American Society of Hematology 2026 guidelines for immune thrombocytopenia: initial and second-line therapy for adults with primary ITP.

Summary of recommendations

These guidelines are based on updated and original systematic reviews of evidence conducted under the direction of The University of Oklahoma. The panel followed best practices for guideline development.1, 2, 3 The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty in the evidence and formulate recommendations.4

These guidelines address the management of primary immune thrombocytopenia (ITP) in adults. ITP is an acquired disorder characterized by a low platelet count because of autoimmune-mediated platelet destruction and impaired platelet production.5,6 The estimated incidence of ITP is 1 to 6 per 100 000 adults.7, 8, 9, 10, 11 Common clinical manifestations include bleeding, fatigue, and reduced health-related quality of life (HRQoL).12 Treatment has evolved in recent years, owing to the development of new therapies.13 In these guidelines, we summarize available evidence and provide recommendations on initial and second-line therapy (needing additional treatment after initial therapy with corticosteroids) for adults with primary ITP. We also provide good practice statements on the role of thrombopoietic agent switching and splenectomy in contemporary practice.

Interpretation of strong and conditional recommendations

The strength of a recommendation is expressed as either strong (“the guideline panel recommends…”) or conditional (“the guideline panel suggests…”) and should be interpreted as described in Figure 1.Figure 1.Interpretation of recommendations.

Interpretation of good practice statements

Good practice statements endorse interventions or practices that the guideline panel agreed have unequivocal net benefit yet may not be widely recognized or used.14 Good practice statements in these guidelines are not based on a systematic review of available evidence. Nevertheless, they may be interpreted as strong recommendations.

Recommendations

Initial therapy for adults with primary ITP

Recommendation 1

For adults with primary ITP requiring initial therapy, the American Society of Hematology (ASH) guideline panel suggests either rituximab plus corticosteroids (with or without IV immunoglobulin [IVIG]) or a thrombopoietic agent plus corticosteroids (with or without IVIG) rather than mycophenolate mofetil (MMF) plus corticosteroids (with or without IVIG) or corticosteroids (with or without IVIG) alone (conditional recommendation based on low certainty in the evidence ⨁⨁◯◯).

If rituximab and thrombopoietic agents are not available options, the panel suggests corticosteroids (with or without IVIG) alone rather than MMF plus corticosteroids (with or without IVIG) (conditional recommendation based on very low certainty in the evidence ⨁◯◯◯).

Remarks:•A demonstrable rise in platelet count with corticosteroids and/or IVIG increases confidence in the diagnosis of ITP. Therefore, it is reasonable to treat a patient with a brief course (≤2 weeks) of corticosteroids (with or without IVIG) to increase confidence in the diagnosis of ITP before implementing combination therapy, especially in cases of diagnostic uncertainty.•Although the most studied corticosteroid component of combination therapy is dexamethasone 40 mg daily × 4 days for 1 to 3 cycles spaced 2 to 4 weeks apart, it is also appropriate to use prednis(ol)one at a starting dose of 0.5 to 2 mg/kg per day.•Whether corticosteroids are used as part of combination therapy or alone, it is advisable to limit their administration to ≤6 weeks to minimize toxicity.•If combination therapy with rituximab is used, the most studied regimen is 375 mg/m2 × 4 weekly doses. However, other doses and schedules of rituximab may be used according to local practice.

Biosimilars to rituximab are suitable substitutes.•If combination therapy with a thrombopoietic agent is used, any approved thrombopoietic agent at a standard starting dose may be used. The optimal duration of therapy with a thrombopoietic agent is uncertain and is typically guided by clinical response, toxicity, and platelet count stability. If a thrombopoietic agent and corticosteroids are used together in a patient who responds, it is advisable to taper the corticosteroids before the thrombopoietic agent.

In some cases, corticosteroids may need to be tapered rapidly to avoid or minimize thrombocytosis.

Treatment for adults with primary ITP needing additional treatment after initial therapy with corticosteroids (with or without IVIG)

Recommendation 2a

For adults with primary ITP needing additional treatment after initial therapy with corticosteroids (with or without IVIG), the ASH guideline panel recommends a thrombopoietic agent (strong recommendation based on moderate certainty in the evidence of effects ⨁⨁⨁◯) or suggests rituximab (conditional recommendation based on low certainty in the evidence ⨁⨁◯◯).

Remarks:•If a thrombopoietic agent is used, any approved thrombopoietic agent at a standard starting dose may be used. Duration of therapy is typically guided by clinical response, toxicity, and platelet count stability.•Rituximab may be preferable for patients who value avoiding chronic medication or who have a contraindication to, are unable to access, or cannot tolerate thrombopoietic agents.•If rituximab is used, the most studied regimen is 375 mg/m2 × 4 weekly doses. However, other doses and schedules of rituximab may be used according to local practice.

Biosimilars to rituximab are suitable substitutes.

Recommendation 2b

For adults with primary ITP needing additional treatment after initial therapy with corticosteroids (with or without IVIG) who are either ineligible for or choose not to receive a thrombopoietic agent or rituximab, the ASH guideline panel suggests a Bruton tyrosine kinase (BTK) inhibitor, MMF, or a spleen tyrosine kinase (SYK) inhibitor (conditional recommendation based on very low certainty in the evidence ⨁◯◯◯).

Remarks:•The panel concluded that current evidence in the population of interest is too indirect to definitively rank BTK inhibitors, MMF, or SYK inhibitors. Side effect profiles, cost, availability, and shared decision-making may be considered in selecting an agent.•The panel concluded that azathioprine (AZA) has a less favorable benefit-to-harm ratio; therefore, it is not equivalent to the other suggested treatment options. Nevertheless, AZA may be useful in some settings due to its low cost, global availability, and safety profile in pregnancy.

Good practice statements

SPLENECTOMY

If feasible, splenectomy should be delayed for ≥1 year after diagnosis because of the potential for remission.

