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Updates in the Management of ITP

Updates in the Management of ITP. Dr. K.C Usha Professor & Head - Dept of Transfusion Medicine Sree Mookambika Institute of Medical Sciences, Kulasekharam , Kanyakumari Dist : Tamil Nadu. ITP. “Idiopathic Thrombocytopenic Purpura” “Immune Thrombocytopenic Purpura”. Introduction.

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Updates in the Management of ITP

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  1. Updates in the Management of ITP Dr. K.C Usha Professor & Head - Dept of Transfusion Medicine SreeMookambika Institute of Medical Sciences, Kulasekharam, Kanyakumari Dist: Tamil Nadu

  2. ITP • “Idiopathic Thrombocytopenic Purpura” • “Immune Thrombocytopenic Purpura”

  3. Introduction • Inherited autoimmune disorder • Abs against pl:Agsllb / llla • ↑Destruction of platelets • Macrophages & cytotoxic T cells involved • ↓ Levels of thrombopoietin in plasma • ↓ Production of platelets • Impaired megakaryocyte function

  4. ITP ( Contd….) • International ITP Working group Removed the terminology “A/c ITP” Since diagnosis made retrospectively Proposed term “Newly diagnosed ITP” • ITP classified into 3 groups • Newly diagnosed : First 3 months • Persistent ITP : Symptoms last b/w 3-12 months • Chronic ITP : Symptoms persist > 12 months • According to international guidelines : • Thrombocytopenia : Pl: count < 100 x 109/ L

  5. Another Classification

  6. Primary ITP • Diagnosed by exclusion • Constitutes 80 % of ITP

  7. Secondary ITP • Due to various underlying diseases

  8. Treatment of ITP • Guidelines published by ASH (2011) • American Society of Hematology • Valid reference for conventional Rx • Rx modalities divided into : • I line therapy • II line therapy • III line therapy

  9. Treatment Modalities • First Line Therapy • Corticosteroids • IV Ig • Anti D Immunoglobulin • Second Line Therapy • Splenectomy • Rituximab • Third Line Therapy • TPO RAS / TRAS • (Thrombopoietin Receptor Agonists) • Commonly used TRAS • Eltrombopag • Romiplostim

  10. ITP in Children • I & II line Rx as in adults • Rituximab suggested as II line • Splenectomy contraindicated • Splenectomy not preferred • Significant bleeding • Need for better quality of life • III line : Initially, TPO RAS not recommended • After successful trials • Now Eltrombopag recommended

  11. Corticosteroids • First choice for initial Rx • Ease of administration • Lower cost • ↓ Ab production • Prevent platelet destruction • Available corticosteroids • Prednisone • Prednisolone • Methyl prednisolone • Dexamethasone

  12. Corticosteroids (Contd) • Oral administration • Dose : • 0.5-2 mg / kg / day for 2 - 4 wks • Gradual tapering • Platelet count to be monitored • Avoid long term use

  13. Corticosteroids (Contd) Adverse effects : • Osteoporosis • Diabetes • Hypertension • Cataract • Weight gain • Avascular necrosis of bones • Growth retardation in children • Personality changes • Opportunistic infections

  14. IV Ig

  15. IV Ig (Contd)

  16. IV Ig (Contd) • Products not interchangeable • Due to numerous differences in • Osmolality • Immunoglobulin A content • Different stabilizers (Sucrose/glucose/maltose)

  17. IV Ig (Contd) Adverse effects • Depends on rate of infusion • Specific products • Headache • Chills • Arthralgia • Back pain • Thrombotic events • Renal impairment

  18. Anti D Immunoglobulin • Gamma globulin against Rh (D) ag • Approved by FDA for Rx of ITP • Oposonize Rh D + RBCs • Opsonised RBC & opsonised platelets • Compete for sequestration in spleen • Blocks macrophage system • ↓ Platelet destruction • Neutralise anti platelet Abs • Patients monitored at least for 8 hours

  19. Anti D Immunoglobulin (Contd) Dose : • 50-75 mg / kg IV • 75 mg / kg preferred Adverse effects : • Headache, fever, chills • Nausea, vomiting • Fatal intravascular hemolysis • Hemoglobinuria ( rare) • Multi organ dysfunction

  20. Splenectomy • Historically gold standard Rx for C/c ITP • Newer Rx regimens ↓ splenectomy rates • Higher response rates in younger pts • Limiting factor : bleeding associated with surgery • Mortality rate : 0.2 % with laparoscopic procedure 1 % with open laparotomy • ↑ Chance for infections • To be vaccinated against various infections

  21. Rituximab • Anti CD 20 • Cytolytic monoclonal Ab • Off-label drug for ITP • Inhibits B cells from producing Abs • Reserved for patients with • High risk of bleeding • Failed treatment with corticosteroids/IVIg/Anti D • Administered early : relapse free survival • Optimal timing of administration • Yet to be determined

