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In the name of God

In the name of God. Chronic ITP Presented by : F.Malek Under supervision of Dr Shamsian. A 10 year old girl known case of chronic ITP since 6 years ago which was admitted in our ward due to Epistaxis and petechia and purpura At time of admission CBC was WBC 16000 HB 12.6 Plt 9000.

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In the name of God

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  1. In the name of God • Chronic ITP • Presented by :F.Malek • Under supervision of Dr Shamsian

  2. A 10 year old girl known case of chronic ITP since 6 years ago which was admitted in our ward due to Epistaxis and petechia and purpura • At time of admission CBC was • WBC 16000 • HB 12.6 • Plt 9000

  3. She has received Dexamethasone • And at the time of discharge • Which was 2 days later The CBC was • WBC 27000 • HB 11.5 • Plt 85000 • Coombs - Reticulocyte 1.1

  4. Abdominopelvicultrasonography Revealed spleen with upper limit of normal size

  5. Patient had received different type of Medications since 6 years ago such as IVIG ( she had showed sensitivity reactions after adminstration) corticosteroids, danazolCyclosporin & Rituximab Parents weren’t cooperative They attend at follow up sessions weakly

  6. At present time patient is candidate for splenectomy hence was referedfor vaccination

  7. Chronic ITP

  8. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Texas.Hematology2012.thrombopoietin, and other new therapeutics . • ITP is defined as a platelet count   not explained by any other cause. • Newly diagnosed ITP refers to the time from onset of thrombocytopenia to 3 months later; • persistent ITP is from 3-12 months after diagnosis. • Chronic ITP is defined as a platelet count that has been   100  × 10 9 /L for longer than 12 months. • Refractory ITP now refers to severe ITP that persists after splenectomy.

  9. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology. • Before splenectomy, patients with ITP are divided into responders and nonresponders to the different treatment modalities. • Approximately 1/3 of children will have persistent/chronic ITP with ongoing thrombocytopenia more than 6 months after diagnosis, • 5%-10% will develop severe, chronic, and/or refractory disease.

  10. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • The initial step is to ensure that the diagnosis is correct. • Second, treating physicians need to determine whether the severity of symptoms warrants aggressive therapy. many children with chronic disease will not have major bleeding symptoms and will likely recover within an additional 12-24 months. • Therefore, continued observation may be the only therapy indicated. • The dilemma is to determine the best second-line therapy for the symptomatic children, with the goals being increase of platelet count, resolution of bleeding, and increased quality of life

  11. Chronic ITP • The primary goal of treatment is prevent of bleeding not CURE • So observation alone is an appropriate approach for many patients especially those with minimally symptoms.

  12. Chronic ITP • Chronic ITP includes all patients who have platelet counts less than 150 × 10 9/L persisting more than 6 months after diagnosis. • In 80% of cases, acute ITP in children spontaneously resolves irrespective of any treatment. • Spontanaousremmision: months to years • %5 recurrent ITP( intermittent episodes). • Of the 20% of patients who are truly chronic, 80% enter remission following splenectomy, but a few will relapse over a period of years.

  13. 2011 Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP) • History:Isolated bleeding symptoms consistent with thrombocytopenia without constitutional symptoms (e.g.significantweightloss,bonepain,nightsweats). • Physicalexamination:Bleeding symptoms in the absence of hepatosplenomegaly,lymphadenopathy,or stigmata of congenital conditions. • Complete bloodcount:Isolated thrombocytopenia(platelet count<100x109 /L). • Anemia only if due to significant bleeding—otherwise normal red cell indices,whitebloodcell count and differential. • Peripheral bloodsmear:Identifie platelet should be normal to largein size.

  14. 2011 Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP) Bone marrow examination: • Is felt to be unnecessary in children with typical ITP prior to initiation of treatment with corticosteroids,prior to splenectomy,or in patients who fail intravenous immunoglobulin(IVIg) therapy.

  15. Chronic ITP/Differential diagnosis • Immunedeficiency: Hypo gammaglubolinemia & Common variable immune deficiency • Lymphoprolifrativedisorders:ALPS& Hodghkine disease • Colagen vascular disease:SLE • Infection: HIV

  16. Evaluation-Chronic ITP • BMA: if not previously done • Ig level • Collagen Vacscular testes • Coombs test • TFT • AntiphospholipidAb test • HIV test • Evaluation of parents CBC & smear for familial types should be considerd

  17. Secondary ITP (H. pylori- associated) • Routine testing for H.pyloriisnot recommended in asymptomatic children with unresolved ITP.