The treating clinician should ensure that patients receive appropriate immunizations ≥2 weeks before splenectomy, when feasible, and counseling regarding antibiotic prophylaxis and lifelong risk of sepsis and thrombosis after splenectomy. The treating clinician should educate the patient on prompt recognition and management of fever with antibiotics. After splenectomy, patients should be followed at least annually for platelet count monitoring and counseling and to ensure adherence to recommended immunization schedules.

THROMBOPOIETIC AGENT SWITCHING

Switching to a different thrombopoietic agent may be considered based on insufficient response, adverse effects, comorbidities, poor adherence, or patient preference.

Shared decision-making with the patient, documentation of the rationale for switching, avoidance of treatment gaps, and close monitoring around the time of switching are good practices to ensure optimal outcomes and continuity of care.

See the broader “Good practice statements” for background on splenectomy and thrombopoietic agent switching.

Values and preferences

These recommendations place a relatively higher value on patient-important outcomes (eg, bleeding, fatigue, HRQoL, thrombosis, infection, sustained response off treatment [SRoT]) and a relatively lower value on surrogate outcomes (eg, platelet count).

Explanations and other considerations

For both multiple-comparison questions, the panel treated all thrombopoietic agents (ie, avatrombopag, eltrombopag, hetrombopag, romiplostim, recombinant human thrombopoietin) as interchangeable. Our systematic literature review included the search terms anti-CD20, rituximab, and Rituxan. Among the identified articles that met our inclusion criteria, the only anti-CD20 agent that was identified was rituximab.

Introduction

Aim of these guidelines and specific objectives

The purpose of these guidelines is to provide a focused update of the 2019 ASH ITP guidelines, specifically with respect to the management of primary ITP in adults.15,16 Through improved provider and patient education of the available evidence and evidence-based recommendations, these guidelines aim to provide clinical decision support for shared decision-making that will result in improved outcomes for adults with ITP.

The target audience includes patients, hematologists, general practitioners, internists, general surgeons, other clinicians, and decision-makers. Policymakers interested in these guidelines include those involved in developing local, national, or international plans, with the goal to foster best practice, reduce costs, and improve patient outcomes. This article may also serve as the basis for adaptation by local, regional, or national guideline panels.

Description of the health problem

ITP is an acquired disorder characterized by autoimmune-mediated platelet clearance and impairment of thrombopoiesis, resulting in thrombocytopenia.5 It may occur in isolation (primary ITP) or in association with a predisposing condition (secondary ITP).17 ITP may present at any age, with incidence peaks in early childhood and older adulthood. The estimated incidence of ITP for adults is 1 to 6 per 100 000.7, 8, 9, 10, 11 Common clinical manifestations include bleeding, fatigue, and reduced HRQoL.12 Bleeding symptoms are highly variable among patients and show limited correlation with platelet count.

Treatment options for ITP have expanded rapidly over recent years. Since the 2019 ASH ITP guidelines were developed, inhibitors of spleen tyrosine kinase and BTK have joined older treatment modalities, including corticosteroids, IVIG, anti-D, rituximab, thrombopoietic agents, splenectomy, MMF, and a host of other immunosuppressive medications, in the ITP armamentarium. Moreover, the pipeline is brimming with new classes of therapeutics, some of which are in late-stage clinical development, including B-cell activating factor receptor inhibitors, anti-CD38 agents, neonatal Fc receptor antagonists, chimeric antigen receptor T-cell therapy, and complement inhibitors.6,13

The explosion in treatment options for ITP has ushered in an era of new opportunities in clinical practice. With the success of currently available treatments in achieving and maintaining hemostatic platelet counts for most patients, the goalposts are shifting. No longer satisfied with platelet count–based outcomes alone, patients and clinicians have begun to focus on more ambitious goals, including improved HRQoL, SRoT, and even cure.

How best to achieve these lofty goals remains unsettled.

The growing list of treatments also presents a challenge. Patients and clinicians have more options than ever from which to choose but must decide how to prioritize, sequence, and potentially combine therapies. Guidance to aid in this determination is lacking.

These guidelines endeavor to tackle some of these opportunities and challenges. Question 1 addresses initial therapy for adults with primary ITP, with an eye toward amelioration of the long-term disease course and minimization of corticosteroid-associated toxicity. Question 2 addresses treatment of adults with primary ITP needing additional treatment after initial therapy with corticosteroids, with the goal of providing ranked options for second-line therapy and potential for SRoT.

Good practice statements on thrombopoietic agent switching and the role of splenectomy in contemporary practice are also included.

As a focused update of the 2019 ASH ITP guidelines,15,16 these guidelines address only specific aspects of the management of primary ITP in adults (age ≥18 years). They do not address other important facets of the disease, including diagnosis, indications for treatment, ITP in pregnancy, and pediatric ITP (age <18 years). Table 1 lists the recommendations from the 2019 ASH ITP guidelines and indicates whether they remain current or have been superseded by recommendations in the 2026 guidelines.Table 1.Recommendations from the 2019 ASH ITP guidelines and their status after publication of the 2026 ASH ITP guidelines2019 recommendationStatus with respect to the 2026 ASH ITP guidelines1a.

For adults with newly diagnosed ITP and a platelet count of <30 × 109/L who are asymptomatic or have minor mucocutaneous bleeding, the ASH guideline panel suggests corticosteroids rather than management with observation (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○). Remark: there may be a subset of patients within this group for whom observation might be appropriate. This should include consideration of the severity of thrombocytopenia, additional comorbidities, use of anticoagulant or antiplatelet medications, need for upcoming procedures, and age of the patient.The threshold for initiating therapy has not been updated.However, the choice of first-line therapy has been updated in recommendation 1 of the 2026 ASH ITP guidelines.1b.

For adults with newly diagnosed ITP and a platelet count of ≥30 × 109/L who are asymptomatic or have minor mucocutaneous bleeding, the ASH guideline panel recommends against corticosteroids and in favor of management with observation (strong recommendation based on very low certainty in the evidence of effects ⨁○○○). Remark: for patients with a platelet count at the lower end of this threshold, for those with additional comorbidities, anticoagulant or antiplatelet medications, or upcoming procedures, and for older patients (aged >60 y), treatment with corticosteroids may be appropriate.2a. For adults with newly diagnosed ITP and a platelet count of <20 × 109/L who are asymptomatic or have minor mucocutaneous bleeding, the ASH guideline panel suggests admission to the hospital rather than management as an outpatient (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).

