Update on the Management of Immune Thrombocytopenic Purpura (ITP) Dr Raymond Wong Department of Medicine & Therapeutics Prince of Wales Hospital

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1 Update on the Management of Immune Thrombocytopenic Purpura (ITP) Dr Raymond Wong Department of Medicine & Therapeutics Prince of Wales Hospital

2 Immune Thrombocytopenia (ITP) Immune-mediated acquired disease of adults and children ITP is characterized by: A low platelet count (<100 x 10 9 /L, transient or persistent) 1 An increased risk of bleeding due to impaired clotting mechanism 2-4 The overall incidence of ITP among adults is estimated at 3.3 per 100,000 person-years 5 Higher incidence in women versus men 6 Male:female ratio increases with age Higher incidence at older ages 6 HCV, hepatitis C virus; HIV, human immunodeficiency virus 1. Rodeghiero F, et al. Blood 2009; 113: ; 2. Stasi R, Provan D. Mayo Clin Proc 2004; 79: ; 3. Chang M, et al. Blood 2003; 102: ; 4. Cooper N, Bussel J. Br J Haematol 2006; 133: ; 5. Terrell D, et al. Am J Hematol 2010; 85: ; 6. Schoonen W, et al. Br J Haematol 2009; 145:

3 Clinical presentation of ITP varies Dependent on the severity of thrombocytopenia, the clinical presentation of ITP varies 1,2 Most patients are asymptomatic but may complain of fatigue and easy bruising As platelet counts fall, symptoms become more severe and may include: - purpuric skin lesions - cutaneous bleeding - epistaxis - gingival or gastrointestinal bleeding - haematuria or menorrhagia Thromboembolic event risk increased 3 1. Stasi R, Provan D. Mayo Clin Proc 2004; 79: ; 2. Cines D, McMillan R. Annu Rev Med 2005; 56: ; 3. Sarpatwari A, et al. Haematologica 2010; 95: Purpura (reddish purple spots) Petechiae Actual scale: 1 cm 2 cm 3 cm

4 Current Understanding of Pathogenesis of ITP 4

5 Immune pathogenesis of Immune Thrombocytopenia (ITP) Evidence that ITP is a B cell disease Platelets ( 10 9 /L) Control megakaryocytes (%) Antiplatelet antibodies: Inhibition of megakaryocytes by plasma from ITP patients: Hours Days Platelet count after infusion with patient plasma 0 1. Harrington WJ et al. J Lab Clin Med 1951;38:1 10; 2. McMillan R et al. Blood 2004;103:

6 Thrombopoietin (TPO) Signaling Pathways TPO TPO TPO TPO Stem cell Bilineal progenitor cell Committed megakaryocyte progenitor cell Immature megakaryocyte Mature megakaryocyte TPO regulates the maturation of megakaryocytes, via signal transduction pathways, into plateletproducing cells Platelets 1. Kuter D, et al. Blood 2002; 100: ; 2. Kaushansky K. N Engl J Med 1998; 339: ; 3. Wolber E, Jelkmann W. News Physiol Sci 2002; 17: Figure adapted with permission from Kaushansky K. N Engl J Med 1998; 339:

7 Thrombopoietin level Thrombopoietin levels are lower than expected in ITP No correlation between platelet count and TPO levels in patients with ITP 1 No significant difference in TPO levels between patients with ITP and controls 2 0 Normal ITP Aplastic anemia 1. Kosugi S et al. Br J Haematol 2003;93: ; 2. Aledort LM et al. Am J Hematol 2004;76:

8 ITP is caused by lower production and higher destruction of platelets Increased platelet destruction (spleen) Healthy (normal platelet counts) Antiplatelet immunity (Ab + T cell) Anti-megakaryocyte immunity (Ab + T cell) Decreased platelet production (bone marrow) ITP effector immunity is primarily comprised of antibodies and T cells Nugent D et al. Br J Haematol 2009;146: Ab, antibody

9 Complex ITP pathophysiology underlies platelet regulation Megakaryocyte Tc cell Tc-cell-mediated platelet destruction Impaired megakaryocyte maturation Reduced platelet production Platelets Platelet phagocytosis Epitope spreading CD28 CD80 Platelet autoantibody production CD80 CD28 TCR MHC II CD154 CD40 CD40 CD154 Th cell B cell IL-2 IFN-γ Adapted from Stasi R et al. Thromb Haemost 2008;99:4 13 Macrophage IFN, interferon; MHC, major histocompatibility complex; Tc, cytotoxic T cell; TCR, T cell receptor

