Optimizing the Clinical Outcomes of Patients With Immune Thrombocytopenia: Clinician Resource Guide
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The document provides a comprehensive reference guide for immune thrombocytopenia (ITP), outlining its definitions, causes, diagnosis, management, and treatment options. It includes detailed sections on initial and subsequent management strategies, first-line, second-line, and third-line treatments, as well as special considerations for both children and adults. The information is aimed at improving clinical outcomes and is part of an educational adjunct to a CME/CNE-approved online activity.
Optimizing the Clinical Outcomes of Patients With Immune Thrombocytopenia: Clinician Resource Guide
- 1. Clinical Tools and Resources for Self-Study and Patient Education IMMUNE THROMBOCYTOPENIA REFERENCE GUIDE The clinical tools and resources contained herein are provided as educational adjuncts to the CME/CNE-approved online activity Optimizing the Clinical Outcomes of Patients With Immune Thrombocytopenia. It has been reviewed by James B. Bussel, MD, and Allison Miller Imahiyerobo, APN (November 2019). To access the activity and earn CME/CNE credit, visit: https://www.i3Health.com/ITP CONTENTS I. Immune Thrombocytopenia: International Working Group Descriptive Terminology..2 II. Causes of Secondary Immune Thrombocytopenia.......................................................3 III. Diagnosing Immune Thrombocytopenia.....................................................................4 IV. Initial Management of Immune Thrombocytopenia....................................................5 V. First-Line Treatment of Immune Thrombocytopenia ...................................................6 VI. Subsequent Management of Immune Thrombocytopenia .........................................7 VII. Immune Thrombocytopenia: Special Considerations for Subsequent Management 8 VIII: Second- and Third-Line Treatment Options for Immune Thrombocytopenia ..........9
- 2. 110ITP Reference Guide I Page 2 of 10 www.i3Health.com I. IMMUNE THROMBOCYTOPENIA: INTERNATIONAL WORKING GROUP DESCRIPTIVE TERMINOLOGY Terminology Description Newly diagnosed <3 mo duration Persistent 3-12 mo duration Chronic >12 mo duration Severe Significant bleeding requiring treatment, whether initiating treatment, additional interventions, or an increase in drug dose Refractory Persistence of severe ITP after splenectomy Response Platelet count ≥30x109 /L and a greater than twofold increase in platelet count from baseline measured on 2 occasions >7 d apart Complete response Platelet count ≥100x109 /L measured on 2 occasions >7 d apart mo = months; d = days; ITP = immune thrombocytopenia. Rodeghiero F, Stasi R, Germsheimer T, et al (2009). Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood, 113(11):2386-2393. DOI:10.1182/blood-2008-07-162503
- 3. 110ITP Reference Guide I Page 3 of 10 www.i3Health.com II. CAUSES OF SECONDARY IMMUNE THROMBOCYTOPENIA HIV = human immunodeficiency virus; HCV = hepatitis C virus; CMV = cytomegalovirus; NSAIDs = non-steroidal anti-inflammatory drugs; CVID = common variable immunodeficiency virus; ALPS = autoimmune lymphoproliferative syndrome. Cines DB, Bussel JB, Liebman HA, et al (2009). The ITP syndrome: pathogenic and clinical diversity. Blood, 113(26):6511-6521. DOI:10.1182/blood-2009-01-129155 Autoimmune Disorders Infections Drugs Vaccinations Immunodeficiency Disorders • Systemic lupus erythematosus • Antiphospholipid syndrome • Evans syndrome • HIV • HCV • Helicobacter pylori • CMV • Heparin • Penicillin • NSAIDs • Many others • Measles • Mumps • Rubella • Varicella • Pneumococcal • CVID • ALPS • DiGeorge • Others
- 4. 110ITP Reference Guide I Page 4 of 10 www.i3Health.com III. DIAGNOSING IMMUNE THROMBOCYTOPENIA ITP Detection Necessary evaluation • History: bleeding symptoms consistent with isolated thrombocytopenia without constitutional symptoms (eg, significant weight loss, bone pain, night sweats) Bone marrow evaluation • Bone marrow examination is unnecessary in patients with the typical features of ITP outlined above, irrespective of the patient’s age • Bone marrow examination is felt to be unnecessary in children with typical ITP prior to initiation of treatment with corticosteroids but is useful prior to splenectomy or in patients who fail intravenous immunoglobulin therapy • The presence of abnormalities in the history, physical