For adults with an established diagnosis of ITP and a platelet count of <20 × 109/L who are asymptomatic or have minor mucocutaneous bleeding, the ASH guideline panel suggests outpatient management rather than hospital admission (conditional recommendation based on very low certainty in the evidence ⨁○○○). Remark: patients who are refractory to treatment, those with social concerns, uncertainty about the diagnosis, significant comorbidities with risk of bleeding, and more significant mucosal bleeding, may benefit from admission to the hospital. Patients not admitted to the hospital should receive education and expedited follow-up with a hematologist.

The need for admission is also variable across the range of platelet counts represented here (0 × 109/L to 20 × 109/L).Not updated2b. For adults with a platelet count of ≥20 × 109/L who are asymptomatic or have minor mucocutaneous bleeding, the ASH guideline panel suggests management as an outpatient rather than hospital admission (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○). Remark: patients who are refractory to treatment, with social concerns, uncertainty about the diagnosis, significant comorbidities with risk of bleeding, and more significant mucosal bleeding, may benefit from admission to the hospital.

Patients not admitted to the hospital should receive education and expedited follow-up with a hematologist. The need for admission is also variable across the range of platelet counts represented here (20 × 109/L to 150 × 109/L).3. For adults with newly diagnosed ITP, the ASH guideline panel recommends against a prolonged course (>6 wk, including treatment and taper) of prednisone and in favor of a short course (≤6 wk) (strong recommendation based on very low certainty in the evidence of effects ⨁○○○).The duration of prednisone has not been updated.However, the choice of first-line therapy has been updated in recommendation 1 of the 2026 ASH ITP guidelines.4.

For adults with newly diagnosed ITP, the ASH guideline panel suggests either prednisone (0.5-2.0 mg/kg per day) or dexamethasone (40 mg/d for 4 d) as the type of corticosteroid for initial therapy (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○). Remark: if a high value is placed on rapidity of platelet count response, an initial course of dexamethasone may be preferred over prednisone, given that dexamethasone showed increased desirable effects with regard to response at 7 d.The choice of prednisone vs dexamethasone has not been updated.However, the choice of first-line therapy has been updated in recommendation 1 of the 2026 ASH ITP guidelines.5. For adults with newly diagnosed ITP, the ASH guideline panel suggests corticosteroids alone rather than rituximab and corticosteroids for initial therapy (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).

Remark: if high value is placed on the possibility for remission over concerns for potential side effects of rituximab, then an initial course of corticosteroids with rituximab may be preferred.This recommendation is retired and replaced with recommendation 1 of the 2026 ASH ITP guidelines.6. For adults with ITP for ≥3 mo who are corticosteroid-dependent or unresponsive to corticosteroids and are going to be treated with a thrombopoietin receptor agonist (TPO-RA), the ASH guideline panel suggests either eltrombopag or romiplostim (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○). Remark: individual patient preference may place a higher value on the use of a daily oral medication or weekly subcutaneous injections.This recommendation is retired and replaced with recommendation 2 of the 2026 ASH ITP guidelines.7.

For adults with ITP lasting ≥3 mo who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests either splenectomy or a TPO-RA (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).This recommendation is retired and replaced with recommendation 2 of the 2026 ASH ITP guidelines.8. For adults with ITP lasting ≥3 mo who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests rituximab rather than splenectomy (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).This recommendation is retired and replaced with recommendation 2 of the 2026 ASH ITP guidelines.9. For adults with ITP lasting ≥3 mo who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests a TPO-RA rather than rituximab (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).

Remark: these recommendations are the result of dichotomous evaluation of treatments that are often being considered simultaneously. Each of these second-line treatments may be effective therapy, and therefore, the choice of treatment should be individualized based on duration of ITP, frequency of bleeding episodes requiring hospitalization or rescue medication, comorbidities, age of the patient, medication adherence, medical and social support networks, patient values and preferences, cost, and availability. Patient education and shared decision-making are encouraged.

If possible, splenectomy should be delayed for ≥1 y after diagnosis because of the potential for spontaneous remission in the first year. Patients who value avoidance of long-term medication may prefer splenectomy or rituximab.Patients who wish to avoid surgery may prefer a TPO-RA or rituximab. Patients who place a high value on achieving a durable response may prefer splenectomy or TPO-RAs.This recommendation is retired and replaced with recommendation 2 of the 2026 ASH ITP guidelines.10a.

For children with newly diagnosed ITP and a platelet count of <20 ×109/L who have no or mild bleeding (skin manifestations) only, the ASH guideline panel suggests against admission to the hospital and in favor of management as an outpatient (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○). Remark: for patients with uncertainty about the diagnosis, those with social concerns, those who live far from the hospital, and those for whom follow-up cannot be guaranteed, admission to the hospital may be preferable.Not updated10b. For children with newly diagnosed ITP and a platelet count of ≥20 × 109/L who have no or mild bleeding (skin manifestations) only, the ASH guideline panel suggests against admission to the hospital and in favor of management as an outpatient (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).

Remark: for patients with uncertainty about the diagnosis, those with social concerns, those who live far from the hospital, or those for whom follow-up cannot be guaranteed, admission to the hospital may be preferable.11. For children with newly diagnosed ITP who have no or minor bleeding, the ASH guideline panel suggests observation rather than corticosteroids (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).Not updated12. For children with newly diagnosed ITP who have no or minor bleeding, the ASH guideline panel recommends observation rather than IVIG (strong recommendation based on moderate certainty in the evidence of effects ⨁⨁⨁○).Not updated13.

For children with newly diagnosed ITP who have no or minor bleeding, the ASH guideline panel recommends observation rather than anti-D immunoglobulin (strong recommendation based on moderate certainty in the evidence of effects ⨁⨁⨁○).Not updated14. For children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL, theASH guideline panel recommends against courses of corticosteroids >7 d and in favor of courses ≤7 d (strong recommendation based on very low certainty in the evidence of effects ⨁○○○).Not updated15. For children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL, the ASH guideline panel suggests prednisone (2-4 mg/kg per day; maximum, 120 mg/d for 5-7 d) rather than dexamethasone (0.6 mg/kg per day; maximum, 40 mg/d for 4 d) (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).Not updated16.

