ASH Draft Recommendations for Immune Thrombocytopenia

Transcription

1 ASH Draft Recommendations for Immune Thrombocytopenia INTRODUCTION American Society of Hematology (ASH) guidelines are based on a systematic review of available evidence. Through a structured process, a guideline panel makes judgements about the evidence and forms recommendations. The public comment period occurs after recommendations are formed but before a manuscript report of the guidelines has been finalized and before ASH organizational approval of the guidelines. Comments collected during the open comment period are provided to the guideline panel for review prior to finalizing the guidelines. These draft recommendations are not final and therefore are not intended for use or citation. To submit comments on the draft recommendations, please visit Only comments submitted via the online survey will be reviewed by the guideline panel. The public comment period for these draft recommendations is November 9 December 10, RECOMMENDATIONS Question 1A: Should adults with newly diagnosed ITP and a platelet count <30 x 10 9 /l who are asymptomatic or with minor mucocutaneous bleeding be treated with corticosteroids or observation? The ASH guideline panel suggests corticosteroids rather than observation in adults with newly diagnosed ITP and a platelet count <30 x 10 9 /l who are asymptomatic or with minor mucocutaneous bleeding. (Conditional recommendation, moderate certainty in the evidence about effects) Question 1B: Should adults with newly diagnosed ITP and a platelet count 30 x 10 9 /l who are asymptomatic or with minor mucocutaneous bleeding be treated with corticosteroids or observation? The ASH guideline panel recommends observation rather than corticosteroids in adults with newly diagnosed ITP and a platelet count 30 x 10 9 /l who are asymptomatic or with minor mucocutaneous bleeding. (Strong recommendation, very low certainty in the evidence about effects) Question 2A: Should adults with ITP and a platelet count <20 x 10 9 /l and no or mild mucocutaneous bleeding only be treated as an outpatient or be admitted to the hospital? The ASH guideline panel suggests admission to the hospital rather than treatment as an outpatient in adults with newly diagnosed ITP and a platelet count <20 x 10 9 /l and no or mild mucocutaneous bleeding. (Conditional recommendation, very low certainty in the evidence about effects) The ASH guideline panel suggests against admission to the hospital rather than treatment as an outpatient in adults with established ITP and a platelet count <20 x 10 9 /l and no or mild mucocutaneous bleeding only. (Conditional recommendation, very low certainty in the evidence about effects) Question 2B: Should adults with ITP and a platelet count 20 x 10 9 /l and no or mild mucocutaneous bleeding only be treated as an outpatient or be admitted to the hospital? The ASH guideline panel suggests against admission to the hospital rather than treatment as an outpatient in adults with newly diagnosed ITP and a platelet count 20 x 10 9 /l and nor mild mucocutaneous bleeding. (Conditional recommendation, very low certainty in the evidence about effects) All materials are copyright American Society of Hematology

2 Question 3: Should adults with newly diagnosed ITP be treated with a short course ( 6 weeks) or prolonged continuous use (including treatment and taper) of prednisone for initial therapy? The ASH guideline panel recommends against prolonged continuous use (including treatment and taper) of prednisone rather than a short course ( 6 weeks) for initial therapy in adults with newly diagnosed ITP. (Strong recommendation, very low certainty in the evidence about effects) Question 4: Should adults with newly diagnosed ITP be treated with prednisone (0.5-2mg/kg/day) or dexamethasone (40mg/day x 4 days) as the type of corticosteroid for initial therapy? The ASH guideline panel suggests either dexamethasone (40 mg/day x 4 days) or prednisone (0.5-2 mg/kg/day) in adults with newly diagnosed ITP as the type of corticosteroid for initial therapy. (Conditional recommendation, very low certainty in the evidence about effects) Remark: If a high value is placed on rapidity of platelet count response over concerns for potential side-effects of dexamethasone then an initial course of dexamethasone over prednisone may be preferred. Question 5: Should adults with newly diagnosed ITP be treated with rituximab with corticosteroids or corticosteroids alone for initial therapy? The ASH guideline panel suggests for corticosteroids alone rather than rituximab and corticosteroids for initial therapy in adults with newly diagnosed ITP. (Conditional recommendation, very low certainty in the evidence about effects) Question 6: Should adults with ITP who are corticosteroid-dependent or unresponsive to corticosteroids and are going to be treated with a TPO-RA receive eltrombopag or romiplostim? The ASH guideline panel suggest either eltrombopag or romiplostim in an adult with ITP who is corticosteroid-dependent or unresponsive to corticosteroids and is going to be treated with a TPO-RA. (Conditional recommendation, low certainty in the evidence about effects) Question 7: Should adults with ITP lasting 3 months who are corticosteroid-dependent or unresponsive to corticosteroids undergo splenectomy or be treated with TPO-RAs? The ASH guideline panel suggests either splenectomy or TPO-RAs in adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids. (Conditional recommendation, very low certainty in the evidence about effects) Remark: Due to the differences in treatment modalities, patient education and shared decision making is encouraged. Patients who value avoidance of long-term medication may prefer splenectomy. Patients who wish to avoid surgery may prefer TPO-RAs. Question 8: Should adults with ITP lasting 3 months who are corticosteroid-dependent or unresponsive to corticosteroids undergo splenectomy or be treated with rituximab? The ASH guideline panel suggests for rituximab rather than splenectomy in adults with ITP lasting > 3 months who are corticosteroid-dependent or have no response to corticosteroids. (Conditional recommendation, very low certainty in the evidence about effects) Question 9: Should adults with ITP lasting 3 months who are corticosteroid-dependent or unresponsive to corticosteroids be treated with rituximab or TPO-RAs? The ASH guideline panel suggests for TPO-RAs rather than rituximab in adults with ITP lasting > 3 months who are corticosteroid-dependent or have no response to corticosteroids. (Conditional recommendation, very low certainty in the evidence about effects) Question 11A: Should children with ITP and a platelet count <20 x 10 9 /l and no or minor bleeding only be treated as an outpatient or be admitted to the hospital? The ASH guideline panel suggests against admission to the hospital rather than treatment as an outpatient in children with newly diagnosed ITP and a platelet count <20 x 10^9 /l and no or minor bleeding only (Conditional recommendation, very All materials are copyright American Society of Hematology

3 low certainty in the evidence about effects) Remark: Best practice is to have patients seen by pediatric hematologist (or team of specialists who deal with ITP) within 1-2 days and to review the peripheral blood smear. Question 11B: Should children with ITP and a platelet count 20 x 10 9 /l and no or minor bleeding only be treated as an outpatient or be admitted to the hospital? The ASH guideline panel suggests against admission to the hospital in children rather than treatment as an outpatient in children with ITP and a platelet count 20 x 10 9 /l and no or minor bleeding only. (Conditional recommendation, very low certainty in the evidence about effects) Question 12: Should children with newly diagnosed ITP and no or minor bleeding be treated with observation or corticosteroids for initial therapy? The ASH guideline panel suggests observation rather than corticosteroids in children with newly diagnosed ITP and no or minor bleeding for initial therapy. (Conditional recommendation, very low certainty in the evidence about effects) Question 13: Should children with newly diagnosed ITP and no or minor bleeding be treated with observation of IVIg? The ASH guideline panel recommends against IVIG rather than observation in children with newly diagnosed ITP and no or minor bleeding. (Strong recommendation, very low certainty in the evidence about effects) Question 14: Should children with newly diagnosed ITP and no or minor bleeding be treated with observation or anti-d immunoglobulin for initial therapy? The ASH guideline panel recommends for observation rather than anti-d immunoglobulin in children with newly diagnosed ITP and no or minor bleeding for initial therapy. (Strong recommendation, very low certainty in the evidence about effects) Question 15: Should children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life, be treated with anti-d immunoglobulin or corticosteroids for initial therapy? The ASH guideline panel recommends for observation rather than anti-d immunoglobulin in children with newly diagnosed ITP and no or minor bleeding for initial therapy. (Strong recommendation, very low certainty in the evidence about effects) Question 16: Should children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life, receive IVIg or anti-d immunoglobulin for initial therapy? The ASH guideline panel suggests either IVIg or anti-d immunoglobulin in children with newly diagnosed ITP and non-lifethreatening mucosal bleeding and/or diminished health related quality of life. (Conditional recommendation, low certainty in the evidence about effects) Question 17: Should children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life receive a course of corticosteroids longer or shorter than 7 days? The ASH guideline panel recommends against a longer course of corticosteroids rather than shorter than 7 days in children with newly diagnosed ITP who require drug therapy. (Strong recommendation, moderate certainty in the evidence about effects) Question 18: Should children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life receive dexamethasone (0.6mg/kg/day for 4 days every 4 weeks) or prednisone (2-4mg/kg/day x 5-7 days) as the type of corticosteroid? The ASH guideline panel suggests prednisone (2-4 mg/kg/day x 5-7 days) rather than dexamethasone (0.6 mg/kg/day x 4 days every 4 weeks) in children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life. (Conditional recommendation, very low certainty in the evidence about effects) Question 19a: Should children with ITP who are responsive to first-line treatment be treated with TPO-RAs or rituximab? All materials are copyright American Society of Hematology

4 The ASH guideline panel suggests for TPO-RAs rather than rituximab in children with ITP who are unresponsive to first-line treatment. (Conditional recommendation, very low certainty in the evidence about effects) Remark: The panel placed high value on avoiding immunosuppression. Question 19b: Should children with ITP who are responsive to first-line treatment be treated with TPO-RAs or splenectomy? The ASH guideline panel suggests for TPO-RAs rather than splenectomy in children with ITP who are unresponsive to firstline treatment. (Conditional recommendation, very low certainty in the evidence about effects) Question 19c: Should children with ITP who are responsive to first-line treatment be treated with rituximab or splenectomy? The ASH guideline panel suggests for rituximab rather than splenectomy in children with ITP who are unresponsive to firstline treatment. (Conditional recommendation, very low certainty in the evidence about effects) Question 20: Should children with newly diagnosed ITP and non-life-threatening-mucosal bleeding and/or diminished health related quality of life be treated with IVIg or corticosteroids? The ASH guideline panel suggests for corticosteroids rather than IVIG in children with newly diagnosed ITP and non-lifethreatening mucosal bleeding and/or diminished health related quality of life. (Conditional recommendation, very low certainty in the evidence about effects) All materials are copyright American Society of Hematology

5 QUESTION Should corticosteroids vs. observation be used for adults with newly diagnosed ITP and a platelet count <30 x 10^9 /l who are asymptomatic or with minor mucocutaneous bleeding (Q1a)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with newly diagnosed ITP and a platelet count <30 x 10^9 /l who are asymptomatic or with minor mucocutaneous bleeding (Q1a) corticosteroids observation Major bleeding; Mortality; Overall health-related quality of life; Remission; Moderate to severe depression; Minor bleeding; SETTING: Study inclusion: All RCTs; all prospective of at least 50 patients (adults). PERSPECTIVE: BACKGROUND: Significant thrombocytopenia is a common finding in adult patients with newly diagnosed ITP. The exact platelet count threshold for considering a patient at increased risk for bleeding is not established, however a platelet count < 30 x10 9 /l is generally thought be clinically important. The decision to treat a patient with only minor bleeding and a platelet count < 30 x10 9 /l is based on a presumed increased risk of subsequent bleeding. In addition, providing therapy upfront with corticosteroids may be able to reduce the likelihood of developing chronic disease. The true impact of corticosteroid treatment compared to no treatment in this population is not known. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Asymptomatic or minor mucocutaneous bleeding (skin bleeding) added to the question; steroids moderate response in 7 days no QOL data - no remission data - no major bleeding - we believe minor bleeding symptoms will improve. Undesirable Effects

6 How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Based on clinical experience and the data. Moderate (maybe high for 7 day response) moderate for side effects (no certainty of remission). Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Different variability in the value of QOL (steroid side effect). Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison?

7 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Probably favors steroids. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Prednisone dose range is 0.5 mg/kg/d - 2 mg/kg/d for 30 days for a 70 kg adult. Cost ranges from $ $52.00 based on data from LexiComp Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

8 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Acceptability Is the acceptable to key stakeholders?

9 No Probably no Probably yes Yes Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

10 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests for corticosteroids rather than observation in adults with newly diagnosed ITP and a platelet count <30 x 10^9/l who are asymptomatic or with minor mucocutaneous bleeding. Conditional recommendation based on moderate certainty in the evidence about effects. Justification Subgroup considerations Treatment may be different between platelet count 2,000 vs 28,000. Considerations for other factors such as age and symptoms. Implementation considerations

11 Monitoring and evaluation Research priorities

12 QUESTION Should corticosteroids vs. observation be used for adults with newly diagnosed ITP and a platelet count > or equal to 30 x 10^9 /l who are asymptomatic or with minor mucocutaneous bleeding (Q1b)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with newly diagnosed ITP and a platelet count 30 x 10^9 /l who are asymptomatic or with minor mucocutaneous bleeding (Q1b) corticosteroids observation Response within 7 days; Remission; Major bleeding; Mortality; Overall health-related quality of life; SETTING: Study inclusion: All RCTs; all prospective of at least 50 patients (adults). PERSPECTIVE: BACKGROUND: Adult patients with newly diagnosed ITP may present with mild thrombocytopenia. In addition, the majority of these patients will have no or mild mucocutaneous bleeding only. For patients with a platelet count 30 x 10 9 /l the risk of subsequent bleeding without treatment is thought by low in absence of additional comorbidities. There are known side effects of corticosteroid therapy, however the possible benefits of treating this patient population with corticosteroids is not known. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Don't know See GRADE evidence table for one-armed observational data. Data for patients with platelet count <= 30,000 is lacking. Undesirable Effects How substantial are the undesirable anticipated effects?

13 Large Moderate Small Trivial See GRADE evidence table for one-armed observational data Steroid side effects are moderate compared to observation; panel discussed whether the side effects were moderate or large but since the side effects are not life threatening the panel voted for moderate undesirable effects. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability If steroids are unnecessary then they are not desired. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison?

14 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Favors observation. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Prednisone dose range is 0.5 mg/kg/d - 2 mg/kg/d for 30 days for a 70 kg adult. Cost ranges from $ $52.00 based on data from LexiComp. Cost is not driving decision; steroids are inexpensive. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

15 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Acceptability Is the acceptable to key stakeholders?

16 No Probably no Probably yes Yes If platelet count about 30,000 then more acceptable. In newly diagnosed patients, the fear of bleeding might influence the patient's acceptability of steroid use. Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

17 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel recommends observation rather than corticosteroids in adults with newly diagnosed ITP and a platelet count 30 x 10^9 /l who are asymptomatic or with minor mucocutaneous bleeding. Strong recommendation based on very low certainty in the evidence about effects. (# 3 high quality data on harm and low quality evidence suggest equivalence of observation and corticosteroids) Justification Subgroup considerations Considerations for patients taking other medications such aspirin. Considerations for older patients.

18 Implementation considerations Healthcare provider may choose to administer steroids as a diagnostic tool. Monitoring and evaluation Research priorities

19 Author(s): OU Sooner GRADE Team Date: August 2017 Question: Corticosteroids compared to observation in adults with newly diagnosed ITP and a platelet count 30 x 10^9 /l who are asymptomatic or with minor mucocutaneous bleeding (Q1b) Setting: Study inclusion: All RCTs; all prospective of at least 50 patients (adults). Bibliography: Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations corticosteroids observation Relative (95% CI) Absolute (95% CI) Certainty Importance Response within 7 days 2 1,2 observational studies a not serious serious b serious c serious d none 48/76 (63.2%) not estimable e VERY LOW Remission 4 2,3,4,5 observational studies a serious f,g serious h serious c,i serious d none 26/109 (23.9%) 109/152 (71.7%) not estimable j VERY LOW Major bleeding 4 2,3,4,5 observational studies a serious f serious k serious c serious d none 1/111 (0.9%) 0/152 (0.0%) not estimable l VERY LOW Mortality 3 3 observational studies a serious f not serious serious c serious d none 0/62 (0.0%) not estimable m VERY LOW Overall health-related quality of life - not reported CI: Confidence interval

20 Explanations a. Response within 7 days: Steroids: 1 RCTs, 1 prospective study; Observation: No studies; Remission: Steroids: 2 prospective studies; Observation: 2 retrospective studies; Major bleeding: Steroids: 1 RCTs, 1 prospective studies; Observation: 2 retrospective studies; Mortality: Steroids: No studies; Observation: 1 retrospective studies b. No studies evaluating observation therefore no estimate of effects for observation c. Evaluating one armed observational studies so not reporting any clinical studies directly comparing observation and steroids d. No relative effect calculated between observation and steroids (therefore no confidence interval) e. Response within 7 days: Steroids: pooled estimate is 61% (95% CI 44-76%) [studies range from 43% to 65% f. Studies evaluating 'observation' are largely retrospective chart reviews with concerns about selection bias and measurement of outcomes g. Evaluating one arm observational studies therefore not reporting any clinical studies directly comparing observation and steroids h. Confidence intervals within an arm do not overlap i. Remission definition not as defined by panel j. Remission: Steroids: pooled estimate is 26% (95% CI 14-43%) [studies range from 23% to 43%]; Observation: pooled estimate is 72% (95% CI 29-94%) [studies range from 50% to 87%] k. Point estimates for one arm variable l. Major bleeding: Steroids: studies range from 0% to 11% m. Mortality: Observation: 1 study range 0% References 1. Mazzucconi, M. G., Francesconi, M., Fidani, P., Di Nucci, G., Gandolfo, G. M., Afeltra, A., Masala, C., Di Prima, M., Rocchi, G., Resta, S., et al.,. Treatment of idiopathic thrombocytopenic purpura (ITP): results of a multicentric protocol. Haematologica; Jul-Aug Matschke, J., Muller-Beissenhirtz, H., Novotny, J., Vester, I., Hertenstein, B., Eisele, L., Lax, H., Ose, C., Duhrsen, U.. A Randomized Trial of Daily Prednisone versus Pulsed Dexamethasone in Treatment-Naive Adult Patients with Immune Thrornbocytopenia: EIS 2002 Study. Acta Haematologica; Zimmer, J., Andres, E., Noel, E., Koumarianou, A., Blickle, J. F., Maloisel, F.. Current management of adult idiopathic thrombocytopenic purpura in practice: a cohort study of 201 patients from a single center. Clinical & Laboratory Haematology; Apr Bizzoni, L., Mazzucconi, M. G., Gentile, M., Santoro, C., Bernasconi, S., Chiarotti, F., Foa, R., Mandelli, F.. Idiopathic thrombocytopenic purpura (ITP) in the elderly: clinical course in 178 patients. European Journal of Haematology; Mar Centurioni, R., Braianzoni, F., Olivieri, A., Rupoli, S., DaLio, L., Montillo, M., D'Addezio, E., Leoni, P.. Treatment of autoimmune thrombocytopenic purpura. Acta Haematologica Polonica; Jul-Dec 1990.