  18. 2011 Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP) • The goal of all treatment strategies for ITP is to achieve a platelet count that is associated with adequate hemostasis, rather than a normal platelet count. • The decision to treat should involve a discussion with the patient and consideration of the severity of bleeding, anticipated surgical procedures, medication side effects, and health-related quality of life.

  19. 2011 Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP) • Special Considerations for Adults and Children: Adults: • Consider treatment for patients with platelet <30x10/L • Longer courses of corticosteroids are preferred over shorter Courses of corticosteroids or IVIg. • IVIg may be used in conjunction with corticosteroids if a More rapid increase in platelet count is required. Either IVIg(1g/kg for one dose,repeated as necessary) • Anti-D(inappropriate patients)may be used as a first-line treatment if corticosteroids are contraindicated.

  20. 2011 Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP) • Children: • A single dose of IVIg(0.8-1.0g/kg) or a shortcourse of corticosteroids should be used as first-line treatment. • IVIg should be used instead of corticosteroids if a more rapid increase in platelet count is required. • There is no evidence to support using corticosteroids for longer courses compared to very brief courses. • Anti-D may be considered for first-line therapy in Rh+ non- splenectomized children with recognition of the risks outlined above.

  21. Assessment of Disease Status:Subsequent Management of ITP • What bleeding is the patient experiencing? Determinethetiming,location,and severity of bleeding symptoms. • Does this patient have a change in history or physical examination that requires evaluation for another diagnosis that could becausing thrombocytopenia? • Does this patient have any contraindications to splenectomy? • How is the diagnosis of ITP affecting the patient’sability to , work,go to school,orparticipatein activities?

  22. Assessment of Disease Status:Subsequent Management of ITP • Is the patient experiencing side effects from chronic • Medication use? • How is the patient coping psychologically with having a low platelet count? • Does the patient respond intermittently to his or her Current drug therapy?

  23. 2011 Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP) In children:, • splenectomy or other interventions with potentially serious complications should be delayed for at least 12 months, unless warranted by severe disease unresponsive to other measures or due to quality of life considerations.

  24. 2011 Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP) • If previous treatment with corticosteroids,IVIg,or anti-D has been successful,these options may be used as needed to prevent bleeding. • If previous treatment with corticosteroids,IVIg,or anti-D has been unsuccessful,subsequent treatment may include splenectomy,rituximab,thrombopoietin receptor agonists, or more potent immunosuppression.

  25. Special Considerations for Children • Splenectomy • Recommended for children with significant or persistent bleeding and lack of response or intolerance of other therapies such as corticosteroids, IVIg, and anti-D, and/or who have a need for improved quality of life.

  26. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • Splenectomy • Nearly 85% of patients undergoing splenectomy will have an immediate platelet response and close to 70% will maintain them at 5 years. • Splenectomy is successful because it removes the primary site of platelet destruction and a site of antiplateletAb production • Laparoscopic splenectomy is considered safe. However, bleeding is possible, particularly if platelet counts are less than 20  × 10 at the time of surgery

  27. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • Splenectomy • If relapse occurs, it is generally within in the first 2 years after splenectomy. • At this point, the patient should have evaluation for and removal of accessory spleen. • If there is no spleen to remove, then alternative therapies such as rituximab or TPO receptor agonists should be considered, because they have been shown to be equally efficacious in splenectomized and nonsplenectomized patients.

  28. Special Considerations for Children • Rituximab • May be considered for children with ITP who have significant ongoing bleeding and/or have a need for improved quality of life despite conventional treatment. • Also may be considered as an alternative to splenectomy in children with chronic ITP or as therapy in those who have failed splenectomy.

  29. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • Rituximab • Mechanism of action,Rituximab depletes B cells by binding to the CD20 antigen surface markers. By removing the autoreactive B-cell clones, autoimmunity can be eradicated. • In addition, rituximab has been shown to increase numbers of T-regulatory cells and prevent the activity of Th1-autoreactive cells specifically against GPIIb/IIIa. • Although it is not FDA approved for the treatment of ITP, more than 5 years of experience in the use of rituximab as a second-line option and numerous additional reports of its safety and efficacy in malignant and rheumatologic diseases is reported.

  30. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • Rituximab • In children, nearly 60% of the initial responders maintained platelet counts >  50  × 10 9 /L for longer than 1 year & had a greater than 80% chance of maintaining the response at 2 years. • An estimated 26% of children will have a 5-year durable response. • O ne theory for the lack of sustained response to rituximab is the persistence of autoreactive B cells in the germinal centers and the BM. • In addition, the majority of plasma cells are preserved in patients receiving anti-CD20 Ab therapy.