For children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL, the ASH guideline panel suggests corticosteroids rather than anti-D immunoglobulin (conditional recommendation based on low certainty in the evidence of effects ⨁⨁○○). Remark: this recommendation assumes corticosteroid dosing as outlined in recommendations 14 and 15. This recommendation is reserved only for children with nonmajor mucosal bleeding.Not updated17.

For children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL, the ASH guideline panel suggests either anti-D immunoglobulin or IVIG (conditional recommendation based on low certainty in the evidence of effects ⨁⨁○○). Remark: this recommendation is reserved only for children with nonmajor mucosal bleeding.Not updated18. For children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL, the ASH guideline panel suggests corticosteroids rather than IVIG (conditional recommendation based on low certainty in the evidence of effects ⨁⨁○○).

Remark: this recommendation assumes that a short course of corticosteroids is being used for treatment as recommended in recommendation 14. This recommendation is reserved only for children with nonmajor mucosal bleeding.Not updated19. For children with ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL and do not respond to first-line treatment, the ASH guideline panel suggests the use of TPO-RAs rather than rituximab (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).Not updated20.

For children with ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL and do not respond to first-line treatment, the ASH guideline panel suggests TPO-RAs rather than splenectomy (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).Not updated21. For children with ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL and do not respond to first-line treatment, the ASH guideline panel suggests rituximab rather than splenectomy (conditional recommendation based on very low certainty in the evidence of effects ⨁○○○).Not updated

Methods

The guideline panel developed and graded the recommendations and assessed the certainty in the supporting evidence following the GRADE approach.4 ASH guided the overall guideline development process, including project funding, panel formation, conflict-of-interest management, internal and external review, and organizational approval, based on policies and procedures intended to meet recommendations for trustworthy guidelines by the Institute of Medicine and the Guidelines International Network.1, 2, 3

In ITP, there are multiple interventions that could simultaneously be considered for second-line therapy. To address this, the guideline panel used the GRADEpro multiple-comparison feature of the GRADEpro software as part of the Evidence-to-Decision (EtD) frameworks.18

Organization, panel composition, planning, and coordination

The work of this panel was coordinated by ASH and The University of Oklahoma (funded by ASH under a paid agreement). Project oversight was provided by the ASH Guideline Oversight Subcommittee, which reported to the ASH Committee on Quality. ASH vetted and appointed individuals to the guideline panel.

The University of Oklahoma conducted systematic reviews of evidence and coordinated the guideline development process, including the use of the GRADE approach. The membership of the panel and the systematic review team is described in supplement 1.

The panel included adult and pediatric hematologist-oncologists, clinical and methodological experts, and both patient and caregiver representatives, all with expertise in ITP. One cochair was a clinical content expert; the other cochair was an expert in guideline development methodology. To promote efficiency and continuity with prior work, approximately half of the guideline panel, including the clinical cochair, was drawn from the panel that authored the 2019 guidelines, whereas the remaining members were newly appointed.

In addition to synthesizing evidence systematically, The University of Oklahoma supported the guideline development process, including determining methods, preparing meeting materials, and facilitating panel discussions. The panel’s work was done using web-based tools (www.gradepro.org) and through face-to-face and online meetings via Zoom.

Guideline funding and management of conflicts of interest

Development of these guidelines was wholly funded by ASH, a nonprofit medical specialty society that represents hematologists. Most members of the guideline panel were members of ASH. ASH staff supported panel appointments and coordinated meetings but had no role in choosing the guideline questions or determining the recommendations.

Members of the guideline panel received travel reimbursement for attendance at in-person meetings. Through The University of Oklahoma, some researchers who contributed to the systematic evidence reviews received salary support. Other researchers participated to fulfill requirements of an academic degree or program.

Conflicts of interest of all participants were managed according to ASH policies based on recommendations of the Institute of Medicine1 and the Guidelines International Network.3 Participants disclosed all financial and nonfinancial interests, including research funding, consulting, speakers’ bureaus, and other relationships. ASH staff and appointed experts from ASH membership reviewed the disclosures and proposed the guideline panel to include a diversity of expertise and perspectives and avoid panel members having relevant conflicts. The proposed panel was reviewed and approved by the ASH Committee on Quality and Executive Committee.

During the guideline development process, all panelists avoided significant direct financial relationships with for-profit health care companies. Many panelists had relevant nonfinancial interests, such as published opinions on the guideline topic. None of the researchers who contributed to the systematic evidence reviews or who supported the guideline development process had any such conflicts.

Recusal procedures were established a priori to manage certain conflicts.4 During deliberations about recommendations, any panel member with an active principal investigator role with a for-profit health care company that could be affected by a recommendation based on the prioritized questions (ie, a commercial entity that marketed any product that could be affected by that recommendation) would have participated in discussions about the evidence and clinical context but would have been recused from making judgments or voting about the direction and strength of the recommendation. In this guideline, no panelist met these recusal criteria, and therefore, no recusals occurred.

Supplement 2 provides the complete participant information forms of all panel members, including disclosures before and during participation in the panel. In part A of the forms, individuals disclosed direct financial interests for 2 years before appointment; in part B, indirect financial interests; and in part C, nonfinancial interests. Part D describes new interests disclosed by individuals after appointment.

Part E summarizes ASH decisions about which interests were judged to be conflicts and how they were managed through disclosure.

Supplement 3 provides the complete participant information forms of researchers who contributed to these guidelines.

Formulating specific clinical questions and determining outcomes of interest

The panel used the GRADEpro Guideline Development Tool (www.gradepro.org)19 to brainstorm and then prioritize the questions described in Table 2. The multiple-comparison feature in GRADEpro allowed the guideline panel to make judgments and comparisons across several interventions simultaneously. Initially, the panel members compared each intervention to the standard of care (SOC).