10 Diagnosis of Immune Thrombocytopenia (ITP) 10

11 Guidelines for diagnosis of ITP ITP remains a diagnosis of exclusion of other conditions or factors that cause thrombocytopenia 1 Assessment of the following is needed to diagnose ITP: 1 Patient and family history Physical examination Complete blood count Peripheral blood film Results do not suggest other aetiologies for thrombocytopenia 1 Other laboratory investigations There is no robust clinical or laboratory test that can establish a diagnosis with accuracy 1 A platelet count <100 x 10 9 /L has been defined as the threshold for diagnosis 2 1. Provan D, et al. Blood 2010; 115: ; 2. Rodeghiero F, et al. Blood 2009; 113:

12 Diagnostic Approach in Suspected ITP Basic evaluation Tests of potential utility Tests of unproven benefit Patient/family history Physical examination CBC and reticulocyte count Peripheral blood film Quantitative immunoglobulin level measurement* Bone marrow (in selected patients) Blood group (Rh) Direct antiglobulin test H. pylori**/***; HIV/HCV** Glycoprotein-specific antibody Antiphospholipid antibodies (including anticardiolipin and lupus anticoagulant) Antithyroid antibodies and thyroid function Pregnancy test in women of childbearing potential Antinuclear antibodies*** PCR for parvovirus and CMV TPO Reticulated platelets PaIgG Bleeding time Platelet survival study Serum complement *Should be considered in children; recommended in children with persistent or chronic ITP **Recommended for adult patients regardless of geographic location ***Not recommended in children according to the American Society of Hematology guidelines (2011) 1 CBC, complete blood count; CMV, cytomegalovirus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PaIgG, platelet-associated immunoglobulin G; PCR, polymerase chain reaction; Rh, rhesus 1. Neunert C, et al. Blood 2011; 117: ; Table reproduced with permission from Provan D, et al. Blood 2010; 115:

13 Diagnosis of ITP The diagnosis of ITP remains one of exclusion; known causes of thrombocytopenia include: Lupus erythematosus, infection (HIV, HCV), thrombotic thrombocytopenic purpura Hereditary thrombocytopenia: absent radius syndrome, radio-ulnar synostosis, congenital amegakaryocytic thrombocytopenia, Wiskott-Aldrich Syndrome, MYH9-associated thrombocytopenia, Bernard-Soulier Syndrome Vaccinations and transfusions Medication/drugs/diet (e.g. platelet-lowering treatments, alcohol, vitamin deficiency, quinine from tonic water) Liver disease Other bone marrow disease/leukemia HCV, hepatitis C virus; HIV, human immunodeficiency virus Provan D, et al. Blood 2010; 115:

14 Role of Bone Marrow Examination in the diagnosis of ITP International consensus report on the investigation and management of primary immune thrombocytopenia Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, Chong BH, Cines DB, Gernsheimer TB, Godeau B, Grainger J, Greer I, Hunt BJ, Imbach PA, Lyons G, McMillan R, Rodeghiero F, Sanz MA, Tarantino M, Watson S, Young J, Kuter DJ. Blood 2010;115: may be informative in patients > 60 years of age, in those with systemic symptoms or abnormal signs, or in some cases pre-splenectomy The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA; American Society of Hematology. Blood 2011;117: is not necessary irrespective of age in patients presenting with typical ITP Provan D, et al. Blood 2010; 115: Neunert C, et al. Blood 2011; 117: ;

15 Treatment strategies for patients with ITP 15

16 Factors That Contribute to ITP Management Decisions The goal of treatment in chronic ITP is not well defined and depends on balancing efficacy against the adverse effects of a given treatment 1 In patients with platelet counts >50 x 10 9 /L treatment is not usually indicated unless the patient has other risk factors (e.g. bleeding or surgery) 1 A platelet count of <30 x 10 9 /L is commonly used as the threshold for treatment in asymptomatic patients 1. Rodeghiero F, et al. Blood 2009; 113: ; 2. Neunert C, et al. Blood 2011; 117: ; 3. Provan D, et al. Blood 2010; 115:

