MANAGEMENT OF PATIENTS WITH THROMBOCYTOPENIA

1. MANAGEMENT OF PATIENTS WITH THROMBOCYTOPENIA ELSHAMI M. ELAMIN, MD CENTRAL CARE CANCER CENTER

2. ITP DITP HIT TTP ITP during pregnancy

3. INTROCUCTION • Hemostasis encompasses a series of interrelated and simultaneously occurring events involving: • Blood vessels • Platelets • Coagulation system • Defects affecting any of these major participants may lead to a hemostatic defect and a bleeding disorder

4. INTRODUCTION • The number of circulating platelets is tightly regulated by the hormone thrombopoietin (TPO) • TPO is produced by the liver • Free TPO removed from circulation by plts

5. THROMBOCYTOPENIA IMMUNE CAUSES NON-IMMUNE CAUSES

6. 1 IMMUNE THROMBOCYTOPENIA

7. ITP TERMINOLOGY OLD (ABANDONED) NEW Immune: Primary Secondary • Idiopathic • Purpura

8. IMMUNE CAUSES • Primary Immune Thrombocytopenia (ITP) • Secondary Immune Thrombocytopenia

9. Primary Immune Thrombocytopenia(ITP)

10. Primary Immune Thrombocytopenia (ITP) • Isolated thrombocytopenia • Plt count <100,000 (100k) • In children: • ITP is typically self-limited • Follows viral/infectious illness • In adults: • ITP is typically becomes persistent or chronic with no obvious precipitating events

11. Old Classification of ITP • Acute ITP (≤ 6 months) • Chronic ITP (> 6 months)

12. New Classification of ITP Source: Rodeghiero 2009.1

13. PATHOPHYSIOLOGY • Historically: • ITP was thought to be due to increased pltdestruction caused by autoantibodies (anti– GPIIb-IIIa and anti–GPIb-IX) • Now: • It is recognized that ITP is also a result of suboptimal platelet production • Plasma level of endogenous thrombopoietin (eTPO) is suboptimal because of: • Accelerated clearance by accelerated removal of eTPO bound to antibody-coated plts • Binding to megakaryocytes in the BM • Absence of increased synthesis in response to thrombocytopenia

14. CLINICAL PRESENTATION • Presentation: • No symptoms • Minimal bruising • Serious bleeding • Mucocutaneous bleeding is the hallmark of severe primary ITP and manifests as: • Petechiae, purpura, ecchymosis, epistaxis, menorrhagia, oral mucosal bleeding, GI bleeding, or rarely, intracranial hemorrhage • Bleeding is not expected with plt >30,000

15. DIAGNOSIS • Exclude other causes • There is no “gold standard” diagnostic test • CBC • Peripheral blood film • BM • HIV • HCV • H. pylori

16. DIAGNOSIS ASH The International Consensus Report (ICR) Did not find sufficient evidence to recommend or suggest the routine use of anti-plt, antiphospholipid, ANA, and TPO levels in evaluation of ptswith suspected ITP • Does not recommend routine measurement of antiplt, antiphospholipid, or ANA • Considers measurement of TPO of unproven or uncertain benefit BM test only to exclude other causes of thrombocytopenia

17. TREATMENT OF ITP

18. TREATMENT GOAL • To achieve a platelet count that will prevent major bleeding • To attain a sustained increase of the platelet count that is considered hemostatic • It is NOTthe goal to normalize platelet count

19. MANAGEMENT OF CHILDERN WITH PRIMARY ITP • During the first month of diagnosis: • Severe hemorrhage occurs in approximately 1 in 200 • Intracerebral hemorrhage occurs in approximately 1 in 800 • Recovery of the platelet count ultimately occurs in 80% of children. • The remaining 20% have persistent thrombocytopenia • Major bleeding is uncommon.

20. MANAGEMENT OF CHILDERN WITH PRIMARY ITP • Family counseling • Supportive care rather than specific drug therapy • Because spontaneous recovery is expected in most children • Drug therapy (Steroids, IVIG, Anti-D)

21. MANAGEMENT OF CHILDERN WITH PRIMARY ITP • Splenectomy: • Persistent thrombocytopenia/bleeding • CR in ~ 75% of children • Deferred until after 5 yrs of age • Risk for overwhelming sepsis • Vaccines for Strep pneumoniae, Neisseria meningitides, and H influenzaetype b • PCN prophylaxis is recommended until adulthood

22. TREATMENT OF ADULTS WITH PRIMARY ITP • ITP in adults: • Recurs and persists • Asymptomatic ptswith mild-moderate thrombocytopenia require no specific treatment • Who should be treated?

23. WHAT IS THE PLATELET COUNT THRESHOLD? ASH ICR Plat >50,000 rarely need treatment in the absence of: Bleeding due to pltdysfunction or another hemostatic defect Comorbidity for bleeding Trauma Surgery Anticoagulation Lifestyle/profession predisposing the patient to trauma • Treat new cases if Plat < 30,000 • However, no evidence for minimum pltcount threshold

24. EMERGENCY TREATMENT

25. Emergency conditions • Active hemorrhage: • CNS • GIT • GUT • Limb- or sight-threatening • High risk of significant bleeding • Need for surgical procedure

26. EMERGENCY TREATMENT GENERAL INITIAL TREATMENT High-dose IV steroids + IVIg Plt transfusion +/- IVIg • Cessation of drugs reducing plt function • Blood pressure control • Menses inhibition • Minimizing trauma