After judgments were made for each intervention, comparisons were then made across the multiple interventions. Unlike pairwise comparisons, the GRADEpro multiple-comparison feature extends the standard EtD framework to multiple comparisons, allowing the guideline panel to assess not only treatment effects but also benefits, harms, certainty in the evidence, values, resources required, equity, acceptability, and feasibility.Table 2.Questions and outcomes prioritized by the guideline panelPICO questionOutcomes1Should adults with primary ITP requiring initial therapy be treated with corticosteroids (with or without IVIG) plus additional agent (MMF, thrombopoietic agent, anti-CD20, SYK inhibitor) or corticosteroids (with or without IVIG)?Length of corticosteroid treatment (steroid exposure)SRoT at 6 moSRoT at 12 moHRQoLMajor/minor bleedingThrombosisInfectionDiarrhea/GI symptoms2For adults with primary ITP needing additional therapy after initial treatment with corticosteroids (with or without IVIG), should thrombopoietic agents, anti-CD20, SYK inhibitors, BTK inhibitors (rilzabrutinib), MMF, anti-CD38, or AZA be used?Durable response (platelet count >30 × 109/L and doubling from baseline at 6 mo on or off treatment)Time to responseSRoT at 6 moSRoT at 12 moReduce the need for rescue therapyHRQoLMajor/minor bleedingThrombosisIncreased risk of infectionDiarrhea/GI symptoms

The panel selected outcomes of interest for each question a priori, following the approach described in detail elsewhere.4 In brief, the panel first brainstormed all possible outcomes before rating their relative importance for decision-making following the GRADE approach.4 Although acknowledging considerable variation in the impact on patient outcomes, the panel considered the outcomes in Table 2 as critical for clinical decision-making across the 2 questions: SRoT at 6 months, SRoT at 12 months, HRQoL, major/minor bleeding, thrombosis, infection, diarrhea/gastrointestinal (GI) symptoms, durable response at 6 months, durable response at 12 months, time to response, and reduction in the need for rescue therapy. For population/intervention/comparison/outcome (PICO) 1, we also considered length of corticosteroid treatment. We also considered individual domains of HRQoL that are relevant to ITP, such as fatigue, anxiety, and depression.

Evidence review and development of recommendations

For each guideline question, The University of Oklahoma prepared a GRADE EtD framework using the GRADEpro Guideline Development Tool (www.gradepro.org).20, 21, 22 The EtD table summarized the results of the systematic reviews of the literature that were updated or performed for this guideline. The panel met twice monthly to review the results of the systematic reviews and to confirm inclusion/exclusion of the identified studies. The EtD table addressed the effects of interventions, resource use (cost-effectiveness), values and preferences (relative importance of outcomes), equity, acceptability, and feasibility.

The guideline panel reviewed the draft EtD tables during and after the guideline panel meeting and made suggestions for corrections. To ensure that recent studies were not missed, searches (supplement 4) were updated on 19 July 2025, and panel members were asked to suggest any studies that may have been missed and fulfilled the inclusion criteria for the individual questions.

Under the direction of The University of Oklahoma, researchers followed the general methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (handbook.cochrane.org) for conducting updated or new systematic reviews of intervention effects. Detailed search strategies, data collection procedures, risk-of-bias assessments, evidence synthesis methods, and ratings of certainty in the evidence are described in supplement 5. Included studies ranged in publication dates and eligibility criteria.

Although the included studies had different primary end points, data were abstracted for any reported end point of interest regardless of whether it was the primary end point of the study. When existing reviews were used, judgments of the original authors about risk of bias were either randomly checked for accuracy and accepted or conducted de novo if they were not available or not reproducible. For new reviews, risk of bias was assessed at the health outcome level using the Cochrane Collaboration’s risk-of-bias tool for randomized trials or nonrandomized studies.23,24 In addition to conducting systematic reviews of intervention effects, the researchers searched for evidence related to baseline risks, values, preferences, and costs and summarized the findings within the EtD frameworks.20, 21, 22 Subsequently, the certainty in the body of evidence (also known as quality of the evidence or confidence in the estimated effects) was assessed for each effect estimate of the outcomes of interest following the GRADE approach based on the following domains: risk of bias, precision, consistency and magnitude of the estimates of effects, directness of the evidence, risk of publication bias, presence of large effects, dose-response relationship, and an assessment of the effect of residual, opposing confounding.

The certainty was categorized into 4 levels ranging from very low to high.25 Within this report, these categories are represented by symbols, as described in Figure 2. Interested readers may find more explanation about the GRADE approach to assessing and rating certainty in a body of evidence in other publications.4Figure 2.Interpretation of certainty in the evidence ratings.

The original PICO 1 question included SYK inhibitors. A systematic literature review was conducted, and no studies were identified that met our inclusion criteria. Therefore, SYK inhibitors were removed from the PICO 1 question.

The original PICO 2 question included anti-CD38 agents. A systematic literature review was conducted, and 1 study was identified that met our inclusion criteria. It was small (N = 22) and did not include a control group.

Therefore, the panel determined that there was insufficient evidence to make a recommendation on anti-CD38 agents. PICO 2 assumes that patients were not treated up front with rituximab or a thrombopoietic agent, as recommended in PICO 1. For more information on the identification of studies, screening, and inclusion for both PICOs 1 and 2, please see supplement 6.

During a 2-day in-person meeting followed by online communication and conference calls, the panel developed clinical recommendations based on the evidence summarized in the EtD tables. For each recommendation, the panel came to consensus on the following: the certainty in the evidence, the balance of benefits and harms of the compared management options, and the assumptions about the values and preferences associated with the decision. The guideline panel also explicitly took into account the extent of resource use associated with alternative management options.

The panel agreed on the recommendations (including direction and strength), remarks, and qualifications by consensus or, if necessary, by voting (an 80% majority was required for a strong recommendation), based on the balance of all desirable and undesirable consequences. The final guidelines, including recommendations, were reviewed and approved by all members of the panel.

Interpretation of strong and conditional recommendations

The recommendations are labeled as either “strong” or “conditional” according to the GRADE approach. The words “the guideline panel recommends” are used for strong recommendations, and “the guideline panel suggests” are used for conditional recommendations. Figure 1 provides GRADE’s interpretation of strong and conditional recommendations by patients, clinicians, health care policymakers, and researchers.