21 QUESTION Should treatment as an outpatient vs. admission to the hospital be used for adults with newly diagnosed ITP and a platelet count <20 x 10^9 /l and no or mild mucocutaneous bleeding (Q2a - initial presentation)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with newly diagnosed ITP and a platelet count <20 x 10^9 /l and no or mild mucocutaneous bleeding (Q2a - initial presentation) treatment as an outpatient admission to the hospital Major bleeding; Mortality; Overall health-related quality of life; Minor bleeding; SETTING: PERSPECTIVE: BACKGROUND: Adults with ITP may present with significant thrombocytopenia (< 20 x 10 9 /l) in the absence of significant bleeding. At this time the patient may be seen either by a primary care physician or emergency room physician without hematology consultation. At the time of initial presentation with ITP the role of admission is not clear. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Newly diagnosed/previously undiagnosed. Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Survey was administered to adult providers on the panel (5 of 8 responded). Limitations of the survey data include recall bias, answering for self vs whole practice. Previously undiagnosed patients (initial presentation). The panelist note that they do not often make the decision of hospitalization up front. Usually they are consulted the following day after the ER physician or general hematologist has already admitted the patient. So the data and following recommendations must be viewed with that in mind.

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24 Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial See data in Desirable Effects. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Survey data only. Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Some patients more adverse to hospital admission than others. Balance of effects

25 Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Intervention is in the hospital - comparison is outpatient; probably favors hospitalization. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Hospitalization vs outpatient. Certainty of evidence of required resources

26 What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Varies Differences based on health care coverage and country. Acceptability

27 Is the acceptable to key stakeholders? No Probably no Probably yes Yes Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies

28 JUDGEMENT COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests admission to the hospital rather than treatment as an outpatient in adults with newly diagnosed ITP and a platelet count <20 x 10^9 /l and no or mild mucocutaneous bleeding. Conditional recommendation based on very low certainty in the evidence about effects. Justification Subgroup considerations

29 Implementation considerations Monitoring and evaluation Research priorities

30 QUESTION Should treatment as an outpatient vs. admission to the hospital be used for adults with established ITP and a platelet count <20 x 10^9 /l and no or mild mucocutaneous bleeding only(q2a)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with established ITP and a platelet count <20 x 10^9 /l and no or mild mucocutaneous bleeding only(q2a) treatment as an outpatient admission to the hospital Major bleeding; Mortality; Overall health-related quality of life; Minor bleeding; SETTING: PERSPECTIVE: BACKGROUND: Patients with ITP may experience changes in the platelet count over time. When following a patient with known ITP there may be times in which the patient experiences the onset of significant thrombocytopenia (< 20 x 10 9 /l) in the absence of significant bleeding. In the setting in which the physician has established relationship with the patient the role of admission during times of significant thrombocytopenia is not clear. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Established ITP patient (after initial presentation). Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large There is a trivial benefit for hospitalization; improved quality of life for being at home; undesirable effects small for hospitalization. Undesirable Effects How substantial are the undesirable anticipated effects?

31 Large Moderate Small Trivial Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Most patients would not want to be hospitalized. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison?

32 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Intervention is hospitalization and the comparison is outpatient care. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Large costs for hospitalization. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

33 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Varies Depends on health insurance and country of residence. Acceptability Is the acceptable to key stakeholders?

34 No Probably no Probably yes Yes Most patients would not want to be hospitalized. Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

35 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests against admission to the hospital rather than treatment as an outpatient in adults with established ITP and a platelet count <20 x 10^9 /l and no or mild mucocutaneous bleeding only. Conditional recommendation based on very low certainty in the evidence about effects. Justification Subgroup considerations

36 Implementation considerations Decision to hospitalize will vary depending on patient platelet count, distance from facility, bleeding history, reliability, social support, close access to health care. Monitoring and evaluation Research priorities

37 QUESTION Should treatment as an outpatient vs. admission to the hospital be used for adults with a platelet count 20 x 10^9 /l and no or mild mucocutaneous bleeding (Q2b)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with a platelet count 20 x 10^9 /l and no or mild mucocutaneous bleeding (Q2b) treatment as an outpatient admission to the hospital Major bleeding; Mortality; Overall health-related quality of life; Minor bleeding; SETTING: PERSPECTIVE: BACKGROUND: CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Both established patients and patients with a new diagnosis (initial presentation and after initial presentation). Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Survey was administered to adult providers on the panel (5 of 8 responded). Limitations of the survey data include recall bias, answering for self vs whole practice. Hospitalization benefit is trivial; undesirable effect is small for hospitalization.

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40 Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability Patients feel differently about hospitalization.

41 No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Favors outpatient treatment. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Hospitalization has a large cost. Certainty of evidence of required resources

42 What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Varies Based on health insurance and country of residence. Acceptability

43 Is the acceptable to key stakeholders? No Probably no Probably yes Yes Varies Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies

44 JUDGEMENT COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests against admission to the hospital rather than treatment as an outpatient in adults with newly diagnosed ITP and a platelet count 20 x 10^9 /l and nor mild mucocutaneous bleeding. Conditional recommendation based on very low certainty in the evidence about effects. Justification Subgroup considerations

45 Implementation considerations Treating patients as outpatient is reasonable with expedited outpatient hematology follow-up. Decision to hospitalize may vary based on comorbidities, distance, social support, concomitant medications, access to care, history of compliance, platelet count, and bleeding history. Monitoring and evaluation Research priorities

46 QUESTION Should a short course ( 6 weeks) vs. prolonged continuous use (including treatment and taper) of prednisone for initial therapy be used for adults with newly diagnosed ITP (Q3)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with newly diagnosed ITP (Q3) a short course ( 6 weeks) prolonged continuous use (including treatment and taper) of prednisone for initial therapy Major bleeding; Overall health-related quality of life; Remission; Infection; Diabetes; Mortality; Durable response; SETTING: Study inclusion: All RCTs; all prospective of at least 50 patients (adults). PERSPECTIVE: BACKGROUND: Standard first-line therapy for adults with newly diagnosed ITP who require treatment is corticosteroids. Despite extensive use for ITP, the exact duration of corticosteroid therapy has not been established. The potential benefits of longer courses of corticosteroids must be weighed against the increased side effects. The impact of the duration of corticosteroid therapy on important patient-related outcomes such as bleeding rates, remission, and key side effects is not known. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Survey was administered to adult providers on the panel (5 of 8 responded). Limitations of the survey data include recall bias, answering for self vs whole practice. Trivial for desirable - for long vs short steroids - long has large undesirable effects.

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49 Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Survey was administered to adult providers on the panel (5 of 8 responded). Limitations of the survey data include recall bias, answering for self vs whole practice.

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51 Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Moderate based on experience. Values Is there important uncertainty about or variability in how much people value the main outcomes?

52 Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Shorter course has less toxicity than a longer course. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Favors a shorter course rather than a longer course. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Prednisone dose range is 0.5 mg/kg/d - 2 mg/kg/d for 30 days for a 70 kg adult. Cost ranges from $ $52.00 based on data from LexiComp.

53 Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison?

54 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Some countries may not have other treatment options beyond steroids, so it may be necessary to continue steroids at a low dose for a longer duration. Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes After 6 weeks the steroids are unacceptable (1-2 months), although acceptability may vary based on steroid dose. Feasibility Is the feasible to implement? No Probably no Probably yes Yes May begin to encounter patient adherence issues with long term use.

55 SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS

56 Recommendation The ASH guideline panel recommends against prolonged continuous use (including treatment and taper) of prednisone rather than a short course ( 6 weeks) for initial therapy in adults with newly diagnosed ITP. Strong recommendation based on very low certainty in the evidence about effects. (# 3 paradigmatic situation; high quality data on harm from prolonged corticosteroid use and low quality evidence suggest equivalence of prolonged and short course corticosteroid use). Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research priorities

57 QUESTION Should dexamethasone (40 mg/day x 4 days) vs. prednisone (0.5-2 mg/kg/day) be used for adults with newly diagnosed ITP as the type of corticosteroid for initial therapy (Q4)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with newly diagnosed ITP as the type of corticosteroid for initial therapy (Q4) dexamethasone (40 mg/day x 4 days) prednisone (0.5-2 mg/kg/day) Response 7 days; Response 1 month; Durable Response; Remission (plt count >100K at 12 months; Major Bleeding; Overall health-related quality of life; SETTING: Study inclusion: All RCTs; all prospective studies of at least 50 patients (adults). PERSPECTIVE: BACKGROUND: The ASH 2011 guidelines recommended longer courses of steroids (e.g., prednisone 1mg/kg orally for 21 days then tapered) shorter courses of steroids (e.g., dexamethasone 40mg orally for 4 days). At that time there were two cohort studies on short courses of dexamethasone both without a comparator group and with significant study limitations. These two studies, alongside others, peaked interest in the use of dexamethasone suggesting possible higher remission rates. More extensive data on this comparison has since been published. The impact of corticosteroid selection on important patient-related outcomes remains unknown. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects?

58 Trivial Small Moderate Large Outcomes of participants (studies) Follow up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects * (95% CI) Risk with prednisone (0.5-2 mg/kg/day) Risk difference with dexamethasone (40 mg/day x 4 days) Lack of bleeding is included as a desirable outcome. Response 7 days 186 (3 RCTs) 1,2,3 HIGH a RR 1.31 (1.11 to 1.54) Study population 558 per 1, more per 1,000 (61 more to 302 more) Response 1 month 247 (3 RCTs) 2,4,5 MODERATE a,b RR 0.96 (0.82 to 1.13) Study population 766 per 1, fewer per 1,000 (138 fewer to 100 more) Durable Response 481 (5 observational studies) 1,2,4,5,6 VERY LOW c RR 1.26 (0.85 to 1.86) Study population 404 per 1, more per 1,000 (61 fewer to 348 more) Remission (plt count >100K at 12 months 364 (4 RCTs) 1,2,4,6 MODERATE a,d RR 2.96 (1.03 to 8.45) Study population 242 per 1, more per 1,000 (7 more to 1,806 more) Major Bleeding 250 (3 RCTs) 3,4,6 MODERATE a,c RR 0.56 (0.31 to 1.02) Study population 210 per 1, fewer per 1,000

59 (145 fewer to 4 more) Overall healthrelated quality of life - not reported Mashhadi, M. A., Kaykhaei, M. A., Sepehri, Z., Miri-Moghaddam, E.. Single course of high dose dexamethasone is more effective than conventional prednisolone therapy in the treatment of primary newly diagnosed immune thrombocytopenia. DARU, Journal of Pharmaceutical Sciences; Din, Banhe, Wang, Xingwen, Shi, Yuye, Li, Yufeng. Long-term effect of highdose dexamethasone with or without low-dose dexamethasone maintenance in untreated immune thrombocytopenia. Acta Haematologica; Praituan, W., Rojnuckarin, P.. Faster platelet recovery by high-dose dexamethasone compared with standard-dose prednisolone in adult immune thrombocytopenia: a prospective randomized trial. Journal of Thrombosis & Haemostasis; Jun Matschke, J., Muller-Beissenhirtz, H., Novotny, J., Vester, I., Hertenstein, B., Eisele, L., Lax, H., Ose, C., Duhrsen, U.. A Randomized Trial of Daily Prednisone versus Pulsed Dexamethasone in Treatment-Naive Adult Patients with Immune Thrornbocytopenia: EIS 2002 Study. Acta Haematologica; Bae, S. H., Ryoo, H. M., Lee, W. S., Joo, Y. D., Lee, K. H., Lee, J. H., Kith, H., Park, J. H., Kim, M. K., Hyun, M. S., Kim, H. J., Zang, D. Y.. High Dose Dexamethasone Vs. Conventional Dose Prednisolone for Adults with Immune Thrombocytopenia: a Prospective Multicenter Phase III Trial. Blood; Nov Wei, Yu, Ji, Xue-bin, Wang, Ya-wen, Wang, Jing-xia, Yang, En-qin, Wang, Zheng-cheng, Sang, Yu-qi, Bi, Zuo-mu, Ren, Cui-ai, Zhou, Fang, Liu, Guo-qiang, Peng, Jun, Hou, Ming. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood; Jan a. No clear violation of randomization or concealed allocation; single blinding in one study only - although outcomes related to platelet count may have influenced longer term outcomes if other tx given; most studies had 'complete' follow-up'; ITT used except for Matschke 2016 b. Confidence intervals do not exclude thresholds for plausible benefit or harm c. Wide confidence intervals that do not exclude thresholds for plausible benefit or harm d. Only 1 study reported remission using platelet count of 100 K; 2 other reported platelet count of 30 K Undesirable Effects How substantial are the undesirable anticipated effects?

60 Large Moderate Small Trivial Varies Based on the opinion of the panel the undesirable effects depends on dosage, duration, population, how quick the response is needed, and intensity of side effects. Very low Low Moderate High No included studies Different definitions of remission, different dosing regimens, no data on QOL. Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability For newly diagnosed patients we noted no important variability but thought there would be important variability for patients with chronic disease. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison?

61 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Small effect with very low evidence however due to the variability of undesirable effects, the panel decided that the balance does not favor either dexamethasone or prednisone. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Prednisone dose range is 0.5 mg/kg/d - 2 mg/kg/d for 30 days for a 70 kg adult. Cost ranges from $ $52.00 based on data from LexiComp. Dexamethasone dose range is 40 mg/d for 4 days for 1-2 cycles. Cost ranges from $ $51.20 based on data from LexiComp. Based on data from LexiComp, the panel thought there would be negligible costs and savings based on whether dexamethasone or prednisone was used. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

62 Very low Low Moderate High No included studies LexiComp data; panel's experience. Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Acceptability Is the acceptable to key stakeholders?

63 No Probably no Probably yes Yes There may be a physician preference based on patient availability for follow-up in the clinic. Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

64 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests either dexamethasone (40 mg/day x 4 days) or prednisone (0.5-2 mg/kg/day) in adults with newly diagnosed ITP as the type of corticosteroid for initial therapy. Conditional recommendation based on very low certainty in the evidence about effects. If a high value is placed on rapidity of platelet count response over concerns for potential side-effects of dexamethasone then an initial course of dexamethasone over prednisone may be preferred. Justification 3 of 16 panel members voted that the recommendation be for conditional for dexamethasone as compared to prednisone. 13 of 16 voted that the recommendation be for conditional for either dexamethasone or prednisone. Subgroup considerations Some panelists expressed concern about using dexamethasone in persons with diabetes and the elderly. Implementation considerations

65 The optimal dosage has not been determined. Value of exposure of corticosteroids beyond 30 days is unknown and must be weighed against the known side effects of prolonged corticosteroid exposure. For these reasons the panel recommended against prolonged high cumulative doses of either corticosteroid is discouraged. Monitoring and evaluation Duration of response to initial therapy is highly variable and should be closely monitored. Platelet count, blood pressure, urine glucose, assessment of health-related quality of life. Research priorities RCTs of dexamethasone vs prednisone with thorough assessment of side effects (including blood pressure and bone density) and quality of life and proper controlled dosing regimens.

66 QUESTION Should rituximab and corticosteroids vs. corticosteroids alone for initial therapy be used for adults with newly diagnosed ITP (Q5)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with newly diagnosed ITP (Q5) rituximab and corticosteroids corticosteroids alone for initial therapy Response 1 month; Durable Response; Remission; Major bleeding; Mortality; Infection; Overall health-related quality of life; SETTING: Study inclusion: All RCTs; all prospective studies of at least 50 patients (adults). PERSPECTIVE: BACKGROUND: Rituximab, a monoclonal CD20 antibody, was first investigated in patients with chronic and/or refractory ITP. Initial studies in these patient populations suggested that rituximab demonstrated greater efficacy if given earlier in the course of ITP. This combined with high relapse rates in adults with ITP following initial therapy with corticosteroids lead to interest in applying rituximab in combination with corticosteroids as initial treatment for patients with newly diagnosed ITP. The aim of this treatment approach is to induce higher remission rates, however the impact on other important patient-related outcomes and cost of care is not known. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Moderate desirable effects for rituximab and corticosteroids together.

67 Outcomes of participants (studies) Follow up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects * (95% CI) Risk with corticosteroids alone for initial therapy Risk difference with rituximab and corticosteroids Response 1 month 163 (2 RCTs) 1,2 LOW a,b RR 0.98 (0.71 to 1.35) Study population 566 per 1, fewer per 1,000 (164 fewer to 198 more) Durable Response 296 (3 RCTs) 1,2,3 HIGH RR 1.70 (1.34 to 2.16) Study population 377 per 1, more per 1,000 (128 more to 437 more) Remission 104 (1 RCT) 1 MODERATE a RR 1.58 (1.00 to 2.52) Study population 333 per 1, more per 1,000 (0 fewer to 507 more) Major bleeding 296 (3 RCTs) 1,2,3 MODERATE c RR 3.12 (0.63 to 15.54) Study population 6 per 1, more per 1,000 (2 fewer to 94 more) Mortality 234 (2 RCTs) 2,3 MODERATE c RR 0.38 (0.04 to 3.58) Study population 24 per 1, fewer per 1,000

68 (23 fewer to 63 more) Infection 163 (2 RCTs) 1,2 MODERATE c RR 3.18 (0.13 to 76.25) Study population 0 per 1,000 0 fewer per 1,000 (0 fewer to 0 fewer) Overall healthrelated quality of life - not reported Li, Zhenyu, Mou, Weiwei, Lu, Guang, Cao, Jiang, He, Xupeng, Pan, Xiuying, Xu, Kailin. Low-dose rituximab combined with short-term glucocorticoids upregulates Treg cell levels in patients with immune thrombocytopenia. International Journal of Hematology; Jan Zaja, Francesco, Baccarani, Michele, Mazza, Patrizio, Bocchia, Monica, Gugliotta, Luigi, Zaccaria, Alfonso, Vianelli, Nicola, Defina, Marzia, Tieghi, Alessia, Amadori, Sergio, Campagna, Selenia, Ferrara, Felicetto, Angelucci, Emanuele, Usala, Emilio, Cantoni, Silvia, Visani, Giuseppe, Fornaro, Antonella, Rizzi, Rita, De Stefano, Valerio, Casulli, Francesco, Battista, Marta Lisa, Isola, Miriam, Soldano, Franca, Gamba, Enrica, Fanin, Renato. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood; Apr Gudbrandsdottir, Sif, Birgens, Henrik Sverre, Frederiksen, Henrik, Jensen, Bjarne Anker, Jensen, Morten Krogh, Kjeldsen, Lars, Klausen, Tobias Wirenfeldt, Larsen, Herdis, Mourits-Andersen, Hans Torben, Nielsen, Claus Henrik, Nielsen, Ove Juul, Plesner, Torben, Pulczynski, Stanislaw, Rasmussen, Inge Helleberg, Ronnov-Jessen, Dorthe, Hasselbalch, Hans Carl. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia. Blood; Mar a. Li paper includes 21/62 patients resistant to 1 and/or 3 different treatments so not acute treatment naive patients b. Confidence intervals do not exclude thresholds for plausible benefit or harm c. Wide confidence intervals that do not exclude thresholds for plausible benefit or harm Undesirable Effects How substantial are the undesirable anticipated effects?

69 Large Moderate Small Trivial More adverse events in rituximab and corticosteroid combination but not severe. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Missing health related quality of life. Two RCTs were not included since most patients were not treatment naive/newly diagnosed. Arnold et al in Blood 2012: 53% (32/60) of included patients had relapsed. Ghanima et al in Lancet 2015: 63% (79/109) of patients had persistent (3-12 months) or chronic (>12 months) ITP (therefore not newly diagnosed (0-3 months). Also 51% (56/109) of patients had been previously treated with corticosteroids. Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison?