examination, or CBC and peripheral blood smear should be further investigated, eg, with a bone marrow examination or other appropriate laboratory investigations, before the diagnosis of ITP is made • There is no consensus on what constitute appropriate laboratory investigations for ITP in either children or adults Additional evaluations • All adult patients with newly diagnosed ITP should undergo testing for HIV and HCV • In the evaluation of suspected ITP, there is insufficient evidence to support the routine use of antiplatelet, antiphospholipid, or antinuclear antibodies; thrombopoietin levels; or platelet parameters obtained using automated analyzers • However, liver tests, immunoglobulin levels, PTT, urinalysis, and reticulocyte count are more equivocal, as are DAT and blood type CBC = complete blood count; PTT = partial thromboplastin time; DAT = direct antiglobulin test. George JN, Woolf SH, Raskob GE, et al (1996). Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood, 88(1):3-40. Neunert CE & Cooper N (2018). Evidence-based management of immune thrombocytopenia: ASH guideline update. Hematology Am Soc Hematol Educ Program, 2018(1):568-575. DOI:10.1182/asheducation- 2018.1.568 Neunert C, Lim W, Crowther M, et al (2011). The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood, 117(16):4190-4207. DOI:10.1182/blood-2010-08-302984 Provan D, Stasi R, Newland AC, et al (2010). International consensus report on the investigation and management of immune primary thrombocytopenia. Blood, 115(2):168-186. DOI:10.1182/blood-2009-06-225565 Staley EM, Cao W, Pham HP, et al (2019). Clinical factors and biomarkers predict outcome in patients with immune- mediated thrombotic thrombocytopenic purpura. Haematologica, 104(1):166-175. DOI:10.3324/haematol.2018.198275
- 5. 110ITP Reference Guide I Page 5 of 10 www.i3Health.com IV. INITIAL MANAGEMENT OF IMMUNE THROMBOCYTOPENIA Overview: Managing ITP Assessment of disease status • What bleeding is the patient experiencing? • Determine the timing, location, and severity of bleeding symptoms. Is the patient’s life at risk? • Does this patient have any additional risk factors for bleeding, such as use of antithrombotic or anti-platelet agents, high-risk occupation, or inability to travel to obtain medical care in an emergency? • Is a surgical procedure anticipated? • Is this patient likely to comply with recommended daily treatments? • Is the bleeding interfering with daily activities or causing significant anxiety? General considerations for initial management of children and adults • First-line treatment includes observation, corticosteroids, IVIg, or anti-D immunoglobulin (anti-D) or a combination of the 3 (eg, steroids + IVIg/IV anti-D) • IVIg may be used in conjunction with corticosteroids if a more rapid increase in platelet count is required • IV anti-D is advised only with premedication with high-dose IV steroids (methylprednisolone or dexamethasone); if there is bleeding causing a decline in hemoglobin, it may be more of a risk for anemia • Patients who have undergone splenectomy or are DAT-positive (with or without autoimmune hemolysis) should not receive IV anti-D • If corticosteroids are contraindicated, either IVIg (1.0 g/kg for one dose, repeated as necessary) or anti-D (50-75 micrograms/kg IV) in appropriate patients may be used Special considerations for adults • For adults: treatment should almost always be given for a platelet count <30x109 /L • Courses of corticosteroids, especially prednisone, should not be given for longer than 6 weeks. This also means second long courses of steroids should not be used Special considerations for children • The majority of children with no bleeding or mild bleeding (petechiae and bruising) can be treated with observation alone regardless of platelet count • In general, treatment should be given to children only for actual bleeding or high risk of serious bleeding, eg, head trauma, mouth blisters, difficult-to-stop epistaxis; however, certain practitioners would treat for platelet counts <10x109 /L • A single dose of IVIg (0.8-1.0 g/kg) or a short course of corticosteroids, eg, prednisone 4 mg/kg x 4-7 days or dexamethasone 24 mg/m2 x 4 days should be used as first-line treatment if treatment is desired IVIg = intravenous immune globulin. Khan AM, Mydra H & Nevarez A (2017). Clinical practice updates in the management of immune thrombocytopenia. P T, 42(12):756-763.
