Title American Society of Hematology 2019 guidelines for immune thrombocytopenia.pdf ✅

CLINICAL GUIDELINES American Society of Hematology 2019 guidelines for immune thrombocytopenia Cindy Neunert,1 Deirdra R. Terrell,2 Donald M. Arnold,3,4 George Buchanan,5 Douglas B. Cines,6 Nichola Cooper,7 Adam Cuker,8 Jenny M. Despotovic,9 James N. George,2 Rachael F. Grace,10 Thomas Kuhne, ̈ 11 David J. Kuter,12 Wendy Lim,13 Keith R. McCrae,14 Barbara Pruitt,15 Hayley Shimanek,16 and Sara K. Vesely2 1 Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Irving Medical Center, New York, NY; 2 Department of Biostatistics and Epidemiology, Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK; 3 Division of Hematology and Thromboembolism, Department of Medicine, and 4 McMaster Centre for Transfusion Research, McMaster University, Toronto, ON, Canada; 5 Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX; 6 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 7 Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom; 8 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 9 Section of Hematology-Oncology, Department of Pediatrics, College of Medicine, Baylor University, Houston, TX; 10Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Department of Pediatrics, Harvard Medical School, Boston, MA; 11University Children’s Hospital Basel, Basel, Switzerland; 12Department of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 13Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Toronto, ON, Canada; 14Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH; 15Coral Gables, FL; and 16Ames, IA Background: Despite an increase in the number of therapies available to treat patients with immune thrombocytopenia (ITP), there are minimal data from randomized trials to assist physicians with the management of patients. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the management of ITP. Methods: In 2015, ASH formed a multidisciplinary guideline panel that included 8 adult clinical experts, 5 pediatric clinical experts, 2 methodologists with expertise in ITP, and 2 patient represen- tatives. The panel was balanced to minimize potential bias from conflicts of interest. The panel reviewed the ASH 2011 guideline recommendations and prioritized questions. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence- to-decision frameworks, to appraise evidence (up to May 2017) and formulate recommendations. Results: The panel agreed on 21 recommendations covering management of ITP in adults and children with newly diagnosed, persistent, and chronic disease refractory to first-line therapy who have non–life-threatening bleeding. Management approaches included: observation, corticosteroids, IV immunoglobulin, anti-D immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists. Conclusions: There was a lack of evidence to support strong recommendations for various management approaches. In general, strategies that avoided medication side effects were favored. A large focus was placed on shared decision-making, especially with regard to second-line therapy. Future research should apply standard corticosteroid-dosing regimens, report patient-reported outcomes, and include cost-analysis evaluations. Summary of recommendations Background These guidelines are based on updated and original systematic reviews of evidence conducted under the direction of the University of Oklahoma Health Sciences Center (OUHSC). The guideline panel followed best practice for guideline development recommended by the Institute of Medicine and the Guidelines International Network (GIN).1-4 The panel used the Grading of Recommendations Submitted 13 September 2019; accepted 21 October 2019. DOI 10.1182/ bloodadvances.2019000966. The full-text version of this article contains a data supplement. © 2019 by The American Society of Hematology 10 DECEMBER 2019 x VOLUME 3, NUMBER 23 3829
Assessment, Development and Evaluation (GRADE) approach5-10 to assess the certainty in the evidence and formulate recommendations. These guidelines focus on the management of immune thrombo- cytopenia (ITP). ITP is an acquired autoimmune disorder charac- terized by a low platelet count resulting from platelet destruction and impaired platelet production. The incidence of ITP is estimated to be 2 to 5 per 100 000 persons in the general population.11-15 Large randomized trials on the management of ITP are lacking, resulting in significant controversy and variation in practice. We summarize available evidence and recommendations regarding first- and second-line management of adults and children with ITP. Interpretation of strong and conditional recommendations The strength of a recommendation is expressed as either strong (“the guideline panel recommends...”) or conditional (“the guideline panel suggests...”) and has the following interpretation: Strong recommendation c For patients: Most individuals in this situation would want the recommended course of action, and only a small proportion would not. c For clinicians: Most individuals should follow the recommended course of action. Formal decision aids are not likely to be needed to help individual patients make decisions consistent with their values and preferences. c For policy makers: The recommendation can be adopted as policy in most situations. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. c For researchers: The recommendation is supported by credible research or other convincing judgments that make additional research unlikely to alter the recommendation. On occasion, a strong recommendation is based on low or very low certainty in the evidence. In such instances, further research may provide important information that alters the recommendations. Conditional recommendation c For patients: The majority of individuals in this situation would want the suggested course of action, but many would not. Decision aids may be useful in helping patients to make decisions consistent with their individual risks, values, and preferences. c For clinicians: Recognize that different choices will be appro- priate for individual patients and that you must help each patient arrive at a management decision consistent with the patient’s values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values, and preferences. c For policy makers: Policy-making will require substantial debate and involvement of various stakeholders. Performance measures about the suggested course of action should focus on whether an appropriate decision-making process is duly documented. c For researchers: This recommendation is likely to be strength- ened (for future updates or adaptation) by additional research. An evaluation of the conditions and criteria (and the related judgments, research evidence, and additional considerations) that determined the conditional (rather than strong) recommen- dation will help identify possible research gaps. Interpretation of good practice statements As described by the GRADE Guidance Group, good practice statements endorse interventions or practices that the guide- line panel agreed have unequivocal net benefit yet may not be widely recognized or used.16 Good practice statements in these guidelines are not based on a systematic review of available evidence. Nevertheless, they may be interpreted as strong recommendations. Recommendations Management of adult patients with newly diagnosed ITP CORTICOSTEROIDS VS OBSERVATION. Recommendation 1a. In adults with newly diagnosed ITP and a platelet count of ,30 3 109 /L who are asymptomatic or have minor mucocutaneous bleed- ing, the American Society of Hematology (ASH) guideline panel suggests corticosteroids rather than management with obser- vation (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Remark: There may be a subset of patients within this group for whom observation might be appropriate. This should include consideration of the severity of thrombocytopenia, additional comorbidities, use of anticoag- ulant or antiplatelet medications, need for upcoming procedures, and age of the patient. Recommendation 1b. In adults with newly diagnosed ITP and a platelet count of $30 3 109 /L who are asymptomatic or have minor mucocutaneous bleeding, the ASH guideline panel recommends against corticosteroids and in favor of management with observa- tion (strong recommendation based on very low certainty in the evidence of effects Å◯◯◯). Remark: For patients with a platelet count at the lower end of this threshold, for those with additional comorbidities, anticoagulant or antiplatelet medications, or upcoming procedures, and for elderly patients (.60 years old), treatment with corticosteroids may be appropriate. Good practice statement. The treating physician should ensure that the patient is adequately monitored for potential corticoste- roid side effects regardless of the duration or type of corticoste- roid selected. This includes close monitoring for hypertension, hyperglycemia, sleep and mood disturbances, gastric irritation or ulcer formation, glaucoma, myopathy, and osteoporosis. Given the potential impact of corticosteroids on mental health, the treating physician should conduct an assessment of health-related quality of life (HRQoL) (depression, fatigue, mental status, etc) while patients are receiving corticosteroids. INPATIENT VS OUTPATIENT MANAGEMENT. Recommendation 2a. In adults with newly diagnosed ITP and a platelet count of ,20 3 109 /L who are asymptomatic or have minor mucocutaneous bleeding, the ASH guideline panel suggests admission to the hospital rather than management as an outpatient (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). In adults with an established diagnosis of ITP and a platelet count of ,20 3 109 /L who are asymptomatic or have minor mucocutaneous bleeding, the ASH guideline panel suggests outpatient management rather than hospital admission (conditional 3830 NEUNERT et al 10 DECEMBER 2019 x VOLUME 3, NUMBER 23
recommendation based on very low certainty in the evidence Å◯◯◯). Remark: Patients who are refractory to treatment, those with social concerns, uncertainty about the diagnosis, significant comorbidities with risk of bleeding, and more significant mucosal bleeding may benefit from admission to the hospital. Patients not admitted to the hospital should receive education and expedited follow-up with a hematologist. The need for admission is also variable across the range of platelet counts represented here (0 to 20 3 109 /L). Recommendation 2b. In adults with a platelet count of $20 3 109 /L who are asymptomatic or have minor mucocutaneous bleeding, the ASH guideline panel suggests management as an outpatient rather than hospital admission (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Remark: Patients who are refractory to treatment, with social concerns, uncertainty about the diagnosis, significant comorbidities with risk of bleeding, and more significant mucosal bleeding may benefit from admission to the hospital. Patients not admitted to the hospital should receive education and expedited follow-up with a hematologist. The need for admission is also variable across the range of