Diagnosis and Management of Immune Thrombocytopenias. Thomas L. Ortel, M.D., Ph.D. Duke University Medical Center 2 November 2016

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1 Diagnosis and Management of Immune Thrombocytopenias Thomas L. Ortel, M.D., Ph.D. Duke University Medical Center 2 November 2016

2 Disclosures Research support: NIH, CDC, Eisai, Pfizer, Daiichi Sankyo, GlaxoSmithKline, Instrumentation Laboratory, Stago Consultant positions: Boehringer Ingelheim, Bristol- Myers/Squibb, Instrumentation Laboratory, CSL Behring, Daiichi Sankyo Off-label medication use: treatment strategies for refractory ITP

3 Objectives Review the diagnostic approach to a patient presenting with isolated thrombocytopenia Understand the connections between the pathophysiology of ITP and the different therapies Review management strategies of patients with primary ITP

4 Patient Presentation 22 year old woman with no prior medical history presents with new-onset spontaneous bruising and red dots over her lower extremities. Physical examination reveals ecchymoses and petechiae. Her spleen is not enlarged. Laboratory data: Hemoglobin 13 g/dl Hematocrit 38% White count 6,000/µL Platelet count 4 x 10 9 /L

5 Differential Diagnosis Pseudothrombocytopenia Immune thrombocytopenia Drug-induced thrombocytopenia Infections (HCV, HIV) Hypersplenism Alcohol Nutrient deficiencies Autoimmune disorders (SLE, APS) Pregnancy

6 Diagnostic evaluation of the patient with presumed ITP Patient history has the patient had any symptoms? Family history evaluate for inherited thrombocytopenia Physical examination assess spleen, lymph nodes, etc Complete blood count confirm isolated low platelet count Peripheral blood film confirm low platelet count is real HIV, HCV evaluate for secondary immune TP If indicated: Bone marrow, if other lines abnormal If indicated: PT/aPTT, liver function studies, ANA, antiphospholipid antibodies, antithyroid antibodies, H. pylori, etc.

7 Immune Thrombocytopenia 80% of patients with ITP have a primary form of the disorder; 20% have a secondary form. Cines DB, et al., Blood, 2009; 113:

8 Primary ITP An autoimmune disorder characterized by: Isolated thrombocytopenia (platelet count < 100 X 10 9 /L) Absence of other causes or disorders associated with thrombocytopenia The diagnosis remains one of exclusion; no robust clinical or laboratory parameters exist that are able to establish an accurate diagnosis Rodeghiero F, et al. Blood 2008;e-pub 12 Nov 2008

9 ITP: Pathophysiology to Treatment Cines DB, Blanchette VS. N Engl J Med, 2002; 346:

10 Treatment of ITP: Primum non nocere Treatment is usually not necessary if the platelet count is 30 x 10 9 /L (Grade 2C recommendation) Neunert C, et al. Blood, 2011; 117:

11 Treatment of ITP: First-line therapy Corticosteroids Intravenous immunoglobulin if a more rapid increase in the platelet count is needed (alternatively, anti-d) Neunert C, et al. Blood, 2011; 117:

12 Treatment of ITP: Corticosteroids Prospective, multicenter, randomized, controlled, openlabel trial comparing high-dose dexamethasone and prednisone Inclusion criteria: Age 18 years with newly-diagnosed primary ITP (bone marrow required for patients >60 years of age) and initial platelet count <30 x 10 9 /L or the presence of bleeding symptoms at presentation Randomized to: dexamethasone 40 mg/d x 4 days with option for a repeat round, vs. prednisone 1 mg/kg daily for four weeks followed by a gradual taper Wei Y, et al. Blood, 2016; 127:

13 Treatment of ITP: Corticosteroids Wei Y, et al. Blood, 2016; 127:

14 Treatment of ITP: Corticosteroids Duration of response Wei Y, et al. Blood, 2016; 127:

15 Treatment of ITP: Corticosteroids Adverse events during treatment Wei Y, et al. Blood, 2016; 127:

16 Treatment of ITP: Second-line therapy Neunert, 2011 Provan, 2010 Splenectomy (Grade 1B) Splenectomy TPO mimetic (Grade 1B) TPO receptor agonists Rituximab (Grade 2C)* Rituximab Azathioprine Cyclosporin A Cyclophosphamide Danazol Dapsone Mycophenolate mofetil Vinca alkaloids * Patients at risk of bleeding who have failed corticosteroids, IVIG, or splenectomy