Document review

Draft recommendations were reviewed by all members of the panel, revised, and then made available online on 12 December 2025 for external review by stakeholders, including allied organizations, other medical professionals, patients, and the public. Sixteen individuals or organizations submitted comments. Remarks were revised to address pertinent feedback; however, no changes were made to the recommendations themselves.

On 21 May 2026, the ASH Guideline Oversight Subcommittee and the ASH Committee on Quality approved that the defined guideline development process was followed, and on 26 May 2026, the officers of the ASH Executive Committee approved the submission of the guidelines for publication under the imprimatur of ASH. The guidelines were then subjected to peer review by Blood Advances.

How to use these guidelines

ASH guidelines are primarily intended to help clinicians and patients make shared decisions about diagnostic and treatment alternatives, with the goal of improving quality of patient care. Other purposes are to inform policy, education, and advocacy and to state future research needs. These guidelines are not intended to serve or be construed as SOC.

Clinicians must make decisions on the basis of the clinical presentation of each individual patient, ideally through a shared process that considers the patient’s values and preferences with respect to the anticipated outcomes of the chosen option.

Decisions may be constrained by the realities of a specific clinical setting and local resources, including, but not limited to, institutional policies, time limitations, or availability of treatments. These guidelines may not include all appropriate methods of care for the clinical scenarios described. As science advances and new evidence becomes available, recommendations may become outdated.

Following these guidelines cannot guarantee successful outcomes. ASH does not warrant or guarantee any products described in these guidelines.

Statements about the underlying values and preferences as well as qualifying remarks accompanying each recommendation are its integral parts and serve to facilitate more accurate interpretation. They should never be omitted when quoting or translating recommendations from these guidelines. The use of these guidelines is also facilitated by the links to the EtD frameworks and interactive summary of findings tables in each section.

Recommendations

The following recommendations represent a focused update of the 2019 ASH ITP guidelines (see Table 1 for the recommendations covered in this article).15 Recommendation 1 addresses initial therapy, and recommendation 2 addresses management after failure of first-line corticosteroids in adults (age ≥18 years) with primary ITP (Figure 3).Figure 3.Interpretation of the treatment pathways for adults with primary ITP. The arrows indicate the sequence of clinical decisions, beginning with assessment of patient values and eligibility and proceeding to suggested treatments. The red header bars define the clinical scenario (initial vs additional therapy), the orange boxes show specific treatment options or actions, and the purple boxes highlight good practice statements.

The green checkmarks denote suggested or recommended options, whereas the symbols at the bottom of each treatment box indicate strength of recommendation and certainty in the evidence as defined in the key. ∗Although the guideline panel suggests a combination of either a thrombopoietic agent or rituximab plus corticosteroids (with or without IVIG) as initial therapy (recommendation 1), it acknowledges that some patients will still be treated with corticosteroids (with or without IVIG) alone as initial therapy. Recommendation 2 addresses management of such patients if treatment beyond initial therapy with corticosteroids is required.

Initial therapy for adults with primary ITP

For adults with primary ITP requiring initial therapy, should corticosteroids (with or without IVIG) plus an additional agent (anti-CD20, MMF, thrombopoietic agent) or corticosteroids (with or without IVIG) alone be used?Recommendation 1For adults with primary ITP requiring initial therapy, the ASH guideline panel suggests either rituximab plus corticosteroids (with or without IVIG) or a thrombopoietic agent plus corticosteroids (with or without IVIG) rather than MMF plus corticosteroids (with or without IVIG) or corticosteroids (with or without IVIG) alone (conditional recommendation based on low certainty in the evidence ⨁⨁◯◯).If rituximab and thrombopoietic agents are not available options, the panel suggests corticosteroids (with or without IVIG) alone rather than MMF plus corticosteroids (with or without IVIG) (conditional recommendation based on very low certainty in the evidence ⨁◯◯◯).Remarks:•A demonstrable rise in platelet count with corticosteroids and/or IVIG increases confidence in the diagnosis of ITP. Therefore, it is reasonable to treat a patient with a brief course (≤2 weeks) of corticosteroids (with or without IVIG) to increase confidence in the diagnosis of ITP before implementing combination therapy, especially in cases of diagnostic uncertainty.•Although the most studied corticosteroid component of combination therapy is dexamethasone 40 mg daily × 4 days for 1 to 3 cycles spaced 2 to 4 weeks apart, it is also appropriate to use prednis(ol)one at a starting dose of 0.5 to 2 mg/kg per day.•Whether corticosteroids are used as part of combination therapy or alone, it is advisable to limit their administration to ≤6 weeks to minimize toxicity.•If combination therapy with rituximab is used, the most studied regimen is 375 mg/m2 × 4 weekly doses. However, other doses and schedules of rituximab may be used according to local practice.

Biosimilars to rituximab are suitable substitutes.•If combination therapy with a thrombopoietic agent is used, any approved thrombopoietic agent at a standard starting dose may be used. The optimal duration of therapy with a thrombopoietic agent is uncertain; it is typically guided by clinical response, toxicity, and platelet count stability. If a thrombopoietic agent and corticosteroids are used together in a patient who responds, it is advisable to taper the corticosteroids before the thrombopoietic agent.

In some cases, corticosteroids may need to be tapered rapidly to avoid or minimize thrombocytosis.

Summary of the evidence

This multiple-comparison question compared 3 different treatments (MMF, thrombopoietic agent, and anti-CD20) plus corticosteroids with or without IVIG to a uniform SOC, which was defined as corticosteroids with or without IVIG. Supplement 7a presents the characteristics of all included studies for PICO 1 for MMF, thrombopoietic agents, and anti-CD20. Supplement 7b presents study-level data for thrombopoietic and anti-CD20 agents for SRoT and HRQoL outcomes.

MMF

We found 1 randomized clinical trial (RCT)26 that addressed this question. The study included newly diagnosed treatment-naïve adults with ITP.