17 Treatments for ITP: mechanisms of action Newland A, et al. Immunotherapy (2018) 10(1), 9 25

18 International Consensus Report (2010): Guidelines on First-line Treatment Options Clinical situation Therapy option First-line therapy (initial treatment for newly diagnosed ITP) Corticosteroids (standard initial treatment) Dexamethasone Methylprednisolone Prednis(ol)one Intravenous anti-d (Rho) immunoglobulin IVIg Second-line therapy Treatment for patients failing first- and second-line therapies IVIg, intravenous immunoglobulin Adapted with permission from Provan D, et al. Blood 2010; 115:

19 ITP: Corticosteroid Treatment Strategy Recommended treatment strategy Response rate Time to Toxicities Duration of response sustained response Dexamethasone 40 mg daily for 4 days every 2 4 weeks for 1 4 cycles Methylprednisolone 30 mg/kg/day for 7 days Prednis(ol)one mg/kg/day for 2 4 weeks Up to 90% of patients respond initially As high as 95% 70 80% of patients respond initially Several days to several weeks 4.7 days (high dose) Several days to several weeks Can include: mood swings, weight gain, anger, fluid retention insomnia, Cushingoid faces, dorsal fat, diabetes, osteoporosis, skin changes, alopecia, hypertension, gastrointestinal distress, ulcers, avascular necrosis, immunosuppression, psychosis, cataracts, opportunistic infections, adrenal insufficiency, hypertension, anxiety. Tolerability decreases with repeated dosing 50 80%, the latter with 3 6 cycles 23% have sustained platelet count (>50 x 10 9 /L) at 39 months Remains uncertain; estimated 10 year disease-free survival for 13 15% Adapted with permission from Provan D, et al. Blood 2010; 115:

20 ITP: Intravenous Immunoglobulin (IVIg) Therapy Profile Have an initial response rate comparable to corticosteroids with a shorter time to response Many recipients attain a platelet increase within 24 hours at a dose of 1 g/kg In some patients, corticosteroids may enhance the IVIg response Safety and efficacy Associated with higher toxicity than corticosteroids, especially headaches There is a need for a prolonged infusion over several hours Rare but serious toxicities include renal failure and thrombosis Transient response Provan D, et al. Blood 2010; 115:

21 ITP: Intravenous Anti-D Immunoglobulin Profile Appropriate for Rhesus D-positive, non-splenectomised ITP patients 1,2 May be an effective alternative to IVIg: 1 It can be infused in a shorter time It has a potentially longer response May reduce the need for splenectomy Limitations Not recommended for use in patients with autoimmune haemolytic anaemia to avoid exacerbation of haemolysis 1,2 Mild anaemia is expected and may be dose-limiting 1 It has a small donor pool and therefore the potential for limited availability 1 IVIg, intravenous immunoglobulin 1. Provan D, et al. Blood 2010; 115: ; 2. Neunert C, et al. Blood 2011; 117:

22 ITP: Second-line Therapy When first-line therapy fails, it is appropriate to move to second-line therapy in an attempt to gain a sustained increase in platelet count Treatment decisions to be individualised based on: Bleeding history Comorbidities Compliance Patient expectations Provan D, et al. Blood 2010; 115:

23 International Consensus Report (2010): Guidelines on Second-line Treatment Options First-line therapy Clinical situation Therapy option Second-line therapy Azathioprine Cyclosporin A Cyclophosphamide Danazol Dapsone Mycophenolate mofetil Rituximab Splenectomy TPO-R agonists (eltrombopag, romiplostim) Vinca alkaloid regimens Treatment for patients failing firstand second-line therapies Adapted with permission from Provan D, et al. Blood 2010; 115:

24 Second-line Immunosuppressive Agents for Adult ITP Patients Adapted from Provan D, et al. Blood 2010; 115:

25 ITP: Rituximab Treatment Chimeric, monoclonal antibody against B-cell antigen CD20 1 that causes a transient elimination of B-cells 2 Rituximab is not currently approved for treatment of ITP The ASH guidelines indicate rituximab as a consideration for patients at risk of bleeding who have failed one line of therapy such as corticosteroids, IVIg, or splenectomy 3 Initial response was seen in 62.5% of cases with a complete response in 46.3% of patients* 4 The 5-year response rate is approximately 21% for adults 5 IVIg, intravenous immunoglobulin *a complete response was defined as platelet count >150 x 10 9 /L and overall response as a platelet count >50 x 10 9 /L 1. Godeau B, et al. Blood 2008; 112: ; 2. Stasi R, et al. Thromb Haemost 2008; 99: 4 13; 3. Neunert C, et al. Blood 2011; 117; ; 4. Arnold D, et al. Ann Intern Med 2007; 146: 25 33; 5. Patel V, et al. Blood 2010; 116: abstract 72