- 6. 110ITP Reference Guide I Page 6 of 10 www.i3Health.com V. FIRST-LINE TREATMENT OF IMMUNE THROMBOCYTOPENIA Dose Response (Initial/Peak) Response Rate Adverse Effects Comments Prednisone 0.5-2.0 mg/kg daily for 2-4 wks then taper 4-14 d/ 7-28 d 70%-80% Insomnia, hypertension, hyperglycemia, mood disorders, weight gain, dizziness, edema Requires dose tapering Dexamethasone 40 mg daily for 4 consecutive days every 2-4 wks, 1-4 cycles 2-14 d/ 4-28 d Up to 90% Same as prednisone, but less common Faster onset of action than prednisone but no increase in off- treatment remission Intravenous Immunoglobulin 1 g/kg daily for 1-2 d 1-3 d/ 2-7 d Up to 85% Headaches which can be severe, infusion-related reactions, fluid overload— hypertension Upfront treatment if corticosteroids are contraindicated or produce suboptimal response Anti-D Immunoglobulin 50-75 mcg/kg 1-3 d/ 3-7 d 70%-80% Hemolysis, fever, chills, headache, nausea; better with steroid prophylaxis Only in D-positive, DAT-negative, non- splenectomized patients; monitor patients for 8 hours after administration Wks = weeks. Neunert CE & Cooper N (2018). Evidence-based management of immune thrombocytopenia: ASH guideline update. Hematology Am Soc Hematol Educ Program, 2018(1):568-575. DOI:10.1182/asheducation- 2018.1.568 Provan D, Stasi R, Newland AC, et al (2010). International consensus report on the investigation and management of immune primary thrombocytopenia. Blood, 115(2):168-186. DOI:10.1182/blood-2009-06-225565
- 7. 110ITP Reference Guide I Page 7 of 10 www.i3Health.com VI. SUBSEQUENT MANAGEMENT OF IMMUNE THROMBOCYTOPENIA Assessment of disease status • What bleeding is the patient experiencing? Determine the timing, location, and severity of bleeding symptoms • Does this patient have findings in history or physical examination, CBC and blood smear, or other laboratory testing that suggest evaluation for another diagnosis that could be causing thrombocytopenia? • How is the diagnosis of ITP affecting the patient’s ability to work, go to school, or participate in activities? Is the patient depressed or very tired? • Does the patient respond sufficiently to his or her current treatment? • Is the patient experiencing side effects from medication use? • How is the patient coping with having a low platelet count? General considerations for subsequent management • Adults who have a platelet count >30x109 /L and are asymptomatic on no treatment do not require further therapy, but depending on the circumstances, require more or less frequent further monitoring • Splenectomy should be delayed for at least 12 months, unless warranted by severe disease unresponsive to other measures • If previous treatment with IVIg or anti-D has been successful, these options may be repeated as needed to prevent bleeding, although too-frequent use of IVIg and IV anti-D may lead to anemia or loss of response • If previous treatment with corticosteroids, IVIg, or anti-D has been unsuccessful, subsequent treatment may include rituximab, thrombopoietin receptor agonists, immunosuppression, or splenectomy Khan AM, Mydra H & Nevarez A (2017). Clinical practice updates in the management of immune thrombocytopenia. P T, 42(12):756-763.