70 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Prednisone dose range is 0.5 mg/kg/d - 2 mg/kg/d for 30 days for a 70 kg adult. Cost ranges from $ $52.00 based on data from LexiComp. Rituxan 375 mg/m2 weekly x 4 doses assuming a 2 meters squared adult. The cost is $31,266 based on data from LexiComp. Dexamethasone dose range is 40 mg/d for 4 days for 1-2 cycles. Cost ranges from $ $51.20 based on data from LexiComp. Costs may vary for different by country. US data. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

71 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Some groups may not have access to rituximab such as rural patients, international countries, patients with poor insurance coverage. Acceptability Is the acceptable to key stakeholders?

72 No Probably no Probably yes Yes Patients may view rituximab as a chemotherapy. Feasibility Is the feasible to implement? No Probably no Probably yes Yes The panel agreed that the major barrier is payment for the rituximab. SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

73 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests for corticosteroids alone rather than rituximab and corticosteroids for initial therapy in adults with newly diagnosed ITP. Conditional recommendation based on very low certainty in the evidence about effects. Justification 13 for coniditional against rituximab and corticosteroids/conditional for corticosteroids only 3 for conditional either Subgroup considerations

74 Implementation considerations If patients place higher value on 6-12 month response rather than risks and costs then rituximab and corticosteroids can be considered. Monitoring and evaluation Research priorities

75 QUESTION Should eltrombopag vs. romiplostim be used for an adult with ITP who is corticosteroid-dependent or unresponsive to corticosteroids and is going to be treated with a TPO-RA (Q6)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: an adult with ITP who is corticosteroid-dependent or unresponsive to corticosteroids and is going to be treated with a TPO-RA (Q6) eltrombopag romiplostim Durable response [Cooper 2012, Cooper 2014]; Major bleeding - romiplostin vs placebo [Wang 2016]; Major bleeding - eltrombopag vs placebo [Wang 2016]; Reduction or discontinuation of corticosteroids - romiplostin vs placebo [Wang 2016]; Reduction or discontinuation of corticosteroids - eltromobopag vs placebo [Wang 2016]; Mortality; Remission; Overall health-related quality of life; SETTING: Study Inclusion: Systematic Reviews PERSPECTIVE: Thrombopoietin-receptor agonists (TPO-RAs) induce platelet production by interacting with the TPO receptor on the megakaryocyte surface. There are currently two FDA approved TPO-RAs for the treatment of adults with chronic ITP. Eltrombopag is a once daily oral medication and romiplostim is a once weekly subcutaneous injection. No randomized trial has compared these two agents and therefore it remains unclear if there is any benefit one agent over the other with regards to important patient-related outcomes. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large

76 Outcomes of participants (studies) Follow up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects * (95% CI) Risk with romiplostim Risk difference with eltrombopag Durable response [Cooper 2012, Cooper 2014] 218 (2 RCTs) 1,2 LOW a,b OR 0.20 (0.01 to 2.13) Study population 494 per 1, fewer per 1,000 (484 fewer to 181 more) Major bleeding - romiplostin vs placebo [Wang 2016] 302 (1 RCT) 3 LOW c,d RR 0.64 (0.31 to 1.35) Study population 56 per 1, fewer per 1,000 (39 fewer to 20 more) Major bleeding - eltrombopag vs placebo [Wang 2016] 180 (1 RCT) 3 LOW c,d RR 0.27 (0.07 to 1.00) Study population 0 per 1,000 0 fewer per 1,000 (0 fewer to 0 fewer) Reduction or discontinuation of corticosteroids - romiplostin vs placebo [Wang 2016] 23 (1 RCT) 3 LOW c,d RR 2.32 (1.21 to 4.45) Study population 870 per 1,000 1,148 more per 1,000 (183 more to 3,000 more) Reduction or discontinuation of corticosteroids - eltromobopag 63 (1 RCT) 3 LOW c,d RR 1.82 (1.05 to 3.16) Study population 0 per 1,000 0 fewer per 1,000 (0 fewer to 0 fewer)

77 vs placeo [Wang 2016] Mortality - not reported Remission - not reported Overall healthrelated quality of life - not reported Cooper, Katy, Matcham, James, Helme, Kawitha, Akehurst, Ron. Update on romiplostim and eltrombopag indirect comparison. International Journal of Technology Assessment in Health Care; Jan Cooper, Katy L., Fitzgerald, Patrick, Dillingham, Kerry, Helme, Kawitha, Akehurst, Ron. Romiplostim and eltrombopag for immune thrombocytopenia: methods for indirect comparison. International Journal of Technology Assessment in Health Care; Jul Wang, L., Gao, Z., Chen, X. P., Zhang, H. Y., Yang, N., Wang, F. Y., Guan, L. X., Gu, Z. Y., Zhao, S. S., Luo, L., Wei, H. P., Gao, C. J.. Efficacy and safety of thrombopoietin receptor agonists in patients with primary immune thrombocytopenia: A systematic review and meta-analysis. Scientific Reports; Dec a. For both agents while on treatment. For eltrombopag platelets , 000 for at least 6 of the last 8 weeks of treatment, excluding premature withdrawals and patients using rescue therapy at any time on treatment; For romiplostim the percentage of patients with platelet count >=50,000 at least 6 of the last 8 weeks of treatment, with no rescue medications at any time during the trial; Indirect comparison: paper using Bayesian methodology to compare romiplostin vs eltrombopag using 2 studies of romiplostin vs placebo and 1 study of eltrombopag vs placebo b. Wide confidence intervals that do not exclude threshold for plausible benefit or harm c. Indirect comparison; no mathematical indirect comparison d. No relative effect between eltrombopag and romiplostin calculated (therefore no confidence interval) Undesirable Effects How substantial are the undesirable anticipated effects?

78 Large Moderate Small Trivial Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison?

79 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Eltromopag dose range is 25 to 75 mg for 30 days. Cost ranges from $4,845 to $13,520 based on data from LexiComp. Romiplostin dose range is 1 to 10 mgc/kg/week for 28 days for a 70 kg adult. Dosing rounding to vial size. Cost ranges from $8,256 to $33,027 based on data from LexiComp. Panel discussed that the median price is about the same for both drugs however the range of price for romiplostim is greater so there is a possibility for greater cost. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

80 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Acceptability Is the acceptable to key stakeholders?

81 No Probably no Probably yes Yes Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

82 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggest either eltrombopag or romiplostim in an adult with ITP who is corticosteroid-dependent or unresponsive to corticosteroids and is going to be treated with a TPO-RA. Conditional recommendation based on low certainty in the evidence about effects. Justification Subgroup considerations

83 Implementation considerations Romiplostim is an injection and eltrobopag is a pill so the administration is different. The drugs also have different side effects. Patient preference should be considered. Some patients respond to one and not the other so it is reasonable to try the other TPOR-RA agent if the patient did not have a response to the first TPO-RA agent. Monitoring and evaluation Research priorities

84 QUESTION Should TPO-RAs vs. splenectomy be used for adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids (Q7)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids (Q7) TPO-RAs splenectomy Response within 1 month; Durable response; Remission; Major bleeding; Reduction or discontinuation of corticosteroids; Infection; Overall health-related quality of life; Operative complications: a side effect of splenectomy; Thrombosis; SETTING: Study inclusion: All RCTs; all prospective studies of at least 50 patients (adults). For splenectomy, the 2004 Kojouri et al systematic review was used and all retrospective studies of at least 100 patients published after 2004 were included. PERSPECTIVE: BACKGROUND: Splenectomy has been the historical management for patients who either fail treatment with corticosteroids or who require ongoing corticosteroid use to maintain their platelet count. Previous appreciated risks associated with splenectomy included life-long risk for infection, operative complications, and vascular complications. These risks were balanced against high remission rates. With the development of new and novel treatments for ITP such as the TPO-RAs the role and timing of splenectomy is less clear. There are no randomized trials comparing splenectomy with the TPO-RAs and it is unknown if one treatment approach is preferred over the other with regards to important patient-related outcomes. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects?

85 Trivial Small Moderate Large See GRADE evidence table for one-armed observational data. Patients respond to both treatments and based on data it is hard to determine that one is better than the other. Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial See GRADE evidence table for one-armed observational data. Long-term data on TPO not available; risk through time not available for both treatments; operative complications only applicable for splenectomy; perhaps splenectomy has more complications (comparator) but panelist did not agree. Consensus was not reached and panel decided to leave this judgement blank. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes?

86 Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Cannot determine since undesirable effects varies/cannot be determined. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Eltromopag dose range is 25 to 75 mg for 30 days. Cost ranges from $4,845 to $13,520 based on data from LexiComp. Romiplostin dose range is 1 to 10 mgc/kg/week for 28 days for a 70 kg adult. Dosing rounding to vial size. Cost ranges from $8,256 to $33,027 based on data from LexiComp. Splenectomy: median hospital cost: $14,317 (from Hamlet, Annals of Surgery 2012). TPO-RAs are more expensive since it is an ongoing expense. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

87 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Low SES patients or patients with certain types of insurance coverage might not be able to afford TPOs. Acceptability Is the acceptable to key stakeholders?

88 No Probably no Probably yes Yes Varies Patient acceptability of long-term use of TPO-RA agents versus surgery may vary. Feasibility Is the feasible to implement? No Probably no Probably yes Yes Romiplostim currently needs administration in an office however there are dietary restrictions with eltrombopag. There are potentially insurance coverage issues and international access may vary. SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

89 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests either splenectomy or TPO-RAs in adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids. Conditional recommendation based on very low certainty in the evidence about effects. Due to the differences in treatment modalities, patient education and shared decision-making is encouraged. Patients who value avoidance of long-term medication may prefer splenectomy. Patients who wish to avoid surgery may prefer TPO-RAs. Justification Subgroup considerations

90 Implementation considerations Monitoring and evaluation Splenectomy should be delayed for 1-year post initial diagnosis. Research priorities More data on the ability of TPO-RA agents to induce long-term remissions off treatment.

91 Author(s): OU Sooner GRADE Team Date: August 2017 Question: TPO-RAs compared to splenectomy in adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids (Q7) Setting: Study inclusion: All RCTs; all prospective studies of at least 50 patients (adults). For splenectomy the 2004 Kojouri et al systematic review was used and all retrospective studies of at least 100 patients published after 2004 were included. Bibliography: Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations TPO- RAs splenectomy Relative (95% CI) Absolute (95% CI) Certainty Importance Response within 1 month 20 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 observational studies a serious b not serious serious c serious d none 448/682 (65.7%) 3342/3855 (86.7%) not estimable e VERY LOW CRITICAL Durable response 4 2,9,12,19 observational studies a serious b not serious serious c serious d none 225/356 (63.2%) 79/149 (53.0%) not estimable f VERY LOW CRITICAL Remission 6 1,6,8,10,20 observational studies a serious b serious g serious c serious d none 1017/1479 (68.8%) not estimable h VERY LOW CRITICAL Major bleeding

92 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations TPO- RAs splenectomy Relative (95% CI) Absolute (95% CI) Certainty Importance 15 2,3,5,6,7,8,9,10,11,12,13,14,15,16,19 observational studies a serious b not serious serious c serious d none 20/575 (3.5%) 72/1566 (4.6%) not estimable i VERY LOW CRITICAL Reduction or discontinuation of corticosteroids - not reported CRITICAL Infection 11 2,3,5,6,7,8,10,11,12,13,14 observational studies a serious b not serious serious c serious d none 17/247 (6.9%) 167/1677 (10.0%) not estimable j VERY LOW CRITICAL Overall health-related quality of life 3 9,13,19 observational studies a not serious serious k not serious c serious d none Three TPO studies. 1. No significant differences between the groups (TPO and placebo/standard of care). 2. Romiplostim group had significantly greater improvements in scores on symptoms, bother, activity, psychological, fear, social quality of life, and overall quality of life scale compared to standard of care group. 3. 5/8 SF-36v2 domain scores, both SF 36v2 summary scores, and the FACTTh6 score at week 26 were significantly improved from baseline VERY LOW CRITICAL Operative complications: a side effect of splenectomy

93 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations TPO- RAs splenectomy Relative (95% CI) Absolute (95% CI) Certainty Importance 9 1,2,3,5,6,8,10,14,20 observational studies a serious b serious g serious c serious d none 630/4922 (12.8%) not estimable l VERY LOW CRITICAL Thrombosis 16 2,3,5,6,7,8,9,10,12,13,14,15,16,17,18,19 observational studies a not serious not serious serious c serious d none 15/606 (2.5%) 36/1526 (2.4%) not estimable m VERY LOW CRITICAL CI: Confidence interval Explanations a. 1 month response: Splenectomy: 1 systematic review and 10 retrospective studies; TPO: 8 RCTs, 1 open-label; Durable response: Splenectomy: 1 retrospective study; TPO: 2 RCTs, 1 open-label; Remission: Splenectomy: 1 systematic review and 5 retrospective studies; TPO: No studies; Major bleeding: Splenectomy: 8 retrospective studies; TPO: 6 RCTs, 1 open-label; Infection: Splenectomy: 8 retrospective studies; TPO: 3 RCTs; Thrombosis: Splenectomy: 8 retrospective studies; TPO: 7 RCTs, 1 open-label; Operative complications: Splenectomy: 1 systematic review and 8 retrospective studies; TPO: No studies/na; QOL: Splenectomy: No studies; TPO: 3 RCTs b. Splenectomy studies are largely retrospective chart reviews with concerns about selection bias and measurement of outcomes c. No clinical trials directly comparing splenectomy and TPOs d. No relative effect calculated between splenectomy and TPO (therefore no confidence interval) e. Response 1 month: TPO: 8 RCTs, 1 open-label; pooled percentage estimated from a random effects model is 65% (95% CI 57-73%) [studies range from 49% to 95%]; Splenectomy: 1 systematic reviews and 10 articles; pooled percentage estimated from a random effects model is 86% (95% CI 85% and 87%) [studies ranged from 76% to 95%] f. Durable response: TPO: 2 RCTs, 1 open-label; pooled percentage estimated from a random effects model is 66% (95% CI 32-89%) [studies range from 42% to 92%]; Splenectomy: 1 retrospective study pooled percentage estimated from a random effects model is 53% (95% 45-61%) g. No estimate of effect for TPO h. Remission: TPO: no studies; Splenectomy: 1 systematic reviews and 5 retrospective articles pooled percentage from a random effects model is 73% (95% CI 65-80%) [studies ranged from 58% to 89%] i. Major bleeding: TPO: 6 RCTs range 2% to 7%; Splenectomy: 8 retrospective studies range from 1% to 16%

94 j. Infection: TPO: 3 RCTs range from 0% to 17%; Splenectomy: 8 retrospective studies range from 5% to 20% k. No estimate of effect for splenectomy arm l. Operative complications: TPO: not applicable; Splenectomy: 1 systematic review and 8 retrospective studies range from 1% to 28% m. Thrombosis: TPO: 7 RCTs, 1 open-label; range from 0% to 7%; Splenectomy: 8 retrospective studies range from 1% to 4% References 1. Kojouri, Kiarash, Vesely, Sara K., Terrell, Deirdra R., George, James N.. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood; Nov Wang, Tingting, Xu, Maoqiang, Ji, Linxiang, Han, Zhong Chao, Yang, Renchi. Splenectomy for adult chronic idiopathic thrombocytopenic purpura: experience from a single center in China. European Journal of Haematology; Nov Vianelli, Nicola, Galli, Monica, de Vivo, Antonio, Intermesoli, Tamara, Giannini, Benedetta, Mazzucconi, Maria Gabriella, Barbui, Tiziano, Tura, Sante, Baccaranion, Michele, Gruppo Italiano per lo Studio delle Malattie Ematologiche, dell'adulto. Efficacy and safety of splenectomy in immune thrombocytopenic purpura: long-term results of 402 cases. Haematologica; Jan Li, Hong-qiang, Zhang, Lei, Zhao, Hui, Ji, Lin-xiang, Yang, Ren-chi. Chronic idiopathic thrombocytopenic purpura in adult Chinese patients: a retrospective single-centered analysis of 1791 cases. Chinese Medical Journal; Jan Sampath, S., Meneghetti, A. T., MacFarlane, J. K., Nguyen, N. H., Benny, W. B., Panton, O. N.. An 18-year review of open and laparoscopic splenectomy for idiopathic thrombocytopenic purpura. American Journal of Surgery; May Gonzalez-Porras, Jose R., Escalante, Fernando, Pardal, Emilia, Sierra, Magdalena, Garcia-Frade, Luis J., Redondo, Santiago, Arefi, Maryam, Aguilar, Carlos, Ortega, Fernando, de Cabo, Erik, Fisac, Rosa M., Sanz, Oscar, Esteban, Carmen, Alberca, Ignacio, Sanchez-Barba, Mercedes, Santos, Maria T., Fernandez, Abel, Gonzalez-Lopez, Tomas J., Grupo de Trombosis y Hemostasia de Castilla y, Leon. Safety and efficacy of splenectomy in over 65-yrs-old patients with immune thrombocytopenia. European Journal of Haematology; Sep Ahmed, Rayaz, Devasia, Anup J., Viswabandya, Auro, Lakshmi, Kavitha M., Abraham, Aby, Karl, Sampath, Mathai, John, Jacob, Paul M., Abraham, Deepak, Srivastava, Alok, Mathews, Vikram, George, Biju. Long-term outcome following splenectomy for chronic and persistent immune thrombocytopenia (ITP) in adults and children : Splenectomy in ITP. Annals of Hematology; Sep Zheng, Chao-xu, Zheng, Dong, Chen, Liu-hua, Yu, Jun-feng, Wu, Zhi-mian. Laparoscopic splenectomy for immune thrombocytopenic purpura at a teaching institution. Chinese Medical Journal; Apr Kuter, David J., Rummel, Mathias, Boccia, Ralph, Macik, B. Gail, Pabinger, Ingrid, Selleslag, Dominik, Rodeghiero, Francesco, Chong, Beng H., Wang, Xuena, Berger, Dietmar P.. Romiplostim or standard of care in patients with immune thrombocytopenia. New England Journal of Medicine; Nov Guan, Yue, Wang, Shixuan, Xue, Feng, Liu, Xiaofan, Zhang, Lei, Li, Huiyuan, Yang, Renchi. Long-term results of splenectomy in adult chronic immune thrombocytopenia. European Journal of Haematology; Mar Bussel, J. B., Cheng, G., Saleh, M. N., Psaila, B., Kovaleva, L., Meddeb, B., Kloczko, J., Hassani, H., Mayer, B., Stone, N. L., Arning, M., Provan, D., Jenkins, J. M., Bussel, James B., Cheng, Gregory, Saleh, Mansoor N., Psaila, Bethan, Kovaleva, Lidia, Meddeb, Balkis, Kloczko, Janusz. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. New England Journal of Medicine; Kuter, D. J., Bussel, J. B., Lyons, R. M., Pullarkat, V., Nichol, J. L., et al.,. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet; Bussel, J. B., Provan, D., Shamsi, T., Cheng, G., Psaila, B., Kovaleva, L., Salama, A., Jenkins, J. M., Roychowdhury, D., Mayer, B., Stone, N., Arning, M.. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet; Feb 2009.