The RCT reported the effect of MMF on durable response at 12 months, major and minor bleeding, infection, overall GI symptoms, time to response, need for rescue medications, and HRQoL.26

The evidence profile and EtD framework for this intervention are available online at https://guidelines.ash.gradepro.org/profile/pB_qrthRaVU.

THROMBOPOIETIC AGENTS

We found 7 studies, 3 RCTs27, 28, 29 and 4 prospective 1-armed cohort studies,30, 31, 32, 33 that addressed this question. Six studies included newly diagnosed treatment-naïve adults with ITP and were classified as direct evidence,27,28,30, 31, 32, 33 and 1 study included treatment-naïve adults with ITP who could have had newly diagnosed, persistent, or chronic ITP and was therefore classified as indirect evidence.29 Data from studies without a comparator arm were reported in the evidence tables, assessed by the panel, and informed the recommendations but are only reported in the text when no evidence from the RCTs is available.

Four studies reported SRoT at 6 months,27,28,30,31 3 studies reported SRoT at 12 months,28,30,31 3 studies assessed durable response at 6 months,29,30,32 1 study assessed durable response at 12 months,30 1 study assessed major bleeding,28 4 studies assessed minor bleeding,27,30, 31, 32 4 studies assessed infection,27, 28, 29,31 1 study assessed overall GI symptoms,28 5 studies assessed thrombosis,27,28,30,31,33 1 study assessed nausea,32 1 study assessed vomiting,32 1 study reported anxiety,27 1 study reported depression,27 1 study reported the need for rescue therapy,27 and 4 studies reported fatigue.27,28,31,32

The evidence profile and EtD framework for this intervention are available online at https://guidelines.ash.gradepro.org/profile/EautU3Ze0ow.

ANTI-CD20

We found 6 studies, 3 RCTs,27,34,35 1 case-control study,36 and 2 retrospective 1-armed cohort studies,37,38 that addressed this question. Five studies included newly diagnosed treatment-naïve adults with ITP and were classified as direct evidence,27,34,36, 37, 38 and 1 study included treatment-naïve adults with ITP who could have had newly diagnosed, persistent, or chronic ITP and was therefore classified as indirect evidence.35 Data from studies without a comparator arm were reported in the evidence tables, assessed by the panel, and informed the recommendations but are only reported in the text when no evidence from the controlled studies is available.

Five studies reported SRoT at 6 months,27,34, 35, 36, 37 4 studies reported SRoT at 12 months,34,36, 37, 38 1 study assessed durable response at 12 months,38 1 study assessed major bleeding,34 1 study assessed minor bleeding,27 4 studies assessed infection,27,34, 35, 36 1 study assessed overall GI symptoms,34 2 studies assessed thrombosis,27,35 1 study reported anxiety,27 1 study reported depression,27 1 study reported the need for rescue therapy,27 1 study reported fatigue,27,28,31,32 and 1 study reported time to response.37

The evidence profile and EtD framework for this intervention are available online at https://guidelines.ash.gradepro.org/profile/JNgz58cv_9U.

Benefits

MMF

MMF increased the odds of durable response at 12 months compared to SOC (46/59 [78%] MMF vs 34/61 [56%] SOC; odds ratio [OR], 2.81; 95% confidence interval [CI], 1.27-6.23). MMF also may reduce the odds for the need for rescue therapy (8/59 [14%] MMF vs 10/61 [16%] SOC; OR, 0.80; 95% CI, 0.29-2.19) and improved time to response (median, 4 days shorter for MMF; no 95% CI calculated); however, the estimates were imprecise, and the CI included no effect. The study assessing minor bleeding, infection, and major bleeding found no difference between those receiving MMF and SOC (minor bleeding: 14/59 [24%] MMF vs 15/61 [25%] SOC; OR, 0.95; 95% CI, 0.4-2.20; infection: 14/59 [24%] MMF vs 14/61 [23%] SOC; OR, 1.04; 95% CI, 0.45-2.43; major bleeding: 1/59 [2%] MMF vs 0/61 [0%] SOC; risk difference, 0.02; 95% CI, −0.02 to 0.05).

Overall, the certainty in the evidence for these estimated effects is very low owing to serious inconsistency and imprecision resulting from the inclusion of only 1 moderate-sized RCT. The panel deemed the benefits to be small to moderate but downgraded to small because SRoT, a prioritized outcome, was not available and durable response had to be used as a surrogate outcome.

THROMBOPOIETIC AGENTS

Thrombopoietic agents increased the odds of SRoT at 6 and 12 months (direct: 6 months: 136/260 [52%] thrombopoietic agent vs 58/175 [33%] SOC; OR, 2.33; 95% CI, 1.48-3.37; 12 months: 46/100 [46%] thrombopoietic agent vs 30/96 [31%] SOC; OR, 1.87; 95% CI, 1.05-3.36) and durable response at 6 months (indirect; 22/25 [88%] thrombopoietic agent vs 30/50 [60%] SOC; OR, 4.89; 95% CI, 1.29-18.53) compared to SOC. Thrombopoietic agents decreased the odds of anxiety (direct: 104/188 [55%] thrombopoietic agent vs 94/105 [90%] SOC; OR, 0.14; 95% CI, 0.07-0.29), depression (direct: 86/188 [46%] thrombopoietic agent vs 99/105 [94%] SOC; OR, 0.05; 95% CI, 0.02-0.12), and minor bleeding (direct: 29/188 [15%] thrombopoietic agent vs 62/105 [59%] SOC; OR, 0.13; 95% CI, 0.07-0.22) compared to SOC. Thrombopoietic agents also may reduce the odds of fatigue (direct: 71/290 [25%] thrombopoietic agent vs 88/201 [44%] SOC; OR, 0.40; 95% CI, 0.05-3.27), the need for rescue therapy (direct: 16/188 [9%] thrombopoietic agent vs 15/105 [14%] SOC; OR, 0.56; 95% CI, 0.26-1.18), and infection (direct: 12/290 [4%] thrombopoietic agent vs 26/201 [13%] SOC; OR, 0.20; 95% CI, 0.00-10.39; indirect: 0/25 [0%] thrombopoietic agent vs 4/50 [8%] SOC; OR, 0.20; 95% CI, 0.01-3.92), but the estimates are imprecise, and CIs include no effect.