platelet counts represented here (20 3 109 /L to 150 3 109 /L). Good practice statement. The referring physician should ensure that the patient has follow-up with a hematologist within 24 to 72 hours of the diagnosis or disease relapse. DURATION AND TYPE OF CORTICOSTEROIDS. Recommendation 3. In adults with newly diagnosed ITP, the ASH guideline panel recommends against a prolonged course (.6 weeks including treatment and taper) of prednisone and in favor of a short course (#6 weeks) (strong recommendation based on very low certainty in the evidence of effects Å◯◯◯). Good practice statement. The treating physician should ensure that the patient is adequately monitored for potential corticoste- roid side effects regardless of duration or type of corticosteroid selected. This includes close monitoring for hypertension, hyperglycemia, sleep and mood disturbances, gastric irritation or ulcer formation, glaucoma, myopathy, and osteoporosis. Given the impact of corticosteroids on mental health, the treating physician should conduct an assessment of HRQoL (depression, fatigue, mental status, etc) while patients are receiving corticosteroids. Recommendation 4. In adults with newly diagnosed ITP, the ASH guideline panel suggests either prednisone (0.5-2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days) as the type of corticosteroid for initial therapy (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Remark: If a high value is placed on rapidity of platelet count response, an initial course of dexamethasone may be preferred over prednisone, given that dexamethasone showed increased desirable effects with regard to response at 7 days. Good practice statement. The treating physician should ensure that the patient is adequately monitored for potential cortico- steroid side effects regardless of the duration or type of cortico- steroid selected. This includes close monitoring for hypertension, hyperglycemia, sleep and mood disturbances, gastric irritation or ulcer formation, glaucoma, myopathy, and osteoporosis. Given the impact of corticosteroids on mental health, the treating physician should assess HRQoL (depression, fatigue, mental status, etc) while patients are receiving corticosteroids. RITUXIMAB AS INITIAL TREATMENT. Recommendation 5. In adults with newly diagnosed ITP, the ASH guideline panel suggests corticosteroids alone rather than rituximab and corticosteroids for initial therapy (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Remark: If high value is placed on the possibility for remission over concerns for potential side effects of rituximab, then an initial course of corticosteroids with rituximab may be preferred. Management of adults with ITP who are corticosteroid- dependent or do not have a response to corticosteroids ELTROMBOPAG VS ROMIPLOSTIM. Recommendation 6. In adults with ITP for $3 months who are corticosteroid-dependent or unresponsive to corticosteroids and are going to be treated with a thrombopoietin receptor agonist (TPO-RA), the ASH guideline panel suggests either eltrombopag or romiplostim (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Remark: Individual patient preference may place a higher value on the use of a daily oral medication or weekly subcutaneous injections. SECOND-LINE THERAPIES: SPLENECTOMY, TPO-RA, AND RITUXIMAB COMPARED 1 AGAINST THE OTHER. Recommendation 7. In adults with ITP lasting $3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests either splenectomy or a TPO-RA (conditional recommen- dation based on very low certainty in the evidence of effects Å◯◯◯). Recommendation 8. In adults with ITP lasting $3 months who are corticosteroid-dependent or have no response to corticoste- roids, the ASH guideline panel suggests rituximab rather than splenectomy (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Recommendation 9. In adults with ITP lasting $3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests a TPO-RA rather than rituximab (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Remark: These recommendations are the result of dichotomous evaluation of treatments that are often being considered simultaneously. Each of these second- line treatments may be effective therapy and therefore the choice of treatment should be individualized based on duration of ITP, frequency of bleeding episodes requiring hospitaliza- tion or rescue medication, comorbidities, age of the patient, medication adherence, medical and social support networks, patient values and preferences, cost, and availability. Patient education and shared decision-making are encouraged. If possible, splenectomy should be delayed for at least 1 year after diagnosis because of the potential for spontaneous remission in the first year. Patients who value avoidance of long-term medication may prefer splenectomy or rituximab. Patients who wish to avoid surgery may prefer a TPO-RA or rituximab. Patients who place a high value on achieving a durable response may prefer splenectomy or TPO-RAs. Good practice statement. The treating physician should ensure that patients have appropriate immunizations prior to splenectomy and that they receive counseling regarding antibiotic prophylaxis 10 DECEMBER 2019 x VOLUME 3, NUMBER 23 ASH 2019 GUIDELINES FOR ITP 3831