  31. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • Rituximab • The median time to response was 3 weeks with a median duration of response of 12.8 months. • Although the most frequently administered dose remains 375 mg/m 2 for 4 consecutive weeks, there are small series of children who had similar response rates with a single dose of 375 mg/m 2 or after lower doses regimens of 100 mg/dose for 4 weeks. • previous response to corticosteroids and history of secondary ITP predicted better response

  32. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • Due to the risk of hypogammaglobulinemia, it is recommended to check baseline Igs before administration of rituximab and then yearly. If levels are abnormal, supplemental IVIg is indicated. • Neutropenia, progressive multifocal leukoencephalopathy, hematologic malignancies, and acute respiratory distress syndrome have also been described with rituximab use. • Most reports of toxicity are not in ITP patients, but in older adults and in young children with autoimmune hemolytic anemia, combined variable immunodeficiency, and other disorders requiring additional immunosuppressive agents

  33. Special Considerations for Children • High-Dose Dexamethasone • May be considered for children or adolescents with ITP who have significant ongoing bleeding and/or have a need for improved quality of life despite conventional treatment. Also may be considered as an alternative to splenectomy in children with chronic ITP or in those who have failed splenectomy. • Immunosuppression • Multiple agents have been reported; however data for any one specific agent remain insufficient for specific recommendations.

  34. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • Other agents • There are multiple studies of other immunosuppressive agents used in chronic refractory ITP in both children and adults. Although they are not new, these agents include azathioprine, cyclophosphamide, danazol, dapsone, cyclosporine, sirolimus, and mycophenolatemofetil. These have been used as single agents or in combination. However, the published evidence for their efficacy, particularly in children, is controversial and limited and their use should be reserved for patients refractory to all other therapies, including splenectomy

  35. Special Considerations for Children • Thrombopoietin Receptor Agonists • Studies are ongoing, but there are no published data to guide the use of these agents in children.

  36. 2 Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • Recombinant TPO and TPO receptor agonists • Endogenous TPO regulates platelet production by increasing the number, ploidy, and maturation of BM megakaryocytes • TPO is made in the liver • TPO receptor activation on megakaryocyte precursors leads to increased number and maturation of cells and prevents apoptosis, thereby increasing platelet production. • This antiapoptotic effect of TPO likely plays an important role in ITP, in which BM megakaryocytes and precursors are increased in number but undergo apoptosis mediated by antiplateletIgG.

  37. Janna M. Childhood immune thrombocytopenia: role of rituximab, recombinant .Dalas. Texas.Hematology 2012.thrombopoietin, and other new therapeuticsAmerican Society of Hematology • In 1994, cloned and purified TPO • 1995, 2 first generation recombinant human TPO agents entered clinical trials. • Both products had half-lives of 40 hours and increased platelet counts in humans • Romiplostim : • FDA approved since 2008, and the majority of patients have had a very good response with an initial dose of 1  g/kg given subcutaneously each week

  38. MansoorN.Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia (ITP): results of the long-term, Blood. November 20, 2012 • Eeltrombopag: • is a small, nonpeptide TPO mimetic that has no homology to endogenous TPO so it is not immunogenic. • It binds to the transmembrane region of the TPO receptor rather than the TPO-binding site. • Therefore eltrombopag does not compete with endogenous TPO and any effect it has is additive., with the half-life being 21-30 hours. • It is orally administered with the starting dose of 50 mg daily. • Polyvalent cations such as calcium, aluminum, magnesium, and zinc also reduce the absorption of eltrombopag, so this drug cannot be given within 4 hours of any foods or medications containing these minerals.

  39. MansoorN.Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia (ITP): results of the long-term, Blood. November 20, 2012 • Thromboembolic events is recommended that the target platelet range be limited to 50-100  × 109 /L to minimize risk. • Myelofibrosis • Liver toxicity, • Cataract • The main concern for the practical use of TPO receptor agonists is the indefinite duration of treatment required and the need to see patients frequently to titrate the dose. Relapse rates are high in patients who have interruption of therapy

  40. MansoorN.Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia (ITP): results of the long-term, Blood. November 20, 2012 • Patients with chronic ITP may have bleeding resulting from low platelet counts. • Eltrombopag increases and maintains hemostatic platelet counts; however, to date, outcome has been reported only for treatment • ≤ 6 months. • This interim analysis of the ongoing open-label EXTEND study • evaluates safety and efficacy of eltrombopag in 299 patients treated up to 3 years. • Splenectomized and non-splenectomized patients achieved platelets • ≥ 50,000/µL at least once (80% and 88%, respectively). Platelets ≥ 50,000/µL and 2x baseline were maintained for a median of 73 of 104 and 109 of 156 cumulative study weeks.