95 14. Park, Young Hoon, Yi, Hyeon Gyu, Kim, Chul Soo, Hong, Junshik, Park, Jinny, Lee, Jae Hoon, Kim, Ho Young, Kim, Hyo Jung, Zang, Dae Young, Kim, Se Hyung, Park, Seong Kyu, Hong, Dae Sik, Lee, Guk Jin, Jin, Jong-Youl, Gyeonggi/Incheon Branch, The Korean Society of Hematology. Clinical Outcome and Predictive Factors in the Response to Splenectomy in Elderly Patients with Primary Immune Thrombocytopenia: A Multicenter Retrospective Study. Acta Haematologica; Bussel, J. B., Kuter, D. J., George, J. N., McMillan, R., Aledort, L. M., Conklin, G. T., Lichtin, A. E., Lyons, R. M., Nieva, J., Wasser, J. S., Wiznitzer, I., Kelly, R., Chen, C., Nichol, J. L., Bussel, James B., Kuter, David J., George, James N., McMillan, Robert, Aledort, Louis M., Conklin, George T.. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. New England Journal of Medicine; Shirasugi, Yukari, Ando, Kiyoshi, Miyazaki, Koji, Tomiyama, Yoshiaki, Okamoto, Shinichiro, Kurokawa, Mineo, Kirito, Keita, Yonemura, Yuji, Mori, Shinichiro, Usuki, Kensuke, Iwato, Koji, Hashino, Satoshi, Wei, Helen, Lizambri, Richard. Romiplostim for the treatment of chronic immune thrombocytopenia in adult Japanese patients: a double-blind, randomized Phase III clinical trial. International Journal of Hematology; Jul Yang, R., Li, J., Jin, J., Huang, M., Yu, Z., Xu, X., Zhang, X., Hou, M.. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. British Journal of Haematology; Tomiyama, Y., Miyakawa, Y., Okamoto, S., Katsutani, S., Kimura, A., Okoshi, Y., Ninomiya, H., Kosugi, H., Nomura, S., Ozaki, K., Ikeda, Y., Hattori, T., Katsura, K., Kanakura, Y.. A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia. Journal of Thrombosis & Haemostasis; May Cheng, Gregory, Saleh, Mansoor N., Marcher, Claus, Vasey, Sandra, Mayer, Bhabita, Aivado, Manuel, Arning, Michael, Stone, Nicole L., Bussel, James B.. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study.[erratum appears in Lancet Jan 29;377(9763):382]. Lancet; Jan Montalvo, Jorge, Velazquez, David, Pantoja, Juan P., Sierra, Mauricio, Lopez-Karpovitch, Xavier, Herrera, Miguel F.. Laparoscopic splenectomy for primary immune thrombocytopenia: clinical outcome and prognostic factors. Journal of Laparoendoscopic & Advanced Surgical Techniques. Part A; Jul 2014.

96 QUESTION Should rituximab vs. splenectomy be used for adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids (Q8)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids (Q8) rituximab splenectomy Response within 1 month; Durable response; Remission; Remission - Cohort Rituximab vs Splenectomy; Major bleeding; Reduction or discontinuation of corticosteroids; Infection; Overall health-related quality of life; Operative complications: a side effect of splenectomy; Thrombosis; Infection - Cohort Rituximab vs Splenectomy; SETTING: Study inclusion: All RCTs; all prospective studies of at least 50 patients (adults). For splenectomy the 2004 Kojouri et al systematic review was used and all retrospective studies of at least 100 patients published after 2004 were included. PERSPECTIVE: BACKGROUND: Splenectomy has been the historical management for patients who either fail treatment with corticosteroids or who require ongoing corticosteroid use to maintain their platelet count. Previous appreciated risks associated with splenectomy included life-long risk for infection, operative complications, and vascular complications. These risks were balanced against high remission rates. With the development of new and novel treatments for ITP such as rituximab the role and timing of splenectomy is less clear. There are no randomized trials comparing splenectomy with rituximab and it is unknown if one treatment approach is preferred over the other with regards to important patient-related outcomes. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects?

97 Trivial Small Moderate Large See GRADE evidence table for one-armed observational data. Splenectomy has a moderate effect compared to rituximab. Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial See GRADE evidence table for one-armed observational data. Splenectomy has moderate undesirable compared to rituximab. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Only have one armed observational data and two retrospective studies that directly compare splenectomy and rituximab. Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability

98 Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Varies depending on patient factors (length of ITP, age, bleeding etc.). Also varies depends on patient preference. Many felt splenectomy should not be done until one year post splenectomy. The order of splenectomy or rituximab may matter. Splenectomy is permanent, so some thought you should try rituximab first and if desired patient response is not obtained then you could try splenectomy. 11/15 varies; 4/15 probably favors rituximab Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Rituxan 375 mg/m2 weekly x 4 doses assuming a 2 meters sqaured adult. The cost is $31,266 based on data from LexiComp. Splenectomy: median hospital cost: $14,317 (from Hamlet, Annals of Surgery 2012). Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

99 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Rituximab is less accessible in Canada and UK. Acceptability Is the acceptable to key stakeholders?

100 No Probably no Probably yes Yes Varies Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

101 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests for rituximab rather than splenectomy in adults with ITP lasting > 3 months who corticosteroid-dependent or have no response to corticosteroids. Conditional recommendation based on very low certainty in the evidence about effects. 12 favor rituximab 4 favor either Justification Subgroup considerations Treatment decision may vary based on length of time patient has ITP. Decision would be different based on length of disease (3 months vs 2 years).

102 Implementation considerations Monitoring and evaluation Research priorities

103 Author(s): OU Sooner GRADE Team Date: August 2017 Question: Rituximab compared to splenectomy in adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids (Q8) Setting: Study inclusion: All RCTs; all prospective studies of at least 50 patients (adults). For splenectomy the 2004 Kojouri et al systematic review was used and all retrospective studies of at least 100 patients published after 2004 were included. Bibliography: Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations rituximab splenectomy Relative (95% CI) Absolute (95% CI) Certainty Importance Response within 1 month 16 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16 observational studies a serious b not serious serious c serious d none 314/506 (62.1%) 3342/3855 (86.7%) not estimable e VERY LOW CRITICAL Durable response 4 7,8,13 observational studies a serious b serious f serious c serious d none 80/203 (39.4%) 79/149 (53.0%) not estimable g VERY LOW CRITICAL Remission 11 1,3,4,6,7,8,9,11,13,17,18 observational studies a serious b not serious serious c serious d none 134/571 (23.5%) 1017/1479 (68.8%) not estimable h VERY LOW CRITICAL Remission - Cohort Rituximab vs Splenectomy

104 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations rituximab splenectomy Relative (95% CI) Absolute (95% CI) Certainty Importance 2 19,20 observational studies serious i not serious serious j not serious none Moulis Study: Splx n=62; rit n=43 12 month CR 88% splx; 59% rit (p=.001) propensity score adjusted at 12 month OR= 4.4 (95% CI 1.7, 11.8) [splx vs rit] Chater 2016: Splx n=66 (LS=29, OS=37); rit n=30 30 month CR 93% LS splx; 87% OS splx; 30% rit (p=.0001) adjusted at 30 month OR= 10.5 (95% CI 3.9, 28.6) [splx vs rit] VERY LOW CRITICAL Major bleeding 12 2,3,4,5,7,8,9,10,11,12,14,16 observational studies a serious b not serious serious c serious d none 10/449 (2.2%) 72/1526 (4.7%) not estimable k VERY LOW CRITICAL Reduction or discontinuation of corticosteroids - not reported CRITICAL Infection 14 2,3,4,5,7,8,9,10,11,12,13,14,16,17 observational studies a serious b not serious serious c serious d none 21/566 (3.7%) 167/1677 (10.0%) not estimable l VERY LOW CRITICAL Overall health-related quality of life - not reported CRITICAL Operative complications: a side effect of splenectomy

105 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations rituximab splenectomy Relative (95% CI) Absolute (95% CI) Certainty Importance 9 1,2,3,9,11,12,14,16,18 observational studies a serious b serious n serious c serious d none 630/4922 (12.8%) not estimable o VERY LOW CRITICAL Thrombosis 10 2,3,5,8,9,10,11,12,14,16 observational studies a serious b not serious serious c serious d none 2/93 (2.2%) 36/1526 (2.4%) not estimable p VERY LOW CRITICAL Infection - Cohort Rituximab vs Splenectomy 2 19,20 observational studies serious i not serious not serious not serious none 5/65 (7.7%) 8/120 (6.7%) not estimable VERY LOW CRITICAL CI: Confidence interval; OR: Odds ratio Explanations a. 1 month response: Splenectomy: 1 systematic review and 10 retrospective studies; Rituximab: 5 prospective studies; Durable response: Splenectomy: 1 retrospective study; Rituximab: 3 prospective studies; Remission: Splenectomy: 1 systematic review and 5 retrospective studies; Rituximab: 5 prospective studies; Major bleeding: Splenectomy: 6 retrospective studies; Rituximab: 3 prospective studies; Infection: Splenectomy: 8 retrospective studies; Rituximab: 6 prospective studies; Thrombosis: Splenectomy: 7 retrospective studies; Rituximab: 2 prospective studies; Operative complications: Splenectomy: 1 systematic review and 3 retrospective studies; Rituximab: No studies/na b. Splenectomy studies are largely retrospective chart reviews with concerns about selection bias and measurement of outcomes c. No clinical trials directly comparing splenectomy and rituximab d. No relative effect calculated between splenectomy and rituximab (therefore no confidence interval) e. Response 1 month: Rituximab: pooled percentage estimated from a random effects model is 62% (95% CI 58-66%) [studies range from 51% to 73%]; Splenectomy: 1 systematic reviews and 10 articles; pooled percentage estimated from a random effects model is 86% (95% CI 85% and 87%) [studies ranged from 76% to 95%]

106 f. No estimate of effect for splenectomy arm g. Durable response: Rituximab: pooled percentage estimated from a random effects model is 39% (95% CI 32-47%) [studies range from 32% to 44%]; Splenectomy: 1 study 53% h. Remission: Rituximab: pooled percentage estimated from a random effects model is 25% (95% 16-37%) [studies range from 8% to 40%]; Splenectomy: 1 systematic reviews and 5 retrospective articles pooled percentage from a random effects model is 73% (95% CI 65-80%) [studies ranged from 58% to 89%] i. Cohort studies; potential differences in populations that received splenectomy vs rituximab; 1 study propensity score adjusted but neither randomized j. Outcome 30 months for one study k. Major bleeding: Rituximab studies range from 1% to 7% l. Infection: Rituximab: studies range from 0% to 40% m. Three TPO studies. 1. No significant differences between the groups. 2. Romiplostim group had significantly greater improvements in scores on symptoms, bother, activity, psychological, fear, social quality of life, and overall quality of life scale compared to standard of care group. 3. 5/8 SF-36v2 domain scores, both SF 36v2 summary scores, and the FACTTh6 score at week 26 were significantly improved from baseline n. No estimate of effect for rituximab o. Operative complications: TPO: not applicable; Splenectomy: 1 systematic review 12% p. Thrombosis: Rituximab: studies range from 0% to 4% References 1. Kojouri, Kiarash, Vesely, Sara K., Terrell, Deirdra R., George, James N.. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood; Nov Wang, Tingting, Xu, Maoqiang, Ji, Linxiang, Han, Zhong Chao, Yang, Renchi. Splenectomy for adult chronic idiopathic thrombocytopenic purpura: experience from a single center in China. European Journal of Haematology; Nov Gonzalez-Porras, Jose R., Escalante, Fernando, Pardal, Emilia, Sierra, Magdalena, Garcia-Frade, Luis J., Redondo, Santiago, Arefi, Maryam, Aguilar, Carlos, Ortega, Fernando, de Cabo, Erik, Fisac, Rosa M., Sanz, Oscar, Esteban, Carmen, Alberca, Ignacio, Sanchez-Barba, Mercedes, Santos, Maria T., Fernandez, Abel, Gonzalez-Lopez, Tomas J., Grupo de Trombosis y Hemostasia de Castilla y, Leon. Safety and efficacy of splenectomy in over 65-yrs-old patients with immune thrombocytopenia. European Journal of Haematology; Sep Khellaf, Mehdi, Charles-Nelson, Anais, Fain, Olivier, Terriou, Louis, Viallard, Jean-Francois, Cheze, Stephane, Graveleau, Julie, Slama, Borhane, Audia, Sylvain, Ebbo, Mikael, Le Guenno, Guillaume, Cliquennois, Manuel, Salles, Gilles, Bonmati, Caroline, Teillet, France, Galicier, Lionel, Hot, Arnaud, Lambotte, Olivier, Lefrere, Francois, Sacko, Salimatou, Kengue, Dieudonne Kilendo, Bierling, Philippe, Roudot-Thoraval, Francoise, Michel, Marc, Godeau, Bertrand. Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood; Nov Ghanima, Waleed, Khelif, Abderrahim, Waage, Anders, Michel, Marc, Tjonnfjord, Geir E., Romdhan, Neila Ben, Kahrs, Johannes, Darne, Bernadette, Holme, Pal Andre, group, Ritp,study. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet; Apr Balague, C., Vela, S., Targarona, E. M., Gich, I. J., Muniz, E., D'Ambra, A., Pey, A., Monllau, V., Ascaso, E., Martinez, C., Garriga, J., Trias, M.. Predictive factors for successful laparoscopic splenectomy in immune thrombocytopenic purpura: study of clinical and laboratory data. Surgical Endoscopy; Aug Tran, Huyen, Brighton, Tim, Grigg, Andrew, McRae, Simon, Dixon, Joanna, Thurley, Daniel, Gandhi, Maher K., Truman, Matt, Marlton, Paula, Catalano, John. A multi-centre, single-arm, open-label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory, relapsed or chronic idiopathic thrombocytopenic purpura (R-ITP1000 study). British Journal of Haematology; Oct 2014.

107 8. Zhou, Hai, Xu, Miao, Qin, Ping, Zhang, Hai-yan, Yuan, Cheng-lu, Zhao, Hong-guo, Cui, Zhong-guang, Meng, Yue-sheng, Wang, Lei, Zhou, Fang, Wang, Xin, Li, Da-qi, Bi, Ke-hong, Zhu, Chuansheng, Guo, Cheng-shan, Chu, Xiao-xia, Wu, Qing-chao, Liu, Xin-guang, Dong, Xiao-yuan, Li, Jie, Peng, Jun, Hou, Ming. A multicenter randomized open-label study of rituximab plus rhtpo vs rituximab in corticosteroid-resistant or relapsed ITP. Blood; Mar Guan, Yue, Wang, Shixuan, Xue, Feng, Liu, Xiaofan, Zhang, Lei, Li, Huiyuan, Yang, Renchi. Long-term results of splenectomy in adult chronic immune thrombocytopenia. European Journal of Haematology; Mar Ahmed, Rayaz, Devasia, Anup J., Viswabandya, Auro, Lakshmi, Kavitha M., Abraham, Aby, Karl, Sampath, Mathai, John, Jacob, Paul M., Abraham, Deepak, Srivastava, Alok, Mathews, Vikram, George, Biju. Long-term outcome following splenectomy for chronic and persistent immune thrombocytopenia (ITP) in adults and children : Splenectomy in ITP. Annals of Hematology; Sep Zheng, Chao-xu, Zheng, Dong, Chen, Liu-hua, Yu, Jun-feng, Wu, Zhi-mian. Laparoscopic splenectomy for immune thrombocytopenic purpura at a teaching institution. Chinese Medical Journal; Apr Vianelli, Nicola, Galli, Monica, de Vivo, Antonio, Intermesoli, Tamara, Giannini, Benedetta, Mazzucconi, Maria Gabriella, Barbui, Tiziano, Tura, Sante, Baccaranion, Michele, Gruppo Italiano per lo Studio delle Malattie Ematologiche, dell'adulto. Efficacy and safety of splenectomy in immune thrombocytopenic purpura: long-term results of 402 cases. Haematologica; Jan Cooper, N., Stasi, R., Cunningham-Rundles, S. S., Feuerstein, M. A., Leonard, J. P., Amadori, S., Bussel, J. B.. The efficacy and safety of B-cell depletion with anti-cd20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. British Journal of Haematology; Apr Park, Young Hoon, Yi, Hyeon Gyu, Kim, Chul Soo, Hong, Junshik, Park, Jinny, Lee, Jae Hoon, Kim, Ho Young, Kim, Hyo Jung, Zang, Dae Young, Kim, Se Hyung, Park, Seong Kyu, Hong, Dae Sik, Lee, Guk Jin, Jin, Jong-Youl, Gyeonggi/Incheon Branch, The Korean Society of Hematology. Clinical Outcome and Predictive Factors in the Response to Splenectomy in Elderly Patients with Primary Immune Thrombocytopenia: A Multicenter Retrospective Study. Acta Haematologica; Li, Hong-qiang, Zhang, Lei, Zhao, Hui, Ji, Lin-xiang, Yang, Ren-chi. Chronic idiopathic thrombocytopenic purpura in adult Chinese patients: a retrospective single-centered analysis of 1791 cases. Chinese Medical Journal; Jan Sampath, S., Meneghetti, A. T., MacFarlane, J. K., Nguyen, N. H., Benny, W. B., Panton, O. N.. An 18-year review of open and laparoscopic splenectomy for idiopathic thrombocytopenic purpura. American Journal of Surgery; May Godeau, Bertrand, Porcher, Raphael, Fain, Olivier, Lefrere, Francois, Fenaux, Pierre, Cheze, Stephane, Vekhoff, Anne, Chauveheid, Marie-Paule, Stirnemann, Jerome, Galicier, Lionel, Bourgeois, Emmanuelle, Haiat, Stephanie, Varet, Bruno, Leporrier, Michel, Papo, Thomas, Khellaf, Mehdi, Michel, Marc, Bierling, Philippe. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood; Aug Montalvo, Jorge, Velazquez, David, Pantoja, Juan P., Sierra, Mauricio, Lopez-Karpovitch, Xavier, Herrera, Miguel F.. Laparoscopic splenectomy for primary immune thrombocytopenia: clinical outcome and prognostic factors. Journal of Laparoendoscopic & Advanced Surgical Techniques. Part A; Jul Moulis, Guillaume, Sailler, Laurent, Sommet, Agnes, Lapeyre-Mestre, Maryse, Derumeaux, Helene, Adoue, Daniel. Rituximab versus splenectomy in persistent or chronic adult primary immune thrombocytopenia: an adjusted comparison of mortality and morbidity. American Journal of Hematology; Jan Chater, C., Terriou, L., Duhamel, A., Launay, D., Chambon, J. P., Pruvot, F. R., Rogosnitzky, M., Zerbib, P.. Reemergence of Splenectomy for ITP Second-line Treatment?. Annals of Surgery; Nov 2016.

108 QUESTION Should TPO-RAs vs. rituximab be used for adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids (Q9)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids (Q9) TPO-RAs rituximab Response within 1 month; Durable response; Remission; Major bleeding; Reduction or discontinuation of corticosteroids; Infection; Overall health-related quality of life; Operative complications: a side effect of splenectomy; Thrombosis; SETTING: Study inclusion: All RCTs; all prospective studies of at least 50 patients (adults). PERSPECTIVE: BACKGROUND: Novel therapies have been developed for patients who fail corticosteroids or who require ongoing corticosteroids. These include rituximab and the thrombopoietin-receptor agonists (TPO- RAs). These therapies are very different in their administration and side effects. The TPO-RAs require ongoing treatment either daily (eltrombopag) or weekly (romiplostim) where as rituximab is delivered in 4 weekly IV doses. In addition, the side effect profiles of these treatments are highly different. Given that no randomized trials have directly compared these two treatment approaches the benefit of one approach over the other with regard to important patient-related outcomes remains unknown. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large See GRADE evidence table for one-armed observational data. Moderate desirable effects for TPO-RAs compared to rituximab. Missing some long-term data for TPO-RAs. Putting more weight on our experience than our data.