26 ITP: Splenectomy Splenectomy: Is considered the traditional second-line therapy in adults with chronic ITP resistant to firstline treatments 1 80% of patients respond to splenectomy with ~66% achieving a lasting response 2 Splenectomy complication and mortality rates have been seen to be higher with laparotomy than in laparoscopy 2 Criteria for splenectomy: 1 Severe thrombocytopenia (platelet count <10 x 10 9 /L) A high risk of bleeding for platelet counts <30 x 10 9 /L The requirement of continuous corticosteroid therapy to maintain safe platelet counts Splenectomy is deferred in most patients for 6 months 2 but often for >12 months 3 after diagnosis 1. Stasi R, et al. Thromb Haemost 2008; 99: 4 13; 2. Provan D, et al. Blood 2010; 115: ; 3. Neunert C, et al. Blood 2011; 117:

27 ITP: Splenectomy Schwartz J, et al. Am J Hematol 2003;72:94-8; Vianelli N, et al. Haematologica 2005;90:72-7

28 ITP: Splenectomy Timing of treatment Standard second-line therapy for ITP 1,2 Generally considered from 6 months after failure of primary treatment 1,2 Efficacy Initial haemostatic response in 70 80% of patients 1,2 Safety/ tolerability 15 25% of patients relapse within 10 years 1 Success rate of ~66% with a sustained complete response 1,3 Splenectomy is associated with significant morbidity and a risk of overwhelming and fatal Streptococcus pneumoniae infection 2 Complications of splenectomy can include infections, long-term relapse, prolonged hospitalisation and risk of death 1,2 Risk of serious post-splenectomy infection is greater in patients >65 years of age 1 There may be a lower mortality rate with laparoscopic splenectomy 1,3 Occasionally, patients may fail to respond to splenectomy because of the failure to remove an accessory spleen 3 1. Provan D, et al. Blood 2010; 115: ; 2. Neunert C, et al. Blood 2011; 117: ; 3. Stasi R, et al. Thromb Haemost 2008; 99: 4 13

29 TPO-R Agonists A novel therapeutic class of agents for chronic adult ITP which stimulate platelet production: Bind and activate the TPO-R, helping to balance platelet production against destruction 1 Agents include TPO peptide agonists (e.g. [romiplostim]) and TPO non-peptide agonists (e.g. [eltrombopag]) Figure not to scale Kuter D. Blood 2007; 109:

30 Licensed TPO-RAs Eltrombopag Romiplostim TPO Fc Carrier Domain TPO-RA Peptides Eltrombopag Small molecule, non-peptide Does not compete with TPO for binding to TPO-R Orally bioavailable, once-daily dosing Low immunogenic potential Advised not to take 2 hours before or 4 hours after a high-calcium meal or products containing polyvalent cations Thrombopoiesis-stimulating peptibody Structurally unrelated to TPO Two dipeptides linked to the Fc fragment of an IgG 1, administered subcutaneously once a week Recycled via FcRn Bussel JB et al. N Engl J Med 2006;355: ; Bussel JB et al. N Engl J Med 2007;357: ; Kuter DJ. Semin Hematol 2010;47:

31 RAISE Study Design Phase III, randomised, double-blind, placebo-controlled study Screening N= mg Eltrombopag + SoC Adult, chronic ITP patients, <30 x 10 9 /L Randomise 2:1 N=62 6-month treatment period Placebo + SoC Randomized patients were stratified by splenectomy status, concomitant maintenance ITP therapy, baseline platelet count 15,000/µL Eltrombopag dose adjustments were allowed (between mg) Reduction of concomitant medication and use of rescue treatments were allowed Cheng G et al. Blood. 2008;112(11):400.