27. Alternative Emergency Treatment Options ASH ICR Anti-D Vinca alkaloids Antifibrinolytics with first-line therapy Splenectomy • Plt transfusion + continuous IVIg • Splenectomy +/- IVIg and/or corticosteroids • Recombinant factor VIIa • Risk of thrombosis • Antifibrinolytics (aminocaproic acid and tranexamic acid)

28. FIRST-LINE TREATMENT

29. FIRST-LINE ASH IRC Steroids X 4 wk or longer Ptswith bleeding, high risk of bleeding, or contraindications to steroids: IVIg(0.4 g/kg/dX5 or IVIg 1 g/kg/d X1-2 days or Anti-D (50-75 μg/kg single dose) • Prednisone 1 mg/kg/d X3 wk • IVIg+ Steroids when a rapid response required • When Steroids are contrain- dicated: • IVIgor anti-D (WinRho)

30. YOUR STEROIDS’ CHOICES • Prednisone: • Starting at 1 mg/kg daily • Tapering over a period of 4 - 8 weeks) OR • High-dose dexamethasone in cycles: • 40 mg daily for 4 days • Repeated monthly for up to 6 cycles or • every other week for 4 cycles OR • Methylprednisolone: • 1 g IV daily X 2–3

31. A.E. OF THERAPY • Corticosteroids: • Behavioral changes • IVIg: • Headache • Anti-D (WinRho): • Hemolysis • Pts with a positive Coombs test should not receive it

32. !! WHEN FIRST-LINE FAILS !!

33. SECOND-LINE TREATMENT

34. SECOND-LINE ASH ICR TPO: Recommended: After failing at least one line of therapy such as corticosteroids or IVIg • TPO: • Recommended: • After splenectomy • If contraindications to splenectomyand failed at least one other therapy • Considered: • If failed one line of therapy such as corticosteroids or IVIg

35. NOVEL APPROACH TO TREAT CHRONIC ITP

36. Thrombopoietin (TPO) receptor agonists • Romiplostim(Nplate): • SC • Eltrombopag (Promacta): • PO • Bind and activate the TPO receptor  increase plt production • They have no structural similarity to endogenous TPO • They do not stimulate cross-reactive TPO antibodies • They are effective in up to 70% of ptswith ITP before and after splenectomy • Responses appear to be more pronounced before splenectomy • Plt count responses are generally maintained as long as the drug is administered

37. Serious A.E. of TPO • Worsening thrombocytopenia after D/C • Bone marrow reticulinformation/Fibrosis with cytopenias • Thrombosis • Hematologic malignancy risk • Hepatotoxicity, cataracts (Promacta)

38. Nplate (Romiplostim) • SC wkly • Common A.E. is headache • 1 mcg/kg (actual body wt) • Lowest dose to maintain plt> 50,000 • Do not attempt to normalize plt counts • Wkly CBC and smear until counts are stable > 50k, then monthly • D/C Nplate if no clinical benefit after 4 wks of max dose

39. SECOND-LINE ASH ICR Anti-CD20 (Rituxan): Considered in ptswith refractory or relapsed ITP Contraindicated in ptswith active HBV • Anti-CD20 (Rituxan): • Considered for pts at risk of bleeding who have failed one line of therapy, such as corticosteroids, IVIg, or splenectomy

40. SECOND-LINE ASH ICR Immunosuppressivesand corticosteroid- sparing drugs (azathioprine): Elderly ptsand when splenectomy is contra- indicated Single agent or in combination with steroids • Immunosuppressivesand corticosteroid- sparing drugs (azathioprine): • Evidence-based recommendations on appropriate indications or timing of use are not made due to inadequate research

41. Surgical treatment (Splenectomy)

42. Splenectomy is recognized by both the ASH 2011 guideline and the ICR recommendations as the only treatment to provide sustained off-treatment remissions lasting ≥1 year in approximately two-thirds of patients

43. SPLENECTOMY ASH ICR Second-line When? Wait ≥6 months after diagnosis due to potential for spontaneous improvement or late remission • For pts who fail steroids • Laparoscopic = open • When? • No optimal timing

44. VACCINATION • Vaccination preferably 4 wks before or 2 wks after splenectomy • Follow CDC recommendations • Revaccination is based on country-specific recommendations • Splenectomizedpts at risk of infection from: • Streptococcus pneumoniae • Neisseria meningitidis • Haemophilusinfluenzae

45. REFRACTORY IMMUNE THROMBOCYTOPENIA

46. REFRACTORY ITP • Ptsare considered to have refractory ITP if they do not attain hemostatic platelet count either: • After splenectomy OR • After first- and second-line medical treatmentOR • After initially responding to splenectomyand relapsing thereafter AND • Either exhibit severe ITP or have a risk of bleeding that requires therapy based on the clinical judgment

47. TREATMENT OF REFRACTORY ITP

48. TREATMENT RECOMMENDATIONS ASH ICR TPO-receptor agonists Not FDA approved: Anti-CD52 (Campath) Combination chemo HSCT • Recommends: • TPO-receptor agonists • suggests: • Anti-CD20 (Rituxan)

49. SUMMARY • Workup of patients with suspected ITP requires: • Thorough search for nonimmune causes(secondary ITP) • Primary ITP in children often resolves spontaneously or with minimal treatment • Adult-onset primary ITP tends to relapse and often requires ongoing therapy • Splenectomyis associated with a durable response in 2/3 of ptswith primary ITP • Relapses occur 15% of adults. • TPO receptor agonists: • Increase plt production • Effective in 60 - 70% of ptswith primary ITP

50. Secondary Immune Thrombocytopenia