109 Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Don't know See GRADE evidence table for one-armed observational data. Some panelists thought small undesirable favoring rituximab others thought they could not make a decision due to lack of data. Consensus was don't know. Small undesirable for TPO-RA, long-term side effects for TPO-RAs unknown. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison?

110 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Probably favors TPO-RAs. We are comparing a maintenance drug (TPO-RAs) versus long-term remission drug. Some felt TPO-RA was more expensive but more effective and that rituximab was less expensive but less effective. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Rituxan 375 mg/m2 weekly x 4 doses assuming a 2 meters squared adult. The cost is $31,266 based on data from LexiComp. Eltromopag dose range is 25 to 75 mg for 30 days. Cost ranges from $4,845 to $13,520 based on data from LexiComp. Romiplostin dose range is 1 to 10 mgc/kg/week for 28 days for a 70 kg adult. Dosing rounding to vial size. Cost ranges from $8,256 to $33,027 based on data from LexiComp. Large costs for TPO. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

111 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Low SES may not be able to afford TPO-RAs; rituximab may not be available in all jurisdictions. Acceptability Is the acceptable to key stakeholders?

112 No Probably no Probably yes Yes Different patients might have different reasons/preferences to take one drug vs the other. Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

113 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests for TPO-RAs rather than rituximab in adults with ITP lasting > 3 months who ar corticosteroid-dependent or have no response to corticosteroids. Conditional recommendation based on very low certainty in the evidence about effects. First vote: 6 conditional for either 6 conditional for TPO Second vote: 8 conditional for TPO 4 conditional for either Justification

114 Subgroup considerations Implementation considerations Monitoring and evaluation Research priorities

115 Author(s): OU Sooner GRADE Team Date: August 2017 Question: TPO-RAs compared to rituximab in adults with ITP lasting >3 months who are corticosteroid-dependent or have no response to corticosteroids (Q9) Setting: Study inclusion: All RCTs; all prospective studies of at least 50 patients (adults). Bibliography: Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations TPO-RAs rituximab Relative (95% CI) Absolute (95% CI) Certainty Importance Response within 1 month 1 1,2,3,4,5,6,7,8,9,10,11,12,13,14 observational studies a serious b not serious serious c serious d none 448/682 (65.7%) 314/506 (62.1%) not estimable e VERY LOW CRITICAL Durable response 6 2,5,7,10,11,12 observational studies a not serious not serious serious c serious d none 225/356 (63.2%) 80/203 (39.4%) not estimable f VERY LOW CRITICAL Remission 5 1,5,7,12,15 observational studies a not serious serious g serious c serious d none 134/571 (23.5%) not estimable h VERY LOW CRITICAL Major bleeding 11 1,2,3,4,5,7,9,10,11,13,14 observational studies a not serious not serious serious c serious d none 20/575 (3.5%) 10/449 (2.2%) not estimable i VERY LOW CRITICAL Reduction or discontinuation of corticosteroids - not reported CRITICAL Infection

116 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations TPO-RAs rituximab Relative (95% CI) Absolute (95% CI) Certainty Importance 9 1,4,5,7,9,11,12,13,15 observational studies a not serious not serious serious c serious d none 17/247 (6.9%) 21/566 (3.7%) not estimable j VERY LOW CRITICAL Overall health-related quality of life 3 2,10,13 observational studies a not serious serious k serious c serious d none not estimable l VERY LOW CRITICAL Operative complications: a side effect of splenectomy - not reported CRITICAL Thrombosis 10 2,3,4,6,7,8,10,11,13,14 observational studies a not serious not serious serious c serious d none 15/606 (2.5%) 2/93 (2.2%) not estimable m VERY LOW CRITICAL CI: Confidence interval Explanations a. 1 month response: Rituximab: 5 prospective studies; TPO: 8 RCTs, 1 open-label; Durable response: Rituximab: 3 prospective studies; TPO: 2 RCTs, 1 open-label; Remission: Rituximab: 5 prospective studies; TPO: No studies; Major bleeding: Rituximab: 4 prospective studies; TPO: 6 RCTs, 1 open-label; Infection: Rituximab: 6 prospective studies ; TPO: 3 RCTs; Thrombosis: Rituximab: 2 prospective studies TPO: 7 RCTs, 1 open-label; QOL: Rituximab: No studies; TPO: 3 RCTs b. Splenectomy studies are largely retrospective chart reviews with concerns about selection bias and measurement of outcomes c. No clinical trials directly comparing splenectomy and TPOs d. No relative effect calculated between splenectomy and TPO (therefore no confidence interval) e. Response 1 month: TPO: 8 RCTs, 1 open-label; pooled percentage estimated from a random effects model is 65% (95% CI 57-73%) [studies range from 49% to 95%]; Rituximab pooled percentage estimated from a random effects model is 62% (95% CI 58-66%) [studies ranged from 51% to 73%]

117 f. Durable response: TPO: 2 RCTs, 1 open-label; pooled percentage estimated from a random effects model is 66% (95% CI 32-89%) [studies range from 42% to 92%]; rituximab pooled percentage estimated from a random effects model is 39% (95% CI 32-47%) [studies range from 32% to 44%] g. No estimate of effect for TPO h. Remission: Rituximab pooled estimate is 25% (95% CI 16-37%) [studies ranged from 8% to 40%] i. Major bleeding: TPO: studies range 2% to 5%; Rituximab studies range from 1% to 7% j. Infection: TPO: studies range from 1% to 17%; Rituximab studies range from 0% to 40% k. No estimate of effect for rituximab arm l. Three TPO studies. 1. No significant differences between the groups. 2. Romiplostim group had significantly greater improvements in scores on symptoms, bother, activity, psychological, fear, social quality of life, and overall quality of life scale compared to standard of care group. 3. 5/8 SF-36v2 domain scores, both SF 36v2 summary scores, and the FACTTh6 score at week 26 were significantly improved from baseline m. Thrombosis: TPO: studies range from 0% to 7%; Rituximab studies range 0% to 4% References 1. Khellaf, Mehdi, Charles-Nelson, Anais, Fain, Olivier, Terriou, Louis, Viallard, Jean-Francois, Cheze, Stephane, Graveleau, Julie, Slama, Borhane, Audia, Sylvain, Ebbo, Mikael, Le Guenno, Guillaume, Cliquennois, Manuel, Salles, Gilles, Bonmati, Caroline, Teillet, France, Galicier, Lionel, Hot, Arnaud, Lambotte, Olivier, Lefrere, Francois, Sacko, Salimatou, Kengue, Dieudonne Kilendo, Bierling, Philippe, Roudot-Thoraval, Francoise, Michel, Marc, Godeau, Bertrand. Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood; Nov Kuter, David J., Rummel, Mathias, Boccia, Ralph, Macik, B. Gail, Pabinger, Ingrid, Selleslag, Dominik, Rodeghiero, Francesco, Chong, Beng H., Wang, Xuena, Berger, Dietmar P.. Romiplostim or standard of care in patients with immune thrombocytopenia. New England Journal of Medicine; Nov Shirasugi, Yukari, Ando, Kiyoshi, Miyazaki, Koji, Tomiyama, Yoshiaki, Okamoto, Shinichiro, Kurokawa, Mineo, Kirito, Keita, Yonemura, Yuji, Mori, Shinichiro, Usuki, Kensuke, Iwato, Koji, Hashino, Satoshi, Wei, Helen, Lizambri, Richard. Romiplostim for the treatment of chronic immune thrombocytopenia in adult Japanese patients: a double-blind, randomized Phase III clinical trial. International Journal of Hematology; Jul Ghanima, Waleed, Khelif, Abderrahim, Waage, Anders, Michel, Marc, Tjonnfjord, Geir E., Romdhan, Neila Ben, Kahrs, Johannes, Darne, Bernadette, Holme, Pal Andre, group, Ritp,study. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet; Apr Tran, Huyen, Brighton, Tim, Grigg, Andrew, McRae, Simon, Dixon, Joanna, Thurley, Daniel, Gandhi, Maher K., Truman, Matt, Marlton, Paula, Catalano, John. A multi-centre, single-arm, open-label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory, relapsed or chronic idiopathic thrombocytopenic purpura (R-ITP1000 study). British Journal of Haematology; Oct Yang, R., Li, J., Jin, J., Huang, M., Yu, Z., Xu, X., Zhang, X., Hou, M.. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. British Journal of Haematology; Zhou, Hai, Xu, Miao, Qin, Ping, Zhang, Hai-yan, Yuan, Cheng-lu, Zhao, Hong-guo, Cui, Zhong-guang, Meng, Yue-sheng, Wang, Lei, Zhou, Fang, Wang, Xin, Li, Da-qi, Bi, Ke-hong, Zhu, Chuansheng, Guo, Cheng-shan, Chu, Xiao-xia, Wu, Qing-chao, Liu, Xin-guang, Dong, Xiao-yuan, Li, Jie, Peng, Jun, Hou, Ming. A multicenter randomized open-label study of rituximab plus rhtpo vs rituximab in corticosteroid-resistant or relapsed ITP. Blood; Mar Tomiyama, Y., Miyakawa, Y., Okamoto, S., Katsutani, S., Kimura, A., Okoshi, Y., Ninomiya, H., Kosugi, H., Nomura, S., Ozaki, K., Ikeda, Y., Hattori, T., Katsura, K., Kanakura, Y.. A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia. Journal of Thrombosis & Haemostasis; May 2012.

118 9. Bussel, J. B., Cheng, G., Saleh, M. N., Psaila, B., Kovaleva, L., Meddeb, B., Kloczko, J., Hassani, H., Mayer, B., Stone, N. L., Arning, M., Provan, D., Jenkins, J. M., Bussel, James B., Cheng, Gregory, Saleh, Mansoor N., Psaila, Bethan, Kovaleva, Lidia, Meddeb, Balkis, Kloczko, Janusz. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. New England Journal of Medicine; Cheng, Gregory, Saleh, Mansoor N., Marcher, Claus, Vasey, Sandra, Mayer, Bhabita, Aivado, Manuel, Arning, Michael, Stone, Nicole L., Bussel, James B.. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study.[erratum appears in Lancet Jan 29;377(9763):382]. Lancet; Jan Kuter, D. J., Bussel, J. B., Lyons, R. M., Pullarkat, V., Nichol, J. L., et al.,. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet; Cooper, N., Stasi, R., Cunningham-Rundles, S. S., Feuerstein, M. A., Leonard, J. P., Amadori, S., Bussel, J. B.. The efficacy and safety of B-cell depletion with anti-cd20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. British Journal of Haematology; Apr Bussel, J. B., Provan, D., Shamsi, T., Cheng, G., Psaila, B., Kovaleva, L., Salama, A., Jenkins, J. M., Roychowdhury, D., Mayer, B., Stone, N., Arning, M.. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet; Feb Bussel, J. B., Kuter, D. J., George, J. N., McMillan, R., Aledort, L. M., Conklin, G. T., Lichtin, A. E., Lyons, R. M., Nieva, J., Wasser, J. S., Wiznitzer, I., Kelly, R., Chen, C., Nichol, J. L., Bussel, James B., Kuter, David J., George, James N., McMillan, Robert, Aledort, Louis M., Conklin, George T.. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. New England Journal of Medicine; Godeau, Bertrand, Porcher, Raphael, Fain, Olivier, Lefrere, Francois, Fenaux, Pierre, Cheze, Stephane, Vekhoff, Anne, Chauveheid, Marie-Paule, Stirnemann, Jerome, Galicier, Lionel, Bourgeois, Emmanuelle, Haiat, Stephanie, Varet, Bruno, Leporrier, Michel, Papo, Thomas, Khellaf, Mehdi, Michel, Marc, Bierling, Philippe. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood; Aug

119 QUESTION Should treatment as an outpatient vs. admission to the hospital be used for children with ITP and a platelet count <20 x 10^9 /l and no or minor bleeding only (11a)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: children with ITP and a platelet count <20 x 10^9 /l and no or minor bleeding only (11a) treatment as an outpatient admission to the hospital Major bleeding; Mortality; Overall health-related quality of life; SETTING: PERSPECTIVE: BACKGROUND: The majority of children with newly diagnosed ITP will present with the acute onset of severe thrombocytopenia (< 20 x 10 9 /l). Despite this most children having no or mild bleeding only. In addition, the risk of subsequent bleeding is presumed to be low. The role of admission in the management of children such as this is not clear. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Both newly diagnosed or established patients with only minor bleeding - admission to hospital. Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Survey was administered to pediatric providers on the panel (6 of 6 responded). Limitations of the survey data include recall bias, answering for self vs whole practice. Desirable effects of hospitalization are trivial; undesirable effects of hospitalization are moderate.

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122 Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Being admitted to the oncology section might cause a parent to worry their child has cancer and also you expose the child to flu or other infections. Certainty of evidence What is the overall certainty of the evidence of effects?

123 Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Some parents may want kids to be hospitalized. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Favors outpatient. Resources required How large are the resource requirements (costs)?

124 Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison?

125 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Varies Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes Varies Feasibility Is the feasible to implement? No Probably no Probably yes

126 Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the

127 CONCLUSIONS Recommendation The ASH guideline panel suggests against admission to the hospital rather than treatment as an outpatient in children with newly diagnosed ITP and a platelet count <20 x 10^9 /l and no or minor bleeding only Conditional recommendation based on very low certainty in the evidence about effects. Best practice is to have patients seen by pediatric hematologist (or team of specialist who deal with ITP) within 1-2 days and to review the peripheral blood smear. Justification Subgroup considerations Implementation considerations

128 Monitoring and evaluation Research priorities

129 QUESTION Should treatment as an outpatient vs. admission to the hospital be used for children with ITP and a platelet count 20 x 10^9 /l and no or minor bleeding only (Q11b)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: children with ITP and a platelet count 20 x 10^9 /l and no or minor bleeding only (Q11b) treatment as an outpatient admission to the hospital Major bleeding; Mortality; Overall health-related quality of life; SETTING: PERSPECTIVE: BACKGROUND: Children with newly diagnosed ITP can present with a more indolent course and mild thrombocytopenia ( 30 x 10 9 /l). In setting, most children will not or mild bleeding only and a very low risk of subsequent bleeding. The role of admission in the management of children such as this is not clear. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Both newly diagnosed and established patients. Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Survey was administered to pediatric providers on the panel (6 of 6 responded). Limitations of the survey data include recall bias, answering for self vs whole practice. Intervention is admission; benefits of hospitalization are trivial; undesirable effects are moderate for hospitalization.

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132 Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes?

133 Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Most patients do not want to be hospitalized. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Favors outpatient treatment. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

134 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity?

135 Reduced Probably reduced Probably no impact Probably increased Increased Varies If you hospitalize all patients you may increase health equity since rural patients may live close to hospital but not close to pediatric hematologist. Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies

136 JUDGEMENT VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests against admission to the hospital in children rather than treatment as an outpatient in children with ITP and a platelet count 20 x 10^9 /l and no or minor bleeding only. Conditional recommendation based on very low certainty in the evidence about effects.

137 Justification Subgroup considerations Unclear diagnosis of ITP with higher platelet count. Distance from the hospital may vary this recommendation. Implementation considerations Monitoring and evaluation Research priorities

138 QUESTION Should corticosteroids vs. observation be used for children with newly diagnosed ITP and no or minor bleeding for initial therapy (Q12)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: children with newly diagnosed ITP and no or minor bleeding for initial therapy (Q12) corticosteroids observation Durable response; Response 1 Month - not prioritized - indirect estimate for durable response; Remission; Major bleeding; Mortality; Overall health-related quality of life; SETTING: PERSPECTIVE: BACKGROUND: Significant thrombocytopenia is a common finding in children with newly diagnosed ITP. Despite having severe thrombocytopenia severe bleeding events are rare in children with ITP. The decision to treat a child with no or minor bleeding is based on a presumed increased risk of subsequent bleeding without treatment. Therapy should therefore be aimed at preventing subsequent bleeding not just increasing the platelet count. The true impact of corticosteroid treatment compared to no treatment with regards to important patient-related outcomes in this population is not known. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Both RCT and observational data were used. RCT data are directly below. See GRADE evidence table at end of document for observational data and RCT data.

139 Outcomes of participants (studies) Follow up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects * (95% CI) Risk with observation Risk difference with corticosteroids Durable response 68 (2 RCTs) 1,2 MODERATE a RR 0.96 (0.74 to 1.25) Study population 781 per 1, fewer per 1,000 (203 fewer to 195 more) Response 1 Month - not prioritized - indirect estimate for durable response 100 (2 RCTs) 3,4 LOW a,b RR 1.28 (0.54 to 3.02) Study population 600 per 1, more per 1,000 (276 fewer to 1,212 more) Remission - not reported Major bleeding 35 (1 RCT) 2 MODERATE a not estimable Study population 0 per 1,000 0 fewer per 1,000 (0 fewer to 0 fewer) Mortality - not reported Overall healthrelated quality of

140 life - not reported 1. Blanchette, V. S., Luke, B., Andrew, M., Sommerville-Nielsen, S., Barnard, D., de Veber, B., Gent, M.. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. Journal of Pediatrics; Dec Fujisawa, K., Iyori, H., Ohkawa, H., Konishi, S., Bessho, F., Shirahata, A., Miyazaki, S., Akatsuka, J., Japanese Study Group on Childhood, I. T. P.. A prospective, randomized trial of conventional, dose-accelerated corticosteroids and intravenous immunoglobulin in children with newly diagnosed idiopathic thrombocytopenic purpura. International Journal of Hematology; Oct Sartorius, J. A.. STEROID TREATMENT OF IDIOPATHIC THROMBOCYTOPENIC PURPURA IN CHILDREN - PRELIMINARY-RESULTS OF A RANDOMIZED COOPERATIVE STUDY. American Journal of Pediatric Hematology Oncology; Buchanan, G. R., Holtkamp, C. A.. PREDNISONE THERAPY FOR CHILDREN WITH NEWLY DIAGNOSED IDIOPATHIC THROMBOCYTOPENIC PURPURA - A RANDOMIZED CLINICAL-TRIAL. American Journal of Pediatric Hematology Oncology; a. Confidence interval does not exclude thresholds for plausible benefit or harm b. Response within 1 month is a surrogate (indirect outcome) outcome for durable response Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Small undesirable effects of corticosteroids based on other published data reporting side effects in corticosteroids in general and panel experience but some uncertainty. Panel also acknowledged there are side effects with observation such as anxiety. Certainty of evidence

141 What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Prevention of ICH more important than other side effects. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Favors observation. Resources required How large are the resource requirements (costs)?

142 Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Prednisone dose range 2 mg/kg/d - 4 mg/kg/d for 7 days for a 30 kg child. Cost ranges from $ $10.92 based on data from LexiComp. From Kumar 2005: Initial treatment charges (in USD): Anti-D: 2,037(833 8,389) IVIG: 2,926(701 9,517) Steroids: 1,737(362 3,995) Observation: 595(367 2,915) Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison?