  41. MansoorN.Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia (ITP): results of the long-term, Blood. November 20, 2012 • Bleeding symptoms (WHO Grades 1–4) decreased from • 56% of patients at baseline to 20% at 2 years and 11% at 3 years. • One hundred (33%) patients were receiving concomitant treatments at study entry, 69 of whom attempted to reduce them; 65% (45/69) had a sustained reduction or permanently stopped ≥ 1 concomitant treatment. • Thirty-eight patients (13%) experienced ≥ 1 adverse events leading to study withdrawal, including patients meeting protocol-defined withdrawal criteria (11 [4%] thromboembolic events, 5 [2%] exceeding liver enzyme thresholds). • No new or increased incidence of safety issues was identified. • Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts in the desired range

  42. .Pediatric Blood & Cancer Rachael F. Grace MD1,2,3Volume 58, Issue 2, pages 221–225, February 2012 • Background • Treatment choice in pediatric immune thrombocytopenia (ITP) is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies. • Methods • The objective of this study was to evaluate univariate and multivariable predictors of platelet count response to rituximab. • 565 patients with chronic ITP enrolled and met criteria for this study in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and October 2010. • Treatment response was defined as a post-treatment platelet count ≥50,000/µl within 16 weeks of rituximab and 14 days of steroids. Treatment response data were captured both retrospectively at enrollment and then prospectively in children or adults.

  43. .Pediatric Blood & Cancer Rachael F. Grace MD1,2,3Volume 58, Issue 2, pages 221–225, February 2012 • Results • Eighty (14.2%) patients were treated with rituximab with an overall response rate of 63.8% (51/80). • Univariate correlates of response to rituximab included the presence of secondary ITP and a positive response to steroids. • In multivariable analysis, response to steroids remained a strong correlate of response to rituximab, OR 6.8 (95% CI 2.0–23.0, P = 0.002). • Secondary ITP also remained a strong predictor of response to rituximab, OR 5.6 (95% CI 1.1–28.6, P = 0.04). Although 87.5% of patients who responded to steroids responded to rituximab, 48% with a negative response to steroids did respond to rituximab. • Conclusion • Response to steroids and presence of secondary ITP were strong correlates of response to rituximab, a finding not previously reported in children or adults.

  44. Volume 47, Issue S5, pages 714–716, 15 October 2006.IncPediatric Blood & Cancer • About 20% of the children diagnosed with acute idiopathic thrombocytopenic purpura (ITP) will run a chronic course. • Only in a minority of these, platelet-count-enhancing treatments are indicated. • Most treatment options are directed at decreasing platelet destruction including corticosteroids, intravenous immunoglobulins, splenectomy, and other immunosuppressive or immune modulating drugs.

  45. Volume 47, Issue S5, pages 714–716, 15 October 2006.IncPediatric Blood & Cancer • In children, rituximab seems to have similar efficacy as in adults with a lasting continuous remission rate of 30–35%. • Toxicity includes fever, pruritus, throat tightness, and serum sickness that may be reason to discontinue rituximab treatment. • No increased frequency of infections is noted. • We conclude that rituximab should be given to those symptomatic ITP patients who would otherwise be referred for splenectomy; only those who fail rituximab treatment should proceed to surgery.

  46. Management of Immune Thrombocytopenic Purpura: An UpdateNew OrleansheOchsner Journal 12:221–227, 2012..RajasekharanWarrier

  47. Treatment Selection/ITPManagement of Immune Thrombocytopenic Purpura: An UpdateNew OrleansheOchsner Journal 12:221–227, 2012..RajasekharanWarrier • The factors that influence the selection of a treatment regimen in a given patient are: • quality-of life impact, adverse events, likelihood of response, bleeding risk, patient/parent anxiety, and economic issues. • A detailed clinical history and thorough physical examination are vital. • The clinical history has important implications not only in diagnosing the disease but also for selecting the treatment regimen. • Based on the clinical history, patients can be subclassified into the following groups: • emergent, acute responsive, acute refractory, chronic persistent, and chronic refractory.

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