following splenectomy. The treating physician should also educate the patient on prompt recognition and management of fever and refer to current recommendations on pre- and postsplenectomy care. Management of children with newly diagnosed ITP OUTPATIENT VS INPATIENT MANAGEMENT. Recommendation 10a. In children with newly diagnosed ITP and a platelet count of ,20 3 109 /L who have no or mild bleeding (skin manifestations) only, the ASH guideline panel suggests against admission to the hospi- tal and in favor of management as an outpatient (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Remark: For patients with uncertainty about the diagnosis, those with social concerns, those who live far from the hospital, and those for whom follow-up cannot be guaranteed, admission to the hospital may be preferable. Recommendation 10b. In children with newly diagnosed ITP and a platelet count of $20 3 109 /L who have no or mild bleeding (skin manifestations) only, the ASH guideline panel suggests against admission to the hospital and in favor of management as an outpatient (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Remark: For patients with uncertainty about the diagnosis, those with social concerns, those who live far from the hospital, or those for whom follow- up cannot be guaranteed, admission to the hospital may be preferable. Good practice statement. The referring physician should ensure that the patient has follow-up with a hematologist within 24 to 72 hours of diagnosis. TREATMENT VS OBSERVATION. Recommendation 11. In children with newly diagnosed ITP who have no or minor bleeding, the ASH guideline panel suggests observation rather than corticosteroids (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Recommendation 12. In children with newly diagnosed ITP who have no or minor bleeding, the ASH guideline panel recom- mends observation rather than IV immunoglobulin (IVIG) (strong recommendation based on moderate certainty in the evidence of effects ÅÅÅ◯). Recommendation 13. In children with newly diagnosed ITP who have no or minor bleeding, the ASH guideline panel recommends observation rather than anti-D immunoglobulin (strong recommen- dation based on moderate certainty in the evidence of effects ÅÅÅ◯). CORTICOSTEROID DURATION AND TYPE. Recommendation 14. In children with newly diagnosed ITP who have non–life- threatening mucosal bleeding and/or diminished HRQoL, the ASH guideline panel recommends against courses of cortico- steroids longer than 7 days and in favor of courses 7 days or shorter (strong recommendation based on very low certainty in the evidence of effects Å◯◯◯). Recommendation 15. In children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or di- minished HRQoL, the ASH guideline panel suggests predni- sone (2-4 mg/kg per day; maximum, 120 mg daily, for 5-7 days) rather than dexamethasone (0.6 mg/kg per day; maximum, 40 mg/kg per day, for 4 days) (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). TREATMENT OF CHILDREN WITH NON–LIFE-THREATENING BLEEDING AND/OR DIMINISHED HRQOL. Recommendation 16. In children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL, the ASH guideline panel suggests corticosteroids rather than anti-D immunoglobulin (conditional recommendation based on low certainty in the evidence of effects ÅÅ◯◯). Remark: This recommenda- tion assumes corticosteroid dosing as outlined recommenda- tions 14 and 15. This recommendation is reserved only for children with nonmajor mucosal bleeding. Recommendation 17. In children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL, the ASH guideline panel suggests either anti-D immunoglobulin or IVIG (conditional recommendation based on low certainty in the evidence of effects ÅÅ◯◯). Remark: This recommendation is reserved only for children with nonmajor mucosal bleeding. Recommendation 18. In children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or di- minished HRQoL, the ASH guideline panel suggests cortico- steroids rather than IVIG (conditional recommendation based on low certainty in the evidence of effects ÅÅ◯◯). Remark: This recommendation assumes that a short course of cortico- steroids is being used for treatment as recommended in recommendation 14. This recommendation is reserved only for children with nonmajor mucosal bleeding. Management of children with ITP who do not have a response to first-line treatment SECOND-LINE THERAPIES: SPLENECTOMY, TPO-RA, AND RITUXIMAB COM- PARED 1 AGAINST THE OTHER. Recommendation 19. In children with ITP who have non–life-threatening mucosal bleeding and/ or diminished HRQoL and do not respond to first-line treatment, the ASH guideline panel suggests the use of TPO-RAs rather than rituximab (conditional recommendation based on very low certainty in the evidence of effects Å◯◯◯). Recommendation 20. In children with ITP who have non–life- threatening mucosal bleeding and/or diminished HRQoL and do not respond to first-line treatment, the ASH guideline panel suggests TPO-RAs rather than splenectomy (conditional recom- mendation based on very low certainty in the evidence of effects Å◯◯◯). Recommendation 21. In children with ITP who have non–life- threatening mucosal bleeding and/or diminished HRQoL and do not respond to first-line treatment, the ASH guideline panel suggests rituximab rather than splenectomy (conditional recom- mendation based on very low certainty in the evidence of effects Å◯◯◯). Good practice statement. The treating physician should ensure that the patient has appropriate immunizations prior to splenec- tomy and that they receive counseling regarding antibiotic prophylaxis following splenectomy. The treating physician should educate the patient on prompt recognition and management of fever and refer to current recommendations on pre- and postsplenectomy care. 3832 NEUNERT et al 10 DECEMBER 2019 x VOLUME 3, NUMBER 23