17 All case series Second-line Treatment of ITP: splenectomy Adults Adults + Children # case series Patients with CR 1731/2623 (66%) 1775/2463 (72%) Case series with 5 yr follow-up # case series 14 7 Patients with CR 456/707 (64%) 323/452 (71%) Kojouri K, et al. Blood, 2004; 104:

18 Splenectomy cons Removal of a perfectly good organ Unpredictability of response Mortality related to the procedure Risk of infection in the asplenic patient Vascular complications, particularly thromboembolic Ghanima W, et al. Blood, 2012; 120: 960-9

19 Treatment of ITP: Second-line therapy Neunert, 2011 Provan, 2010 Splenectomy (Grade 1B) Splenectomy TPO mimetic (Grade 1B) TPO receptor agonists Rituximab (Grade 2C)* Rituximab Azathioprine Cyclosporin A Cyclophosphamide Danazol Dapsone Mycophenolate mofetil Vinca alkaloids * Patients at risk of bleeding who have failed corticosteroids, IVIG, or splenectomy

20 Second-line treatment of ITP: Rituximab Prospective, multicenter, randomized, double-masked, placebo-controlled trial comparing rituximab vs. placebo Inclusion criteria: Corticosteroid-unresponsive adults (age 18 years) with primary ITP and a platelet count <30 x 10 9 /L Randomized to: rituximab 375 mg/m 2 weekly x 4 weeks or placebo. Concurrent treatment with steroids only was allowed during the study Ghanima W, et al. Lancet, 2015; 385:

21 Treatment of ITP: Rituximab Enrolled: 118 patients Overall response Complete response Ghanima W, et al. Lancet, 2015; 385:

22 Treatment of ITP: Rituximab Time to treatment failure Ghanima W, et al. Lancet, 2015; 385:

23 Treatment of ITP: Rituximab Conclusion: Despite no reduction in the rate of longterm treatment failure with rituximab, a small benefit cannot be ruled out, as suggested by an apparently longer duration of response and numerically higher response rates with rituximab Ghanima W, et al. Lancet, 2015; 385:

24 First-line treatment of ITP: Rituximab Prospective, multicenter, randomized, open-label trial comparing dexamethasone alone or in combination with rituximab Inclusion criteria: Age 18 years with newly-diagnosed primary ITP and initial platelet count 25 x 10 9 /L, or 50 x 10 9 /L and concomitant bleeding symptoms Randomized to: dexamethasone 40 mg/d x 4 days (repeat up to 6 cycles) vs. dexamethasone 40 mg/d x 4 days + rituximab 375 mg/m 2 weekly x 4 weeks Gudbrandsdottir S, et al. Blood, 2013; 121:

25 Treatment of ITP: Rituximab Gudbrandsdottir S, et al. Blood, 2013; 121:

26 Treatment of ITP: Second-line therapy Neunert, 2011 Provan, 2010 Splenectomy (Grade 1B) Splenectomy TPO mimetic (Grade 1B) TPO receptor agonists Rituximab (Grade 2C)* Rituximab Azathioprine Cyclosporin A Cyclophosphamide Danazol Dapsone Mycophenolate mofetil Vinca alkaloids * Patients at risk of bleeding who have failed corticosteroids, IVIG, or splenectomy

27 Decreased Platelet Production in ITP 38 patients with mild to moderately severe chronic ITP. Turnover Untreated Prednisone Splenectomy <31 X 10 9 /L/day (decreased) X 10 9 /L/day (normal) >51 X 10 9 /L/day (increased) 7 (41%) 2 (13%) 4 (33%) 9 (53%) 6 (40%) 4 (33%) 1 (6%) 7 (47%) 4 (33%) Ballem PJ et al. J Clin Invest 1987;80:33-40

28 c-mpl (TPO receptor) TPO receptor: c-mpl 2 cytokine receptor homology modules (CRMs) Binding leads to activation of JAK2 and STAT5 phosphorylation cell proliferation; differentiation & anti-apoptotic signaling Major effect: promotes viability and growth of Meg-CFUs Kuter, D. J. Blood 2007;109:

29 Thrombopoietin First cloned/purified in aa (95kDa) glycoprotein Receptor binding domain (1-153 aa) homology to EPO Carbohydrate rich domain ( ) important for protein stability Receptor binding Kuter, D. J. Blood 2007;109:

30 Thrombocytopenia caused by the development of antibodies to thrombopoietin PEG-rHuMGDF (first 163 aa of TPO coupled to PEG) associated with the development of persistent thrombocytopenia (13 of 325 normal volunteers) Li J, et al, Blood 2001;98:3241-8

31 Thrombopoietic Agents Recombinant peptide libraries screened for binding to the TPO receptor. High-binding peptides sequenced to confirm no homology to TPO. Dimerized peptide exhibited comparable activity to TPO. Romiplostim Cwirla SE, et al. Science 1997;276:1696-9

32 Thrombopoietic Agents High-throughput screening of non-peptide libraries for induction of a luciferase reporter gene in a TPOresponsive cell line. 4-diazo-3-hydroxy-1- naphthalene sulfonic acids exhibited TPO activity. Core structure modified to enhance function. Eltrombopag Duffy KJ et al. J Med Chem 2001;44:

33 Romiplostim or Standard Care for ITP 234 patients randomly assigned to standard of care (n=77) or weekly SQ injections of romiplostim (n=157) Kuter DJ et al. N Engl J Med 2010;363:

34 Is Romiplostim Always Forever? Retrospective review of patients with chronic ITP at MGH and Princess Alexandra Hospital in Brisbane, Australia Of 423 patients identified, 116 had received a TPO receptor agonist, and 43 (10%) had received romiplostim for >6 months Median time between ITP diagnosis and initiation of romiplostim: 2.6 years All had received multiple treatments, and 44% had undergone splenectomy Marshall AL, et al. Haematologica, 2016;e-pub ahead of print.

35 Is Romiplostim Always Forever? 12 of 43 patients discontinued romiplostim after >6 months of therapy Characteristic Number Underwent splenectomy while on romiplostim 2/12 Median (range) duration of romiplostim therapy Follow-up after romiplostim discontinuation Most recent platelet count since romiplostim discontinuation 1.8 ( ) years 2.8 ( ) years 205 (56-366) X 10 9 /L Patients with prior splenectomy 6/12 Marshall AL, et al. Haematologica, 2016;e-pub ahead of print.

36 Summary: Second-line options in ITP Ghanima W, et al. Blood, 2012; 120: 960-9

37 Treatment of ITP: Additional therapies Neunert, 2011 Provan, 2010 Splenectomy (Grade 1B) Splenectomy TPO mimetic (Grade 1B) TPO receptor agonists Rituximab (Grade 2C)* Rituximab Azathioprine Cyclosporin A Cyclophosphamide Danazol Dapsone Mycophenolate mofetil Vinca alkaloids * Patients at risk of bleeding who have failed corticosteroids, IVIG, or splenectomy

38 Treatment of ITP: MMF Retrospective review of 46 patients with severe ITP 29 had primary ITP, 17 had secondary ITP Median duration of follow-up: 15 months (2-90 months) Complete response: 15 patients (33%) Overall response: 24 patients (52%) Taylor A, et al. Br J Haematol, 2015; 171:

39 Special Situations: Surgery and ITP Surgery Recommended Platelet Count Dental prophylaxis (scaling, deep cleaning) x 10 9 /L Simple dental extraction 30 x 10 9 /L Complex dental extraction 50 x 10 9 /L Regional dental block 30 x 10 9 /L Minor surgery 50 x 10 9 /L Major surgery 80 x 10 9 /L Major neurosurgery 100 x 10 9 /L Cuker A, Cines DB. Hematology, 2010; 2010:

40 Special Situations: Pregnancy and ITP Treatment is indicated in the following situations When the patient is symptomatic (bleeding) When the platelet count is less than x 10 9 /L To achieve an increase in the platelet count to a level considered safe for a procedure (eg, epidural anesthesia, >75 x 10 9 /L) First-line treatments include corticosteroids and IVIG Second-line treatments that may be used in selected individuals include azathioprine, cyclosporine A Delivery needs to consider the risk of severe neonatal thrombocytopenia

41 Summary Primary ITP is a diagnosis of exclusion First-line therapy includes corticosteroids, IVIG Second-line therapy includes splenectomy, rituximab, and/or thrombopoietic mimetics Multiple alternative strategies have been tried in patients with ITP that fails first and second-line strategies Special situations require achieving target platelet counts for procedures and pregnancy