143 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes Is observation acceptable to key stakeholders? Probably yes; patient and family education leads to greater acceptability. Feasibility Is the feasible to implement? No Probably no Probably yes

144 Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the

145 CONCLUSIONS Recommendation The ASH guideline panel suggests observation rather than corticosteroids in children with newly diagnosed ITP and no or minor bleeding for initial therapy. Conditional recommendation based on very low certainty in the evidence about effects. Justification The panel was in agreement to grade this as a strong recommendation but the quality of the evidence was very low. This recommendation does not meet the paradigmatic situations in which a strong recommendation may be warranted despite low or very low confidence in effect estimates (#3 when low quality evidence suggest equivalence of two alternatives, but high quality evidence of less harm for one of the competing alternatives). Even though corticosteroids can have significant side effects/harm, the risk for harm for the usual dose of 7 days is low. Subgroup considerations Implementation considerations Monitoring and evaluation

146 Research priorities

147 Author(s): OU Sooner GRADE Team Date: August 2017 Question: Corticosteroids compared to observation in children with newly diagnosed ITP and no or minor bleeding for initial therapy (Q12) Observational data Setting: Study inclusion: All RCTs; all prospective studies of at least 25 patients (children). For observation also included retrospective studies of at least 25 patients (children). Bibliography: Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations corticosteroids observation Relative (95% CI) Absolute (95% CI) Certainty Importance Durable response - Randomized Clinical Trials 2 1,2 randomised trials not serious not serious not serious serious a none 27/36 (75.0%) 25/32 (78.1%) RR 0.96 (0.74 to 1.25) 31 fewer per 1,000 (from 195 more to 203 fewer) MODERATE CRITICAL Response 1 Month - Randomized Clinical Trials - not prioritized - indirect evidence for durable response 2 3,4 randomised trials not serious not serious serious b serious a none 46/55 (83.6%) 27/45 (60.0%) RR 1.28 (0.54 to 3.02) 168 more per 1,000 (from 276 fewer to 1,000 more) LOW CRITICAL Durable response - Observational Studies 12 2,5,6,7,8,9,10,11,12,13 observational studies c serious d not serious serious e not serious f none 172/219 (78.5%) 220/252 (87.3%) not estimable g VERY LOW CRITICAL

148 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations corticosteroids observation Relative (95% CI) Absolute (95% CI) Certainty Importance Remission - Randomized Clinical Trials - not reported CRITICAL Remission - Observational Studies 5 7,11,14,15,16 observational studies c serious d serious h serious e serious f none 36/47 (76.6%) 227/357 (63.6%) not estimable i VERY LOW CRITICAL Major bleeding - Randomized Clinical Trials 1 2 randomised trials not serious not serious not serious serious a none 0/19 (0.0%) 0/16 (0.0%) not estimable MODERATE CRITICAL Major bleeding - Observational Studies 6 2,7,8,11,15 observational studies c serious d not serious serious e serious f none 0/82 (0.0%) 0/176 (0.0%) not estimable VERY LOW CRITICAL Mortality - Randomized Clinical Trials - not reported CRITICAL Mortality - Observational Studies 6 2,7,9,11,12,15 observational studies c serious d not serious serious e serious f none 0/53 (0.0%) 0/285 (0.0%) not estimable VERY LOW CRITICAL Overall health-related quality of life - Observational Studies/Randomized Clinical Trials - not reported CRITICAL

149 CI: Confidence interval; RR: Risk ratio Explanations a. Confidence interval does not exclude thresholds for plausible benefit or harm b. Response within 1 month is a surrogate (indirect outcome) outcome for durable response c. Durable response: Steroids: 3 RCTs, 3 prospective studies; Observation: 5 retrospective studies, 1 prospective study; Remission: Steroids: 1 RCT; Observation: 4 retrospective studies; Major bleeding: Steroids: 2 RCTs; Observation: 4 retrospective studies; Mortality: Observation: Steroids: 1 RCT; Observation: 5 retrospective studies d. Studies evaluating 'observation' are largely retrospective chart reviews with concerns about selection bias and measurement of outcomes e. Evaluating observational studies so not reporting any clinical studies directly comparing observation and steroids f. No relative effect calculated between observation and steroids (therefore no confidence interval) g. Durable response: Steroids: pooled estimate is 77% (95% CI 65-85%) [study estimates range from 56% to 89%]; Observation pooled estimate is 85% (95% CI 71-93%) [study estimates range from 63% to 96%] h. Confidence intervals within an arm do not overlap i. Remission: Steroids: 1 study 77% (95% CI 62% to 87%); Observation pooled estimate is 68% (95% CI 51-82%) [study estimates range from 51% to 95%] References 1. Blanchette, V. S., Luke, B., Andrew, M., Sommerville-Nielsen, S., Barnard, D., de Veber, B., Gent, M.. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. Journal of Pediatrics; Dec Fujisawa, K., Iyori, H., Ohkawa, H., Konishi, S., Bessho, F., Shirahata, A., Miyazaki, S., Akatsuka, J., Japanese Study Group on Childhood, I. T. P.. A prospective, randomized trial of conventional, dose-accelerated corticosteroids and intravenous immunoglobulin in children with newly diagnosed idiopathic thrombocytopenic purpura. International Journal of Hematology; Oct Sartorius, J. A.. Steroid treatment of idiopathic thrombocytopenic purpura in children. Preliminary results of a randomized cooperative study. American Journal of Pediatric Hematology/Oncology; Summer Buchanan, G. R., Holtkamp, C. A.. Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura. A randomized clinical trial. American Journal of Pediatric Hematology/Oncology; Winter V, Blanchette, P, Imbach, M, Andrew, M, Adams, J, McMillian, E, Wang, R, Milner, K, Ali, D, Barnard, M, Bernstein, KW, Chan, D, Esseltine, B, deveber, S, Israels, N, Kobrinsky, B, Luke. Randomised trials of intravenous immunoglobulin G, intravenous anti-d, and oral prednisone in childhood acute immune thromobcytopenic purpura. Lancet; Ozsoylu, S.. HIGH-DOSE INTRAVENOUS METHYLPREDNISOLONE FOR CHRONIC IDIOPATHIC THROMBOCYTOPENIC PURPURA. Acta Haematologica; Dickerhoff, R., von Ruecker, A.. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. Journal of Pediatrics; Nov Duru, Feride, Fisgin, Tunc, Yarali, Nese, Kara, Abdurrahman. Clinical course of children with immune thrombocytopenic purpura treated with intravenous immunoglobulin G or megadose methylprednisolone or observed without therapy. Pediatric Hematology & Oncology; Jun Kumar, Manjusha, Vik, Terry A., Johnson, Cynthia S., Southwood, M. Elaine, Croop, James M.. Treatment, outcome, and cost of care in children with idiopathic thrombocytopenic purpura. American Journal of Hematology; Mar 2005.

150 10. Mazzucconi, M. G., Francesconi, M., Fidani, P., Di Nucci, G., Gandolfo, G. M., Afeltra, A., Masala, C., Di Prima, M., Rocchi, G., Resta, S., et al.,. Treatment of idiopathic thrombocytopenic purpura (ITP): results of a multicentric protocol. Haematologica; Jul-Aug Imbach, P., Berchtold, W., Wagner, H. P., Gaedicke, G., Barandun, S., et al.,. Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet; Yildiz, Inci, Ozdemir, Nihal, Celkan, Tiraje, Soylu, Selen, Karaman, Serap, Canbolat, Aylin, Dogru, Omer, Erginoz, Ethem, Apak, Hilmi. Initial Management of Childhood Acute Immune Thrombocytopenia: Single-Center Experience of 32 Years. Pediatric Hematology & Oncology; Ou, Chun-Yen, Hsieh, Kai-Sheng, Chiou, Yee-Hsuan, Chang, Yu-Hsiang, Ger, Luo-Ping. A comparative study of initial use of intravenous immunoglobulin and prednisolone treatments in childhood idiopathic thrombocytopenic purpur. Acta Paediatrica Taiwanica; Sep-Oct Mori, P. G., Lanza, T., Mancuso, G., De Mattia, D., Catera, P., Miano, C., Del Principe, D., Cottafava, F.. Treatment of acute idiopathic thrombocytopenic purpura (AITP): cooperative Italian study group results. Pediatric Hematology & Oncology; Baronci, C., Petrone, A., Miano, C., Lombardi, A., Caniglia, M., Russo, L. A., Luciani, M., Pinto, R. M., Rana, I., Caruso, R., De Rossi, G.. Treatment of acute idiopathic thrombocytopenic purpura in children. A retrospective evaluation of 120 cases. Annali Dell'Istituto Superiore di Sanita; Sezgin Evim, M., Baytan, B., Gunes, A. M.. Childhood immune thrombocytopenia: Long-term follow-up data evaluated by the criteria of the international working group on immune thrombocytopenic purpura Cocukluk cagi{dotless}nda immun trombositopeni: Uluslararasi{dotless} immun trombositopeni cali{dotless}sma grubunun kriterlerine gore uzun izlem verilerinin degerlendirilmesi. Turkish Journal of Hematology; 2014.

151 QUESTION Should IVIG vs. observation be used for children with newly diagnosed ITP and no or minor bleeding (Q13)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: children with newly diagnosed ITP and no or minor bleeding (Q13) IVIG observation Durable Response; Major bleeding; Mortality; Overall health-related quality of life; Remission; New outcome; SETTING: Study inclusion: All RCTs; all prospective of at least 25 patients (children). For observation also included retrospective studies of at least 25 patients (children). PERSPECTIVE: BACKGROUND: Significant thrombocytopenia is a common finding in children with newly diagnosed ITP. Despite having severe thrombocytopenia severe bleeding events are rare in children with ITP. The decision to treat a child with no or minor bleeding is based on a presumed increased risk of subsequent bleeding without treatment. Therapy should therefore be aimed at preventing subsequent bleeding not just increasing the platelet count. The true impact of IVIG treatment compared to no treatment with regards to important patient-related outcomes in this population is not known. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Both RCT and observational data were used. RCT data are directly below. See GRADE evidence table at end of document for observational data and RCT data. Trivial desirable effects for IVIG.

152 Outcomes of participants (studies) Follow up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects * (95% CI) Risk with observation Risk difference with IVIG Durable Response 34 (1 RCT) 1 LOW a RR 1.09 (0.82 to 1.46) Study population 813 per 1, more per 1,000 (146 fewer to 374 more) Major bleeding - not reported Mortality - not reported Overall healthrelated quality of life - not reported Remission - not reported New outcome 0 ( studies) - not estimable Study population 0 per 1,000 0 fewer per 1,000 (0 fewer to 0 fewer)

153 1. Blanchette, V. S., Luke, B., Andrew, M., Sommerville-Nielsen, S., Barnard, D., de Veber, B., Gent, M.. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. Journal of Pediatrics; Dec a. Confidence interval does not exclude thresholds of plausible benefit or harm d observational data were used. RCT data are directly below. See GRADE evidence table at end of document for observational data and RCT data. Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial The panel felt there are moderate undesirable effects for IVIG even though they were not captured based on experience. Side effects include headache which may lead to CT scans. Side effects are serious but not life-threatening so the panel judged the undesirable effects as moderate. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies

154 Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Favors observation. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings IVIG dose range is 1 mg/kg - 2 mg/kg for 30 kg child. Cost ranges from $3, $10, based on data from LexiComp (range is inclusive of pricing variation among IVIG preparations). From Kumar 2005: Initial treatment charges (in USD): Anti-D: 2,037(833 8,389) IVIG: 2,926(701 9,517) Steroids: 1,737(362 3,995) Observation: 595(367 2,915)

155 Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity?

156 Reduced Probably reduced Probably no impact Probably increased Increased Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes Issues with IVIG include Jehovah s witness patients who do not want blood product. Also, half day to receive infusion can be problematic. Some patients who have received report not wanting it again. Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability

157 JUDGEMENT BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel recommends against IVIG rather than observation in children with newly diagnosed ITP and no or minor bleeding. Strong recommendation based on very low certainty in the evidence about effects. (#3 paradigmatic situation when low quality evidence suggest equivalence of IVIG and observation, but high quality evidence of less harm for observation as compared to IVIG; IVIG has a black box warning for risk of renal failure). Justification

158 Subgroup considerations Implementation considerations Monitoring and evaluation Research priorities

159 Author(s): OU Sooner GRADE Team Date: August 2017 Question: IVIG compared to observation in children with newly diagnosed ITP and no or minor bleeding for initial therapy (Q13) Observational data Setting: Study inclusion: All RCTs; all prospective studies of at least 25 patients (children). For observation also included retrospective studies of at least 25 patients (children). Bibliography: Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations IVIG observation Relative (95% CI) Absolute (95% CI) Certainty Importance Durable Response - Randomized Clinical Trials 1 randomised trials not serious not serious not serious very serious a none 16/18 (88.9%) 13/16 (81.3%) RR 1.09 (0.82 to 1.46) 73 more per 1,000 (from 146 fewer to 374 more) LOW CRITICAL Durable response - Observational Studies 15 1,2,3,4,5,6,7,8,9,10,11,12,13 observational studies b serious c not serious serious d not serious e none 202/249 (81.1%) 232/268 (86.6%) not estimable f VERY LOW CRITICAL Remission - Randomized Clinical Trials - not reported CRITICAL Remission - Observational Studies 7 2,5,14,15,16,17,18 observational studies b serious c serious g,h serious d serious e none 64/82 (78.0%) 227/357 (63.6%) not estimable i VERY LOW CRITICAL

160 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations IVIG observation Relative (95% CI) Absolute (95% CI) Certainty Importance Major bleeding - Randomized Clinical Trials - not reported CRITICAL Major bleeding - Observational Studies 10 3,5,6,9,12,15,17,18 observational studies b serious c serious g serious d serious e none 1/158 (0.6%) 0/192 (0.0%) not estimable j VERY LOW CRITICAL Mortality - Randomized Clinical Trials - not reported CRITICAL Mortality - Observational Studies 7 3,5,7,13,15,18 observational studies b serious c serious g serious d serious e none 1/55 (1.8%) 0/301 (0.0%) not estimable VERY LOW CRITICAL Overall health-related quality of life- Randomized Clinical Trials and Observational Studies - not reported CRITICAL Hemolysis (yes/no) - Randomized Clinical Trials not estimable - CRITICAL Hemolysis (yes/no) - Observational Studies 3 9,19,20 observational studies not serious serious k serious d serious e none 8/126 (6.3%) not estimable VERY LOW CRITICAL

161 CI: Confidence interval; RR: Risk ratio Explanations a. Confidence interval does not exclude thresholds of plausible benefit or harm b. Durable response: IVIG: 8 RCTs; Observation: 2 RCTS, 5 retrospective studies; Remission: IVIG: 3 RCTS; Observation: 4 retrospective studies; Major bleeding: IVIG: 5 RCTs; Observation: 1 RCT, 4 retrospective studies; Mortality: IVIG: 1 RCT; Observation: 1 RCT, 5 retrospective studies; Hemolysis (yes/no): IVIG: 3 RCTs; Observation: No studies c. Studies evaluating 'observation' are largely retrospective chart reviews with concerns about selection bias and measurement of outcomes d. Evaluating observational studies with each arm of data separately so not reporting any clinical studies directly comparing IVIG and observation e. No relative effect calculated between IVIG and observation (therefore no confidence interval) f. Durable response: IVIG: pooled estimate is 80% (95% CI 75-85%) [study estimates range from 74% to 91%]; Observation pooled estimate is 84% (95% CI 72-91%) [study estimates range from 63% to 96%] g. No steroids studies therefore no estimate of effects for steroids h. Confidence intervals within an arm do not overlap i. Remission: IVIG pooled estimate is 77% (95% CI 67-85%) [study estimates range from 67% to 83%]; Observation pooled estimate is 68% (95% CI 51-82%) [study estimates range from 51% to 95%] j. Major bleeding: IVIG: Study estimates range from 0% to 2% (5 studies); Observation: Study estimates 0% (5 studies) k. No observational studies therefore no estimate of effects for observation References 1. V, Blanchette, P, Imbach, M, Andrew, M, Adams, J, McMillian, E, Wang, R, Milner, K, Ali, D, Barnard, M, Bernstein, KW, Chan, D, Esseltine, B, deveber, S, Israels, N, Kobrinsky, B, Luke. Randomised trials of intravenous immunoglobulin G, intravenous anti-d, and oral prednisone in childhood acute immune thromobcytopenic purpura. Lancet; Celik, Muhittin, Bulbul, Ali, Aydogan, Gonul, Tugcu, Deniz, Can, Emrah, Uslu, Sinan, Dursun, Mesut. Comparison of anti-d immunoglobulin, methylprednisolone, or intravenous immunoglobulin therapy in newly diagnosed pediatric immune thrombocytopenic purpura. Journal of Thrombosis & Thrombolysis; Feb Fujisawa, K., Iyori, H., Ohkawa, H., Konishi, S., Bessho, F., Shirahata, A., Miyazaki, S., Akatsuka, J., Japanese Study Group on Childhood, I. T. P.. A prospective, randomized trial of conventional, dose-accelerated corticosteroids and intravenous immunoglobulin in children with newly diagnosed idiopathic thrombocytopenic purpura. International Journal of Hematology; Oct Ozsoylu, S.. HIGH-DOSE INTRAVENOUS METHYLPREDNISOLONE FOR CHRONIC IDIOPATHIC THROMBOCYTOPENIC PURPURA. Acta Haematologica; Dickerhoff, R., von Ruecker, A.. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. Journal of Pediatrics; Nov Duru, Feride, Fisgin, Tunc, Yarali, Nese, Kara, Abdurrahman. Clinical course of children with immune thrombocytopenic purpura treated with intravenous immunoglobulin G or megadose methylprednisolone or observed without therapy. Pediatric Hematology & Oncology; Jun Kumar, Manjusha, Vik, Terry A., Johnson, Cynthia S., Southwood, M. Elaine, Croop, James M.. Treatment, outcome, and cost of care in children with idiopathic thrombocytopenic purpura. American Journal of Hematology; Mar 2005.