- 8. 110ITP Reference Guide I Page 8 of 10 www.i3Health.com VII. IMMUNE THROMBOCYTOPENIA: SPECIAL CONSIDERATIONS FOR SUBSEQUENT MANAGEMENT Children Adults Splenectomy Almost never recommended for children: ideally, they must have significant and/or persistent bleeding and lack of response/intolerance to other therapies (eg, corticosteroids, IVIg, anti-D, TPO-RAs, rituximab, and/or other treatments) Recommended for adults who have failed corticosteroid therapy (and usually rituximab and TPO-RA) and have had ITP for ≥1 year without relative contraindications such as CVID; similar efficacy with laparoscopic procedures Rituximab May be considered as second-line treatment for children with ITP who have significant ongoing bleeding and/or a need for improved quality of life despite first-line treatment May be considered for adults at risk of bleeding who have failed 1 line of therapy, such as corticosteroids, IVIg, or splenectomy Thrombopoietin receptor agonists Both eltrombopag and romiplostim are licensed for children age 1 or older; while they are licensed for children with chronic disease, they are increasingly used in children with persistent ITP Recommended for adults who have failed one previous therapy of ITP; while licensed for chronic ITP, the recommendation to shorten steroid use to 6 weeks means that TPO-RA (and rituximab) are used in persistent ITP High-dose dexamethasone Infrequently used as first-line treatment for children with ITP who need treatment to acutely elevate their platelet count; also used in conjunction with other treatments to increase the platelet count sooner while awaiting the effect of another treatment Same as for children except used more readily as first-line treatment TPO-RAs = thrombopoietin receptor agonists. Neunert CE & Cooper N (2018). Evidence-based management of immune thrombocytopenia: ASH guideline update. Hematology Am Soc Hematol Educ Program, 2018(1):568-575. DOI:10.1182/asheducation- 2018.1.568 Provan D, Stasi R, Newland AC, et al (2010). International consensus report on the investigation and management of immune primary thrombocytopenia. Blood, 115(2):168-186. DOI:10.1182/blood-2009-06-225565
- 9. 110ITP Reference Guide I Page 9 of 10 www.i3Health.com VIII: SECOND- AND THIRD-LINE TREATMENT OPTIONS FOR IMMUNE THROMBOCYTOPENIA Dose Response (Initial/Peak) Response Rate Adverse Events Comments Splenectomy N/A 1-56 d/ 7-56 d 60%-80% Bleeding, overwhelming sepsis, thrombotic events Consider after multiple treatment failures and at least >1 year from diagnosis; in children, at least age 5 Rituximab 375 mg/m2 IV over 4 h once weekly for 4 wks 7-56 d/ 14-180 d 60% First infusion reactions, serum sickness, neutropenia, rare hypo- gammaglobulinemia Second-line therapy option, especially in adolescent females and women of child-bearing age Eltrombopag 50-75 mg daily 7-28 d/ 14-90 d 80% Hepatotoxicity, thrombotic events Second-line option in children and adults Romiplostim 1 mcg/kg SQ once weekly 14-21 d/ not reported 79%-88% Arthralgia, thrombotic events Second-line option in children and adults Avatrombopag 20 mg daily (adjusted to 5- 40 mg based on response) 7 d 70% Headache, thrombotic events Second-line option in adults only Fostamatinib 100 mg BID (increase to 150 mg BID in 2-4 wks based on response) 15 d 43% Diarrhea, hypertension, nausea, dizziness, ALT increase Second-line treatment, usually used after TPO- RA IV = intravenous; h = hours; SQ = subcutaneous; BID = twice daily; ALT = alanine transaminase.
- 10. 110ITP Reference Guide I Page 10 of 10 www.i3Health.com Bussel JB, Arnold DM, Boxer MA, et al (2019). Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program. Am J Hematol, 94(5):546-553. DOI:10.1002/ajh.25444 Bussel J, Arnold DM, Grossbard E, et al (2018). Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol, 93(7):921-930. DOI:10.1002/ajh.25125 Bussel JB, Cheng G, Saleh MN, et al (2007). Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22):2237-2247. DOI:10.1056/NEJMoa073275 Bussel JB, Kuter DJ, George JN, et al (2006). AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med, 355(16):1672-1681. DOI:10.1056/NEJMoa054626 Chapin J, Lee CS, Zhang H, et al (2016). Gender and duration of disease differentiate responses to rituximab- dexamethasone therapy in adults with immune thrombocytopenia. Am J Hematol, 91(9):907-911. DOI:10.1002/ajh.24434 Jurczak W, Chojnowski K, Mayer J, et al (2018). Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor antagonist for the treatment of chronic immune thrombocytopenia. Br J Haematol, 183(3):479-490. DOI:10.1111/bjh.15573