32 RAISE: Sustained Increase in Median Platelet Count versus Placebo During Treatment with Eltrombopag Median platelet counts rose from 16 x 10 9 /L to ~36 x 10 9 /L after 1 week in the eltrombopag group Study week Number of patients Placebo Eltrombopag Cheng G, et al. Lancet 2011; 377: Erratum: Lancet 2011; 377: On treatment Posttreatment Eltrombopag Placebo

33 RAISE: Eltrombopag Reduces Clinically Significant Bleeding versus Placebo Over 6 months treatment, the odds of bleeding and clinically significant bleeding with eltrombopag were respectively 76% and 65% less compared with placebo (OR 0.24, 95% CI 0.16, 0.38; p< and OR 0.35, 95% CI 0.19, 0.64; p=0.0008) Eltrombopag Placebo World Health Organization Bleeding Scale: Grade 2, mild blood loss; Grade 3, gross blood loss; Grade 4, debilitating blood loss CI, confidence interval; OR, odds ratio Cheng G, et al. Lancet 2011; 377: Erratum: Lancet 2011; 377: 382

34 EXTEND Study Design Eltrombopag extended Dosing (EXTEND) is an open-label safety and efficacy study of long-term treatment of adult patients with chronic ITP who had previously completed a eltrombopag olamine study 1,2 Start 50 mg eltrombopag olamine dosing period Patients enrolled N=301 Screening Dose modulated to platelet count Stage 1: eltrombopag olamine dosing initiation ( 100 x 10 9 /L*) Stage 2 : Minimizing ITP medications ( 50 x 10 9 /L) Stage 3: Optimizing eltrombopag olamine dosing ( 50 x 10 9 /L) Stage 4: Maintenance dosing The bars for each stage in the figure represent the period during which a cohort of patients were recruited to that phase of the study, and not the time over which a patient might take eltrombopag olamine * 50 x 10 9 /L in patients not receiving concomitant ITP medications at baseline Only required for patients receiving concomitant ITP medications at baseline 1. Saleh et al. Blood 2011; 118: Abstract 3296; 2. Saleh et al. Poster presented at the 53rd Annual Meeting of the American Society of Hematology, Dec, 2011

35 EXTEND: Exposure Mean average daily dose 50.2 (range, 1 75) mg/day Overall median duration of exposure 2.4 years (range, 2 days to 8.8 years) 103 patients received rescue therapy 62% of patients were receiving eltrombopag 50 or 75 mg at the end of the study Dose, mg Last recorded dose of eltrombopag, n (%) N= (12.9) >0 to <25 26 (8.6) (14.2) >25 to <50 6 (2.0) (23.2) (39.1) Wong R, et al. Blood 2017

36 EXTEND Study: Long-term Eltrombopag in patients with ITP 276/302 (91.4%) achieved platelet counts /L without rescue treatment 259/302 (85.8%) achieved platelet counts /L without rescue treatment IQR, interquartile range a Platelet count data were collected throughout the study as part of the complete blood count, weekly during the first 4 weeks, and at any dose change (eltrombopag or concomitant ITP medication). If a patient continued on a stable dose during any stage of the study for >4 weeks, platelets were assessed every 4 weeks; b Fewer than 15 patients had platelet counts at each assessment after Week 250. Wong R, et al. Blood 2017

37 EXTEND: Proportion of Patients Able to Permanently Stop or Reduce Concomitant ITP Medications Taken at Baseline Number taking concomitant medication at baseline 101/302 (33%) Permanently stopped one or more concomitant ITP medications 34/101 (34%) Reduced or permanently stopped 1 concomitant ITP medications without requiring rescue therapy 39/101 (39%) Sustained reduction of at least 24 weeks 37/39 (95%) Wong R, et al. Blood 2017

38 EXTEND: Incidence of Bleeding (WHO Bleeding Scale) Wong R, et al. Blood 2017

39 Spleen tyrosine kinase (Syk) inhibition Fosamatinib An oral SYK inhibitor, was developed for the treatment of patients with ITP and other additional autoimmune disorders Newland A, et al. Immunotherapy (2018) 10(1), 9 25

40 Fosamatinib in the treatment of ITP 2 randomized study of fosamatinib versus placebo in ITP Bussell J, et al. Am J Hematology 2018 [Epub ahead of print]

41 Advances in the Management of ITP Concepts about the mechanisms of ITP have shifted from the traditional view of platelet destruction mediated by antibodies, to a much more complex situation where impaired platelet production has emerged as playing a significant role. Immunosuppressive therapy continue to be the mainstay of initial therapy. Patients who do not go into early remission (persistent ITP) should use steroid-sparing agents. Thrombopoietin receptor agonists (TPO-RAs) have been demonstrated to be very effective in a high percentage of even refractory patients with ITP. They are generally well-tolerated with good safety profile.

42 Thank you