  22. Rituximab (Contd) • Adequate hydration required • Monitor serum electrolytes & renal function • Dose : • 375 mg / m2 once weekly • Repeated for 4 consecutive weeks • Infused over a period of 4 hours • Initial response in 7- 56 days • Average 38 days

  23. Rituximab(Contd) • Adverse effects : • Pruritis, urticaria • Fever, chills • Nausea, vomiting • Serum sickness • Anti histamines / anti pyretics administered 30 mts prior to infusion • Patients treated for > 12 months • Infection • Malignancies • Pulmonary embolism • Pneumonitis • CNS hemorrhage

  24. TPO-RAS / TRAS • TPO Receptor Agonists • Approved by FDA • Rapidly responding immunosuppressant • Acts on both platelets & megakaryocytes • ↑ Platelet production • Approx 2 wks for desirable effects • Uncertainty about Rx duration • Effective in randomized trials • Enable durable remissions

  25. TPO-RAS/TRAS (Contd) • Rx option for Refractory ITP • Cross placenta • Safety in pregnancy not demonstrated • Commonly used TPO RAS • Eltrombopag • Romiplostim

  26. Eltrombopag • Double blind randomised control trials • Assessed efficacy & safety • Route of administration : Oral • Can be used in children • Duration of remission based on • Antibody levels • Megakaryocyte pool in bone marrow • Pl: count to be measured wkly • Adverse effects • Elevated hepatic enzymes • Thromboembolic events

  27. Romiplostim • Used effectively in C/c ITP • Irrespective of splenectomy done or not • ↑ Platelet count & ↓bleeding • Single IV / Subcutaneous dose • Dose : 10 mcg / kg • Initial response within 5-8 days • Return to baseline by day 28 • CBC to be monitored daily • Till pl: count reaches 50 x 109 / L

  28. Romiplostim (Contd) Adverse effects • Headache, fatigue • Epistaxis, arthralgia • Bone marrow reticulin formation • Thromboembolism

  29. Other Immunosuppressive Agents • Mycophenolate Mofetil ( MMF) • Rapamycin ( Sirolumus ) • Azathioprine • Cyclosporine • MMF prevents proliferation of lymphocytes • ↓ Antibody production

  30. Combination therapy • When monotherapy fails • More effective in C / c patients • A) Triple therapy • High dose Dexamethasone • Low dose Rituximab • Cyclosporine • B) Combination of : • TPO RAS • Another immunosuppressant

  31. Agents Under Trial • Totrombopag Choline • Thrombopoietin receptor agonist • Phase II trial • LGD 4665 • New molecular entity • Small molecule • Thrombopoietin receptor agonist • Oral administration

  32. Agents Under Trial(Contd) • MDX -33 • Humanized monoclonal Ab • Appears to be promising • ARK – 501 • Under trial

  33. Molecule Targeting Therapies • Anti CD 20 (Rituximab , Veltuzumab) • Anti CD 40 L (IDEC 131, CD 154) • Anti CD 52 (Alemtuzumab , Compath 1 H) • Anti CD 80 / 86 (Abatacept , CTLA4 – IG) • Anti IL 2 receptor (Daclizumab)

  34. PlateletTransfusion • When immediate hemostasis required • Effects transient • Transfused platelets get opsonised • Removed from circulation

  35. Haematopoietic Stem Cell Transplantation • Remission seen in few cases • Newly formed pl: get opsonised • Fatal toxicities • GVHD • Septicemia • Reserved for severe refractory ITP with bleeding

  36. Future Directions • Targeting Neonatal Fc receptor (FcR) • ↓ Half life of offending Ab • ↑ Clearance of Ab • Interference with TNF signalling • TNF neutralising therapies • Using Etanarcept & Infliximab • Other ligands in TNF family : • BAFF • APRIL

  37. Future Directions (Contd) BAFF • B cell activating factor in TNF family • Monoclonal Ab used to block BAFF • ↓ Production of offending Ab • ↓ Platelet destruction APRIL • Proliferation inducing ligand • Essential for B cell survival • During maturation in spleen • Produced by monocytes / macrophages • Blocking APRIL : ↓ Ab production • ↓ Platelet destruction

  38. Conclusion • No confirmatory tests for ITP • Novel therapies ↓ rate of splenectomy • Rx regimes to be individualised • Corticosteriod: drug of choice for initial Rx • Rituximab : Off - label Rx

  39. Conclusion (Contd) • Before starting Rx consider • Type of ITP • Duration of disease • Cost involved • Any additional risk factors • Maintain pl: count at levels which ↓ risk of bleeding

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