4£6000£6000 TPO receptor agonists prersistent & chronic Romiplostim £1700-£3400£20,000-£40,000 Eltrombopag (50mg)£2000£24000

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

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

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

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