162 8. Rosthoj, S., Nielsen, S., Pedersen, F. K.. Randomized trial comparing intravenous immunoglobulin with methylprednisolone pulse therapy in acute idiopathic thrombocytopenic purpura. Danish I.T.P. Study Group. Acta Paediatrica; Aug Erduran, Erol, Aslan, Yakup, Gedik, Yusuf, Orhan, Fazil. A randomized and comparative study of intravenous immunoglobulin and mega dose methylprednisolone treatments in children with acute idiopathic thrombocytopenic purpura. Turkish Journal of Pediatrics; Oct-Dec Ozsoylu, S., Sayli, T. R., Ozturk, G.. Oral megadose methylprednisolone versus intravenous immunoglobulin for acute childhood idiopathic thrombocytopenic purpura. Pediatric Hematology & Oncology; Oct-Dec Imbach, P.. A multicenter European trial of intravenous immune globulin in immune thrombocytopenic purpura in childhood. Vox Sanguinis; Benesch, M., Kerbl, R., Lackner, H., Berghold, A., Schwinger, W., Triebl-Roth, K., Urban, C.. Low-dose versus high-dose immunoglobulin for primary treatment of acute immune thrombocytopenic purpura in children: Results of a prospective, randomized single-center trial. Journal of Pediatric Hematology Oncology; Oct Yildiz, Inci, Ozdemir, Nihal, Celkan, Tiraje, Soylu, Selen, Karaman, Serap, Canbolat, Aylin, Dogru, Omer, Erginoz, Ethem, Apak, Hilmi. Initial Management of Childhood Acute Immune Thrombocytopenia: Single-Center Experience of 32 Years. Pediatric Hematology & Oncology; Mori, P. G., Lanza, T., Mancuso, G., De Mattia, D., Catera, P., Miano, C., Del Principe, D., Cottafava, F.. Treatment of acute idiopathic thrombocytopenic purpura (AITP): cooperative Italian study group results. Pediatric Hematology & Oncology; Baronci, C., Petrone, A., Miano, C., Lombardi, A., Caniglia, M., Russo, L. A., Luciani, M., Pinto, R. M., Rana, I., Caruso, R., De Rossi, G.. Treatment of acute idiopathic thrombocytopenic purpura in children. A retrospective evaluation of 120 cases. Annali Dell'Istituto Superiore di Sanita; Sezgin Evim, M., Baytan, B., Gunes, A. M.. Childhood immune thrombocytopenia: Long-term follow-up data evaluated by the criteria of the international working group on immune thrombocytopenic purpura Cocukluk cagi{dotless}nda immun trombositopeni: Uluslararasi{dotless} immun trombositopeni cali{dotless}sma grubunun kriterlerine gore uzun izlem verilerinin degerlendirilmesi. Turkish Journal of Hematology; Papagianni, Andromachi, Economou, Marina, Tragiannidis, Athanasios, Karatza, Eliza, Tsatra, Ioanna, Gombakis, Nikolaos, Athanassiadou-Piperopoulou, Fani, Athanasiou-Metaxa, Miranda. Standard-dose intravenous anti-d immunoglobulin versus intravenous immunoglobulin in the treatment of newly diagnosed childhood primary immune thrombocytopenia. Journal of Pediatric Hematology/Oncology; May Imbach, P., Berchtold, W., Wagner, H. P., Gaedicke, G., Barandun, S., et al.,. Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet; Blanchette, V., Imbach, P., Andrew, M., Adams, M., Luke, B., et al.,. Randomized trial of intravenous immunoglobulin G, intravenous anti-d, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet; Tarantino, M. D., Young, G., Bertolone, S. J., Kalinyak, K. A., Shafer, F. E., Kulkarni, R., Weber, L. C., Davis, M. L., Lynn, H., Nugent, D. J.. Single dose of anti-d immune globulin at 75mg/kg is as effective as intravenous immune globulin at rapidly raising the platelet count in newly diagnosed immune thrombocytopenic purpura in children. Journal of Pediatrics; 2006.

163 QUESTION Should anti-d immunoglobulin vs. observation be used for children with newly diagnosed ITP and no or minor bleeding for initial therapy (Q14)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: children with newly diagnosed ITP and no or minor bleeding for initial therapy (Q14) anti-d immunoglobulin observation Durable response; Remission; Major bleeding; Hemolysis: Yes/No; Mortality; Overall health-related quality of life; SETTING: Study inclusion: All RCTs; all prospective studies of at least 25 patients (children). For observation also included retrospective studies of at least 25 patients (children). PERSPECTIVE: BACKGROUND: Significant thrombocytopenia is a common finding in children with newly diagnosed ITP. Despite having severe thrombocytopenia severe bleeding events are rare in children with ITP. The decision to treat a child with no or minor bleeding is based on a presumed increased risk of subsequent bleeding without treatment. Therapy should therefore be aimed at preventing subsequent bleeding not just increasing the platelet count. The true impact of anti-d immunoglobulin treatment compared to no treatment with regards to important patient-related outcomes in this population is not known. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large See GRADE evidence table for one-armed observational data. Trial desirable effects for Anti-D.

164 Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial See GRADE evidence table for one-armed observational data. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison?

165 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Probably favors observation. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Anti-D mcg.kg for a 30 kg child ranges from $975-$3037 from LexiComp. From Kumar 2005: Initial treatment charges (in USD): Anti-D: 2,037(833 8,389) IVIG: 2,926(701 9,517) Steroids: 1,737(362 3,995) Observation: 595(367 2,915) Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

166 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Anti-D is not available in many European countries and requires the patient to be Rh+. Acceptability Is the acceptable to key stakeholders?

167 No Probably no Probably yes Yes Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

168 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel recommends for observation rather than anti-d immunoglobulin in children with newly diagnosed ITP and no or minor bleeding for initial therapy. Strong recommendation based on very low certainty in the evidence about effects. (#3 paradigmatic situation when low quality evidence suggest equivalence of anti-d and observation, but high quality evidence of less harm for observation as compared to anti-d; Anti-D has a black box warning for risk of hemolysis). Justification Subgroup considerations Implementation considerations

169 Monitoring and evaluation Research priorities

170 Author(s): OU Sooner GRADE Team Date: August 2017 Question: Anti-D immunoglobulin compared to observation in children with newly diagnosed ITP and no or minor bleeding for initial therapy (Q14) Setting: Study inclusion: All RCTs; all prospective studies of at least 25 patients (children). For observation also included retrospective studies of at least 25 patients (children). Bibliography: Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations anti-d immunoglobulin observation Relative (95% CI) Absolute (95% CI) Certainty Importance Durable response 11 1,2,3,4,5,6,7,8,9,10,11 observational studies a serious b not serious serious c not serious d none 159/221 (71.9%) 245/284 (86.3%) not estimable e VERY LOW CRITICAL Remission 6 8,11,12,13,14,15 observational studies a serious b serious f serious c serious d none 20/30 (66.7%) 227/357 (63.6%) not estimable g VERY LOW CRITICAL Major bleeding 2 6,8 observational studies a serious b serious h serious c serious d none 0/208 (0.0%) not estimable VERY LOW CRITICAL Hemolysis: Yes/No 3 2,3,16 observational studies a not serious serious i,j serious c serious d none 32/211 (15.2%) not estimable k VERY LOW CRITICAL Mortality

171 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations anti-d immunoglobulin observation Relative (95% CI) Absolute (95% CI) Certainty Importance 4 3,8,10,17 observational studies a serious b not serious serious c serious d none 0/148 (0.0%) 0/301 (0.0%) not estimable VERY LOW CRITICAL Overall health-related quality of life - not reported CRITICAL CI: Confidence interval Explanations a. Durable response: Observation: 7 retrospective studies; Anti-D: 3 RCTs, 1 prospective study; Remission: Observation: 4 retrospective studies; Anti-D: 2 RCTs; Major bleeding: Observation: 1 retrospective study; Hemolysis: Anti-D: 2 RCTS, 1 prospective study; Mortality: Observation: 3 retrospective studies; Anti-D: 1 RCT b. Observational studies are largely retrospective chart reviews with concerns about selection bias and measurement of outcomes c. No clinical studies directly comparing observation and anti-d d. No relative effect calculated between observation and anti-d (therefore no confidence interval) e. Durable response: Observation pooled estimate is 85% (95% CI 73-92%) [study estimates range from 63% to 88%]; anti-d pooled estimate is 71% (95% CI 64-78%) [study estimates range from 64% to 85%] f. Confidence intervals within an arm do not overlap g. Remission: Observation pooled estimate is 68% (95% CI 51-81%) [study estimates range from 51% to 93%]; anti-d pooled estimate is 69% (95% CI 52-82%) [study estimates range from 67% to 70%] h. No Anti-D studies therefore no estimate of effects for anti-d i. Point estimates are variable within one arm j. No observational studies therefore no estimate of effects for observation k. Hemolysis: Study estimates range from 2% to 80% References 1. V, Blanchette, P, Imbach, M, Andrew, M, Adams, J, McMillian, E, Wang, R, Milner, K, Ali, D, Barnard, M, Bernstein, KW, Chan, D, Esseltine, B, deveber, S, Israels, N, Kobrinsky, B, Luke. Randomised trials of intravenous immunoglobulin G, intravenous anti-d, and oral prednisone in childhood acute immune thromobcytopenic purpura. Lancet; 1994.

172 2. Moser, A. M., Shalev, H., Kapelushnik, J.. Anti-D exerts a very early response in childhood acute idiopathic thrombocytopenic purpura. Pediatric Hematology & Oncology; Sep Swain, T. R., Jena, R. K., Swain, K. P.. High dose intravenous anti-d immune globulin is more effective and safe in Indian paediatric patients of immune thrombocytopenic purpura. Journal of Clinical and Diagnostic Research; 01 Dec Celik, Muhittin, Bulbul, Ali, Aydogan, Gonul, Tugcu, Deniz, Can, Emrah, Uslu, Sinan, Dursun, Mesut. Comparison of anti-d immunoglobulin, methylprednisolone, or intravenous immunoglobulin therapy in newly diagnosed pediatric immune thrombocytopenic purpura. Journal of Thrombosis & Thrombolysis; Feb Blanchette, V. S., Luke, B., Andrew, M., Sommerville-Nielsen, S., Barnard, D., de Veber, B., Gent, M.. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. Journal of Pediatrics; Dec Fujisawa, K., Iyori, H., Ohkawa, H., Konishi, S., Bessho, F., Shirahata, A., Miyazaki, S., Akatsuka, J., Japanese Study Group on Childhood, I. T. P.. A prospective, randomized trial of conventional, dose-accelerated corticosteroids and intravenous immunoglobulin in children with newly diagnosed idiopathic thrombocytopenic purpura. International Journal of Hematology; Oct Ozsoylu, S.. HIGH-DOSE INTRAVENOUS METHYLPREDNISOLONE FOR CHRONIC IDIOPATHIC THROMBOCYTOPENIC PURPURA. Acta Haematologica; Dickerhoff, R., von Ruecker, A.. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. Journal of Pediatrics; Nov Duru, Feride, Fisgin, Tunc, Yarali, Nese, Kara, Abdurrahman. Clinical course of children with immune thrombocytopenic purpura treated with intravenous immunoglobulin G or megadose methylprednisolone or observed without therapy. Pediatric Hematology & Oncology; Jun Kumar, Manjusha, Vik, Terry A., Johnson, Cynthia S., Southwood, M. Elaine, Croop, James M.. Treatment, outcome, and cost of care in children with idiopathic thrombocytopenic purpura. American Journal of Hematology; Mar Sezgin Evim, M., Baytan, B., Gunes, A. M.. Childhood immune thrombocytopenia: Long-term follow-up data evaluated by the criteria of the international working group on immune thrombocytopenic purpura Cocukluk cagi{dotless}nda immun trombositopeni: Uluslararasi{dotless} immun trombositopeni cali{dotless}sma grubunun kriterlerine gore uzun izlem verilerinin degerlendirilmesi. Turkish Journal of Hematology; Mori, P. G., Lanza, T., Mancuso, G., De Mattia, D., Catera, P., Miano, C., Del Principe, D., Cottafava, F.. Treatment of acute idiopathic thrombocytopenic purpura (AITP): cooperative Italian study group results. Pediatric Hematology & Oncology; Baronci, C., Petrone, A., Miano, C., Lombardi, A., Caniglia, M., Russo, L. A., Luciani, M., Pinto, R. M., Rana, I., Caruso, R., De Rossi, G.. Treatment of acute idiopathic thrombocytopenic purpura in children. A retrospective evaluation of 120 cases. Annali Dell'Istituto Superiore di Sanita; Papagianni, Andromachi, Economou, Marina, Tragiannidis, Athanasios, Karatza, Eliza, Tsatra, Ioanna, Gombakis, Nikolaos, Athanassiadou-Piperopoulou, Fani, Athanasiou-Metaxa, Miranda. Standard-dose intravenous anti-d immunoglobulin versus intravenous immunoglobulin in the treatment of newly diagnosed childhood primary immune thrombocytopenia. Journal of Pediatric Hematology/Oncology; May Celik,, M.,, Bulbul,, A.,, Aydogan,, G.,, Tugcu,, D.,, Can,, E.,, Uslu,, S.,, Dursun,, M.,. Comparison of anti-d immunoglobulin, methylprednisolone, or intravenous immunoglobulin therapy in newly diagnosed pediatric immune thrombocytopenic purpura. Journal of Thrombosis & Thrombolysis; Blanchette, V., Imbach, P., Andrew, M., Adams, M., Luke, B., et al.,. Randomized trial of intravenous immunoglobulin G, intravenous anti-d, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet; Yildiz, Inci, Ozdemir, Nihal, Celkan, Tiraje, Soylu, Selen, Karaman, Serap, Canbolat, Aylin, Dogru, Omer, Erginoz, Ethem, Apak, Hilmi. Initial Management of Childhood Acute Immune Thrombocytopenia: Single-Center Experience of 32 Years. Pediatric Hematology & Oncology; 2015.

173 QUESTION Should anti-d immunoglobulin vs. corticosteroids be used for children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life (Q15)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life (Q15) anti-d immunoglobulin corticosteroids Durable Response; Remission; Hemolysis hemoglobin < 100 gm/l; Overall health-related quality of life; Major Bleeding; Mortality; SETTING: Study inclusion: All RCTs; all prospective of at least 25 patients (children). PERSPECTIVE: BACKGROUND: Some children with ITP will experience more significant bleeding and/or have diminished health-related quality of life from ITP. In the absence of life-threatening bleeding first-line therapy includes corticosteroids, IVIG, and anti-d immunoglobulin. Each of these treatments is different with regards to route of administration, time to response, and potential side effects. The FDA placed a black box warning on Anti-D immunoglobulin secondary to fatal intravascular hemolysis. Since that time ongoing data suggests that the original safety signal may not remain a significant concern. The role of anti-d immunoglobulin in reference to corticosteroids should therefore be reexamined in setting of new safety data and other important patient-related outcomes. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Don't know Both RCT and observational data were used. RCT data are directly below. See GRADE evidence table at end of document for observational data Panel members thought we were missing too much data. Relevant data was not available.

174 Outcomes of participants (studies) Follow up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects * (95% CI) Risk with corticosteroids Risk difference with anti-d immunoglobulin Durable Response 66 (1 RCT) 1 LOW a RR 0.72 (0.54 to 0.97) Study population 879 per 1, fewer per 1,000 (404 fewer to 26 fewer) Remission - not reported Hemolysis hemoglobin < 100 gm/l 77 (1 RCT) 1 HIGH RR 0.77 (0.64 to 0.92) Study population 0 per 1,000 0 fewer per 1,000 (0 fewer to 0 fewer) Overall healthrelated quality of life - not reported Major Bleeding - not reported Mortality - not reported

175 1. Blanchette, V., Imbach, P., Andrew, M., Adams, M., Luke, B., et al.,. Randomized trial of intravenous immunoglobulin G, intravenous anti-d, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet; a. Confidence interval does not exclude thresholds for plausible benefit or harm Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Small undesirable effects for Anti-D. Most patients who take corticosteroids have side effects where few patients who take anti-d have side effects. However the Anti-D side effects are more serious. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Only 1 RCT and observational data. Values Is there important uncertainty about or variability in how much people value the main outcomes?

176 Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Don't know Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Prednisone dose range 2 mg/kg/d - 4 mg/kg/d for 7 days for a 30 kg child. Cost ranges from $ $10.92 based on data from LexiComp. Anti-D mcg.kg for a 30 kg child ranges from $975-$3037 from LexiComp. From Kumar 2005: Initial treatment charges (in USD): Anti-D: 2,037(833 8,389) IVIG: 2,926(701 9,517) Steroids: 1,737(362 3,995) Observation: 595(367 2,915) Anti-D is more expensive. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

177 Very low Low Moderate High No included studies Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Anti-D is not available everywhere, for example it is not available in Switzerland. Acceptability Is the acceptable to key stakeholders?

178 No Probably no Probably yes Yes Feasibility Is the feasible to implement? No Probably no Probably yes Yes Not available in many European countries and patients with must be Rh+ status to receive Anti-D. SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

179 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests for corticosteroids rather than anti-d immunoglobulin in children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life. Conditional recommendation based on very low certainty in the evidence about effects. 8 voted conditional against anti-d/for corticosteroids 6 vote conditional for either 1 abstained Conditional recommendation for corticosteroids Justification Patients values factored into the decision. Different patients may prefer different options (up to 4 hour infusion vs pills). Subgroup considerations

180 Implementation considerations Monitoring and evaluation Research priorities

181 Author(s): OU Sooner GRADE Team Date: August 2017 Question: Corticosteroids compared to anti-d immunoglobulin in children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life (Q15) Observational data Setting: Study inclusion: All RCTs; all prospective studies of at least 25 patients (children). Bibliography: Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations corticosteroids anti-d immunoglobulin Relative (95% CI) Absolute (95% CI) Certainty Importance Durable Response - Randomized Clinical Trials 1 1 randomised trials not serious not serious not serious very serious a none 21/33 (63.6%) 29/33 (87.9%) RR 0.72 (0.54 to 0.97) 246 fewer per 1,000 (from 26 fewer to 404 fewer) LOW CRITICAL Durable response - Observational Studies 10 2,3,4,5,6,7,8,9,10 observational studies b,c not serious not serious serious d not serious e none 170/222 (76.6%) 138/188 (73.4%) not estimable f VERY LOW CRITICAL Remission - Randomized Clinical Trials - not reported Remission- Observational Studies 3 4,9,11 observational studies b not serious serious g serious d serious e none 36/47 (76.6%) 20/30 (66.7%) not estimable h VERY LOW CRITICAL

182 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations corticosteroids anti-d immunoglobulin Relative (95% CI) Absolute (95% CI) Certainty Importance Major Bleeding - Randomized Clinical Trials - not reported CRITICAL Major bleeding - Observational Studies 4 5,6,9 observational studies b not serious serious i serious d serious e none 0/118 (0.0%) not estimable VERY LOW CRITICAL Hemolysis hemoglobin < 100 gm/l - Randomized Clinical Trials 1 1 randomised trials not serious not serious not serious not serious none 9/38 (23.7%) 0/39 (0.0%) RR 0.77 (0.64 to 0.92) 0 fewer per 1,000 (from 0 fewer to 0 fewer) HIGH CRITICAL Hemolysis: a side effect of anti-d immunoglobulin - Observational Studies 2 2,3 observational studies b not serious serious i,j serious d serious e none 0/118 (0.0%) 23/173 (13.3%) not estimable k VERY LOW CRITICAL Mortality - Randomized Clinical Trials - not reported CRITICAL Mortality- Observational Studies 2 3,9 observational studies b not serious not serious serious d serious e none 0/53 (0.0%) 0/148 (0.0%) not estimable VERY LOW CRITICAL

183 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations corticosteroids anti-d immunoglobulin Relative (95% CI) Absolute (95% CI) Certainty Importance Overall health-related quality of life - Randomized Clinical Trials and Observational Studies - not reported CRITICAL CI: Confidence interval; RR: Risk ratio; OR: Odds ratio Explanations a. Confidence interval does not exclude plausible benefit or harm b. Durable response: Steroids: 4 RCTS, 3 prospective study; Anti-D: 2 RCTs, 1 prospective study; Remission: Steroids: 1 RCTs; Anti-D: 2 RCTs; Hemolysis (yes/no): Steroids: No studies; Anti-D: 1 RCTS, 1 prospective study; Mortality: Steroids: 1 RCT; Anti-D: 1 RCT; Major bleeding: Steroids: 4 RCTs; Anti-D: No studies c. Major bleeding: Steroids: Study estimates 0% (4 studies); Anti-D: No studies d. No clinical studies directly comparing steroids and anti-d e. No relative effect calculated between steroids and anti-d (therefore no confidence interval) f. Durable response: Steroid pooled estimate is 75% (95% CI 65-82%) [study estimates range from 56% to 89%]; anti-d pooled estimate is 75% (95% CI 64-84%) [study estimates range from 73% to 85%] g. Confidence intervals within an arm do not overlap h. Remission: Steroids:1 study 77%; anti-d pooled estimate is 67% (95% CI 48-81%) [study estimates range from 60% to 70%] i. No anti-d studies therefore no estimate of effects for anti-d j. Point estimates are variable within one arm k. Hemolysis: Steroids: No studies; Anti-D: Study estimates range from 2% to 80% (2 studies) References 1. Blanchette, V., Imbach, P., Andrew, M., Adams, M., Luke, B., et al.,. Randomized trial of intravenous immunoglobulin G, intravenous anti-d, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet; Moser, A. M., Shalev, H., Kapelushnik, J.. Anti-D exerts a very early response in childhood acute idiopathic thrombocytopenic purpura. Pediatric Hematology & Oncology; Sep Swain, T. R., Jena, R. K., Swain, K. P.. High dose intravenous anti-d immune globulin is more effective and safe in Indian paediatric patients of immune thrombocytopenic purpura. Journal of Clinical and Diagnostic Research; 01 Dec 2016.

184 4. Celik, Muhittin, Bulbul, Ali, Aydogan, Gonul, Tugcu, Deniz, Can, Emrah, Uslu, Sinan, Dursun, Mesut. Comparison of anti-d immunoglobulin, methylprednisolone, or intravenous immunoglobulin therapy in newly diagnosed pediatric immune thrombocytopenic purpura. Journal of Thrombosis & Thrombolysis; Feb Blanchette, V. S., Luke, B., Andrew, M., Sommerville-Nielsen, S., Barnard, D., de Veber, B., Gent, M.. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. Journal of Pediatrics; Dec Fujisawa, K., Iyori, H., Ohkawa, H., Konishi, S., Bessho, F., Shirahata, A., Miyazaki, S., Akatsuka, J., Japanese Study Group on Childhood, I. T. P.. A prospective, randomized trial of conventional, dose-accelerated corticosteroids and intravenous immunoglobulin in children with newly diagnosed idiopathic thrombocytopenic purpura. International Journal of Hematology; Oct Mazzucconi, M. G., Francesconi, M., Fidani, P., Di Nucci, G., Gandolfo, G. M., Afeltra, A., Masala, C., Di Prima, M., Rocchi, G., Resta, S., et al.,. Treatment of idiopathic thrombocytopenic purpura (ITP): results of a multicentric protocol. Haematologica; Jul-Aug Ou, Chun-Yen, Hsieh, Kai-Sheng, Chiou, Yee-Hsuan, Chang, Yu-Hsiang, Ger, Luo-Ping. A comparative study of initial use of intravenous immunoglobulin and prednisolone treatments in childhood idiopathic thrombocytopenic purpur. Acta Paediatrica Taiwanica; Sep-Oct Imbach, P., Berchtold, W., Wagner, H. P., Gaedicke, G., Barandun, S., et al.,. Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet; Ozsoylu, S., Irken, G., Karabent, A.. High-dose intravenous methylprednisolone for acute childhood idiopathic thrombocytopenic purpura. European Journal of Haematology; May Papagianni, Andromachi, Economou, Marina, Tragiannidis, Athanasios, Karatza, Eliza, Tsatra, Ioanna, Gombakis, Nikolaos, Athanassiadou-Piperopoulou, Fani, Athanasiou-Metaxa, Miranda. Standard-dose intravenous anti-d immunoglobulin versus intravenous immunoglobulin in the treatment of newly diagnosed childhood primary immune thrombocytopenia. Journal of Pediatric Hematology/Oncology; May 2011.

185 QUESTION Should anti-d immunoglobulin vs. IVIG be used for children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life (Q16)? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life (Q16) anti-d immunoglobulin IVIG Durable Response; Remission; Hemolysis Yes/No; Overall health-related quality of life; Mortality; Major Bleeding; Hemolysis - Mean decrease in hemoglobin; Response 7 days Added; SETTING: Study inclusion: All RCTs; all prospective of at least 25 patients (children). PERSPECTIVE: BACKGROUND: Some children with ITP will experience more significant bleeding and/or have diminished health-related quality of life from ITP. In the absence of life-threatening bleeding first-line therapy includes corticosteroids, IVIG, and anti-d immunoglobulin. Each of these treatments is different with regards to route of administration, time to response, and potential side effects. The FDA placed a black box warning on Anti-D immunoglobulin secondary to fatal intravascular hemolysis. Since that time ongoing data suggests that the original safety signal may not remain a significant concern. The role of anti-d immunoglobulin in reference to corticosteroids should therefore be reexamined in setting of new safety data and other important patient-related outcomes. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Both RCT and observational data were used. RCT data are directly below. See GRADE evidence table at end of document for observational data and RCT data. IVIG - ; anti-d comparison; IVIG has a trivial anticipated desirable effects compared to anti-d (dosing differs between trials standard dose now 1 g/kg/day x1 for IVIG; 75 micrograms/kg x1 for anti-d).

186 Outcomes of participants (studies) Follow up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects * (95% CI) Risk with IVIG Risk difference with anti-d immunoglobulin Durable Response 136 (2 RCTs) 1,2 MODERATE a RR 0.80 (0.63 to 1.01) Study population 807 per 1, fewer per 1,000 (299 fewer to 8 more) Remission 161 (3 RCTs) 1,2,3 MODERATE a RR 0.85 (0.69 to 1.06) Study population 785 per 1, fewer per 1,000 (243 fewer to 47 more) Hemolysis Yes/No 107 (1 RCT) 1 MODERATE a RR 0.84 (0.69 to 1.01) Study population 87 per 1, fewer per 1,000 (27 fewer to 1 more) Overall healthrelated quality of life - not reported Mortality - not reported

187 Major Bleeding - not reported Hemolysis - Mean decrease in hemoglobin 252 (5 studies) MD 0.33 lower (1.02 lower to 0.37 higher) Response 7 days Added 254 (4 RCTs) MODERATE a RR 1.01 (0.90 to 1.15) Study population 866 per 1,000 9 more per 1,000 (87 fewer to 130 more) 1. Blanchette, V., Imbach, P., Andrew, M., Adams, M., Luke, B., et al.,. Randomized trial of intravenous immunoglobulin G, intravenous anti-d, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet; Celik,, M.,, Bulbul,, A.,, Aydogan,, G.,, Tugcu,, D.,, Can,, E.,, Uslu,, S.,, Dursun,, M.,. Comparison of anti-d immunoglobulin, methylprednisolone, or intravenous immunoglobulin therapy in newly diagnosed pediatric immune thrombocytopenic purpura. Journal of Thrombosis & Thrombolysis; Papagianni, Andromachi, Economou, Marina, Tragiannidis, Athanasios, Karatza, Eliza, Tsatra, Ioanna, Gombakis, Nikolaos, Athanassiadou- Piperopoulou, Fani, Athanasiou-Metaxa, Miranda. Standard-dose intravenous anti-d immunoglobulin versus intravenous immunoglobulin in the treatment of newly diagnosed childhood primary immune thrombocytopenia. Journal of Pediatric Hematology/Oncology; May a. Confidence interval does not exclude thresholds for plausible benefit or harm Undesirable Effects How substantial are the undesirable anticipated effects?

188 Large Moderate Small Trivial Don't know Data above in Desirable Effects. Panel brought up the headache side-effect of IVIG which may lead to CT scan which was not prioritized; unknown details of reported hemolysis. 7 day response for RCT data was added back in. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies low based on different dosing and all outcomes not addressed. Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Concerns of hemolysis vs headache/ct scan. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison?

189 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Don't know Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings IVIG dose range is 1 mg/kg - 2 mg/kg for 30 kg child. Cost ranges from $3, $10, based on data from LexiComp (range is inclusive of pricing variation among IVIG preparations). Anti-D mcg.kg for a 30 kg child ranges from $975-$3037 from LexiComp. IVIG 1 mg/kg vs Anti-D 75 mcg/kg are similar. From Kumar 2005: Initial treatment charges (in USD): Anti-D: 2,037(833 8,389) IVIG: 2,926(701 9,517) Steroids: 1,737(362 3,995) Observation: 595(367 2,915) Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

190 Very low Low Moderate High No included studies Are not accounting for administration, potential CT scan for IVIG, etc. Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included studies Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Anti-D not available in all countries (IVIG is more available). Acceptability Is the acceptable to key stakeholders?

191 No Probably no Probably yes Yes IVIG acceptability. Feasibility Is the feasible to implement? No Probably no Probably yes Yes SUMMARY OF JUDGEMENTS JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

192 JUDGEMENT ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation The ASH guideline panel suggests either IVIG or anti-d immunoglobulin in children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life. Conditional recommendation based on low certainty in the evidence about effects. Justification Subgroup considerations Implementation considerations

193 Different patients may prefer different treatments. Monitoring and evaluation Research priorities

194 Author(s): OU Sooner GRADE Team Date: August 2017 Question: IVIG compared to anti-d immunoglobulin in children with newly diagnosed ITP and non-life-threatening mucosal bleeding and/or diminished health related quality of life (Q16) Observational data Setting: Study inclusion: All RCTs; all prospective studies of at least 25 patients (children). Bibliography: Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations IVIG anti-d immunoglobulin Relative (95% CI) Absolute (95% CI) Certainty Importance Durable Response - Randomized Clinical Trials 2 1,2 randomised trials not serious not serious not serious serious a none 34/53 (64.2%) 67/83 (80.7%) RR 0.80 (0.63 to 1.01) 161 fewer per 1,000 (from 8 more to 299 fewer) MODERATE CRITICAL Durable response - Observational Studies 9 3,4,5,6,7,8,9,10,11 observational studies b not serious not serious serious c not serious d none 151/184 (82.1%) 125/168 (74.4%) not estimable e VERY LOW CRITICAL Remission - Randomized Clinical Trials 3 1,2,12 randomised trials not serious not serious not serious serious a none 45/68 (66.2%) 73/93 (78.5%) RR 0.85 (0.69 to 1.06) 118 fewer per 1,000 (from 47 more to 243 fewer) MODERATE CRITICAL

195 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations IVIG anti-d immunoglobulin Relative (95% CI) Absolute (95% CI) Certainty Importance Remission- Observational Studies 1 9 observational studies b not serious serious f serious c serious d none 39/47 (83.0%) not estimable g VERY LOW CRITICAL Response 7 days Added - Randomized Clinical Trials 4 2,13,14,15 randomised trials not serious not serious not serious serious a none 122/135 (90.4%) 103/119 (86.6%) RR 1.01 (0.90 to 1.15) 9 more per 1,000 (from 87 fewer to 130 more) MODERATE CRITICAL Hemolysis Yes/No - Randomized Clinical Trials 1 1 randomised trials not serious not serious not serious serious a none 9/38 (23.7%) 6/69 (8.7%) RR 0.84 (0.69 to 1.01) 14 fewer per 1,000 (from 1 more to 27 fewer) MODERATE CRITICAL Hemolysis - Mean Decrease in hemoglobin - Randomized Clinical Trials 5 2,12,13,15,16 randomised trials not serious not serious not serious serious a none MD 0.33 lower (1.02 lower to 0.37 higher) MODERATE CRITICAL

196 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations IVIG anti-d immunoglobulin Relative (95% CI) Absolute (95% CI) Certainty Importance Hemolysis Yes/No - Observational Studies 3 3,4,7 observational studies b not serious serious h serious c serious d none 0/22 (0.0%) 23/173 (13.3%) not estimable i VERY LOW CRITICAL Mortality - Randomized Clinical Trials - not reported CRITICAL Mortality- Observational Studies 2 4,9 observational studies b not serious not serious serious c serious d none 1/55 (1.8%) 0/148 (0.0%) not estimable VERY LOW CRITICAL Major Bleeding - Randomized Clinical Trials - not reported CRITICAL Major bleeding- Observational Studies 5 5,7,8,9,11 observational studies b not serious serious j serious c serious d none 1/161 (0.6%) not estimable k VERY LOW CRITICAL Overall health-related quality of life - Randomized Clinical Trials and Observational Studies - not reported CRITICAL CI: Confidence interval; RR: Risk ratio; MD: Mean difference Explanations a. Confidence interval does not exclude plausible benefit or harm

197 b. Durable response: IVIG: 7 RCTS; Anti-D: 1 RCTs, 1 prospective study; Remission: IVIG: 1 RCTs; Anti-D: No studies; Hemolysis (yes/no): IVIG: 1 RCT; Anti-D: 1 RCTS, 1 prospective study; Mortality: IVIG: 1 RCT; Anti-D: 1 RCT; Major bleeding: IVIG: 5 RCTs; Anti-D: No studies c. Using observational arms so not utilizing studies directly comparing IVIG and anti-d d. No relative effect calculated between IVIG and anti-d (therefore no confidence interval) e. Durable response: IVIG pooled estimate is 81% (95% CI 74-86%) [study estimates range from 74% to 91%]; anti-d pooled estimate is 75% (95% CI 64-84%) [study estimates range from 73% to 85%] f. Confidence intervals within an arm do not overlap g. Remission: IVIG 83% (95% CI 69-91%) [1 study]; anti-d no studies h. Point estimates are variable within one arm i. Hemolysis: IVIG: 1 study 0%; Anti-D: Study estimates range from 2% to 80% j. No Anti-D studies therefore no estimate of effects for anti-d k. Major bleeding: IVIG: Study estimates range from 0% to 2% (5 studies); Anti-D: no estimates References 1. Blanchette, V., Imbach, P., Andrew, M., Adams, M., Luke, B., et al.,. Randomized trial of intravenous immunoglobulin G, intravenous anti-d, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet; Celik,, M.,, Bulbul,, A.,, Aydogan,, G.,, Tugcu,, D.,, Can,, E.,, Uslu,, S.,, Dursun,, M.,. Comparison of anti-d immunoglobulin, methylprednisolone, or intravenous immunoglobulin therapy in newly diagnosed pediatric immune thrombocytopenic purpura. Journal of Thrombosis & Thrombolysis; Moser, A. M., Shalev, H., Kapelushnik, J.. Anti-D exerts a very early response in childhood acute idiopathic thrombocytopenic purpura. Pediatric Hematology & Oncology; Sep Swain, T. R., Jena, R. K., Swain, K. P.. High dose intravenous anti-d immune globulin is more effective and safe in Indian paediatric patients of immune thrombocytopenic purpura. Journal of Clinical and Diagnostic Research; 01 Dec Fujisawa, K., Iyori, H., Ohkawa, H., Konishi, S., Bessho, F., Shirahata, A., Miyazaki, S., Akatsuka, J., Japanese Study Group on Childhood, I. T. P.. A prospective, randomized trial of conventional, dose-accelerated corticosteroids and intravenous immunoglobulin in children with newly diagnosed idiopathic thrombocytopenic purpura. International Journal of Hematology; Oct Rosthoj, S., Nielsen, S., Pedersen, F. K.. Randomized trial comparing intravenous immunoglobulin with methylprednisolone pulse therapy in acute idiopathic thrombocytopenic purpura. Danish I.T.P. Study Group. Acta Paediatrica; Aug Erduran, Erol, Aslan, Yakup, Gedik, Yusuf, Orhan, Fazil. A randomized and comparative study of intravenous immunoglobulin and mega dose methylprednisolone treatments in children with acute idiopathic thrombocytopenic purpura. Turkish Journal of Pediatrics; Oct-Dec Benesch, M., Kerbl, R., Lackner, H., Berghold, A., Schwinger, W., Triebl-Roth, K., Urban, C.. Low-dose versus high-dose immunoglobulin for primary treatment of acute immune thrombocytopenic purpura in children: Results of a prospective, randomized single-center trial. Journal of Pediatric Hematology Oncology; Oct Imbach, P., Berchtold, W., Wagner, H. P., Gaedicke, G., Barandun, S., et al.,. Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet; Ozsoylu, S., Sayli, T. R., Ozturk, G.. Oral megadose methylprednisolone versus intravenous immunoglobulin for acute childhood idiopathic thrombocytopenic purpura. Pediatric Hematology & Oncology; Oct-Dec 1993.

198 11. Blanchette, V. S., Luke, B., Andrew, M., Sommerville-Nielsen, S., Barnard, D., de Veber, B., Gent, M.. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. Journal of Pediatrics; Dec Papagianni, Andromachi, Economou, Marina, Tragiannidis, Athanasios, Karatza, Eliza, Tsatra, Ioanna, Gombakis, Nikolaos, Athanassiadou-Piperopoulou, Fani, Athanasiou-Metaxa, Miranda. Standard-dose intravenous anti-d immunoglobulin versus intravenous immunoglobulin in the treatment of newly diagnosed childhood primary immune thrombocytopenia. Journal of Pediatric Hematology/Oncology; May Tarantino, M. D., Young, G., Bertolone, S. J., Kalinyak, K. A., Shafer, F. E., Kulkarni, R., Weber, L. C., Davis, M. L., Lynn, H., Nugent, D. J.. Single dose of anti-d immune globulin at 75mg/kg is as effective as intravenous immune globulin at rapidly raising the platelet count in newly diagnosed immune thrombocytopenic purpura in children. Journal of Pediatrics; Shahgholi, Elham, Vosough, Parvaneh, Sotoudeh, Kambiz, Arjomandi, Khadijeh, Ansari, Shahla, Salehi, Soraya, Faranoush, Mohammad, Ehsani, Mohammad Ali. Intravenous immune globulin versus intravenous anti-d immune globulin for the treatment of acute immune thrombocytopenic purpura. Indian Journal of Pediatrics; Dec Farahmandinia, Z., Naderi, A., Sabzevari, F., Parvaresh, S.. Comparison of intravenous immunoglobulin (IVIG) and intravenous anti-d for treatment of acute idiopathic thrombocytopenic purpura. International Journal of Hematology-Oncology and Stem Cell Research; Son, Dong Woo, Jeon, In-sang, Yang, Sung Wan, Cho, Sang Hee. A single dose of anti-d immunoglobulin raises platelet count as efficiently as intravenous immunoglobulin in newly diagnosed immune thrombocytopenic purpura in Korean children. Journal of Pediatric Hematology/Oncology; Aug 2008.

199 QUESTION Should a course of corticosteroids longer vs. shorter than 7 days be used for children with newly diagnosed ITP who require drug therapy (Q17)? POPULATION: children with newly diagnosed ITP who require drug therapy (Q17) Commented [CN1]: I think this should read non lifethreatening mucosal bleeding anr/or impaired health realted quality of life like the other questions. The panel did not like who require treatment INTERVENTION: COMPARISON: MAIN OUTCOMES: a course of corticosteroids longer shorter than 7 days Major bleeding; Overall health-related quality of life; Mood or mental changes: a side effect of corticosteroids; Durable response; Remission; Infection; Mortality; SETTING: S PERSPECTIVE: BACKGROUND: Corticosteroids are considered appropriate first-line therapy for children with newly diagnosed ITP who require treatment for either bleeding symptoms or impaired health-related quality of life. Despite extensive use for pediatric ITP, the exact duration of corticosteroid therapy has not been established. The potential benefits of longer courses of corticosteroids must be weighed against the increased side effects. The impact of the duration of corticosteroid therapy on important patient-related outcomes such as bleeding rates, remission, and key side effects is not known. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Survey was administered to pediatric providers on the panel (6 of 6 responded). Limitations of the survey data include recall bias, answering for self vs whole practice No differences in desirable outcomes, but large undesirable effects with longer vs shorter courses of steroids.

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201 Undesirable Effects How substantial are the undesirable anticipated effects?