Studies assessing overall GI symptoms (direct: 9/102 [9%] thrombopoietic agent vs 7/96 [7%] SOC; OR, 1.23; 95% CI, 0.44-3.45) found no difference between those receiving a thrombopoietic agent and the SOC groups. Overall, the certainty in the evidence for these estimated effects is low because of risk of bias, inconsistency, and imprecision of the estimates. The panel judged the desirable effects of thrombopoietic agents to be moderate, mainly driven by increased SRoT at 6 and 12 months, reduced minor bleeding, reduced need for rescue therapy, and improvement in various HRQoL dimensions.

The panel noted that the duration of treatment with a thrombopoietic agent was variable, as was thrombopoietic agent dosing among the included studies.

ANTI-CD20

Anti-CD20 agents may increase the odds of SRoT at 6 months (direct: 63/122 [52%] anti-CD20 vs 52/162 [32%] SOC; OR, 2.33; 95% CI, 0.88-6.12; indirect: 31/49 [63%] anti-CD20 vs 19/52 [37%] SOC; OR, 2.99; 95% CI, 1.33-6.72), and SRoT at 12 months (direct: 47/80 [59%] anti-CD20 vs 25/81 [31%] SOC; OR, 4.23; 95% CI, 0.98-18.32). Anti-CD20 decreased the odds of minor bleeding (9/64 [14%] anti-CD20 vs 62/105 [59%] SOC; OR, 0.11; 95% CI, 0.05-0.25), anxiety (5/64 [8%] anti-CD20 vs 94/105 [90%] SOC; OR, 0.01; 95% CI, 0.00-0.03), depression (11/64 [17%] anti-CD20 vs 99/105 [94%] SOC; OR, 0.01; 95% CI, 0.00-0.04), fatigue (2/64 [3%] anti-CD20 vs 88/105 [77%] SOC; OR, 0.01; 95% CI, 0.00-0.04), and the need for rescue therapy (1/64 [2%] anti-CD20 vs 15/105 [14%] SOC; OR, 0.10; 95% CI, 0.01-0.74). Overall, the certainty in the evidence for these estimated effects is low because of serious inconsistency and serious imprecision in the estimates for some outcomes, related to the number of studies and heterogeneity in study designs, as well as indirectness in 1 study.

The panel judged the desirable effects of anti-CD20 agents to be moderate, driven primarily by increased SRoT at 6 and 12 months, reduction in minor bleeding, reduction in the need for rescue therapy, and improvement in various HRQoL dimensions. The panel noted that the effect of anti-CD20 on B-cell depletion and memory of B cells can last for many months; consequently, exposure to the pharmacodynamic effects of the drug persists well after treatment is completed.

Harms and burden

MMF

One study reported adverse effects26 with a decrease in a domain of HRQoL as measured by the Functional Assessment of Cancer Therapy-Fatigue, with a median score 3.3 points lower (95% CI, 0.04-6.6 points lower) in the MMF group as compared to the SOC group. MMF may also increase the odds of overall GI symptoms (20/59 [34%] MMF vs 15/61 [25%] SOC; OR, 1.57; 95% CI, 0.71-3.48), but the estimate is imprecise, and the CI includes no effect. There is very low certainty in the estimate of the risk of adverse effects because of serious inconsistency and imprecision resulting from the inclusion of only 1 moderate-sized RCT.

However, given the available evidence, the guideline panel considered the undesirable effects to be moderate, mainly driven by negative impact on HRQoL.

THROMBOPOIETIC AGENTS

Thrombopoietic agents may increase the odds of major bleeding (direct: 2/102 [2%] thrombopoietic agent vs 0/96 [0%] SOC; OR, 4.80; 95% CI, 0.23-101.29) and thrombosis (direct: 29/290 [10%] thrombopoietic agent vs 0/201 [0%] SOC; OR, 11.49; 95% CI, 0.76-174.32), but the estimates are imprecise, and the CIs include no effect. There is low certainty in the estimate of the risk of adverse effects because of risk of bias, inconsistency, and imprecision of the estimates. However, given the available evidence, the guideline panel considered the undesirable effects to be small, mostly driven by a potential increased risk of thrombosis.

The panel noted that some studies excluded patients with risk factors for thrombosis and that patients with prothrombotic risk factors are likely to be at greater risk.

ANTI-CD20

Anti-CD20 agents increased the odds of thrombosis (9/64 [14%] anti-CD20 vs 0/105 [0%] SOC; OR, 36.12; 95% CI, 2.06-632.13) and infection (direct: 38/147 [26%] anti-CD20 vs 26/196 [13%] SOC; OR, 2.50; 95% CI, 1.01-6.21; indirect: 1/49 [2%] anti-CD20 vs 0/52 [0%] SOC; OR, 3.25; 95% CI, 0.13-81.63). Anti-CD20 may increase the odds of major bleeding (2/62 [3%] anti-CD20 vs 1/71 [1%] SOC; OR, 2.33; 95% CI, 0.21-26.37) and GI symptoms (14/62 [23%] anti-CD20 vs 11/71 [16%] SOC; OR, 1.59; 95% CI, 0.66-3.83), but the estimates are imprecise, and the CIs include no effect. There is low certainty in the estimate of the risk of adverse effects because of serious inconsistency, serious imprecision, and serious indirectness for some outcomes, related to number of studies and heterogeneity in study designs.

However, given the available evidence, the guideline panel considered the undesirable effects for anti-CD20 to be small, mainly driven by increased risk of infection. The panel noted that serious infections (eg, progressive multifocal leukoencephalopathy) are very rare in patients with ITP. The panel noted that treatment with anti-CD20 attenuates the response to vaccinations for ≥6 months.

The panel noted other important adverse effects that were not prioritized, such as hepatitis B reactivation, neutropenia, serum sickness, and infusion reactions.

Other EtD criteria and considerations

The guideline panel noted that the cost of MMF is negligible, whereas the cost of rituximab and thrombopoietic agents is moderate. The panel further determined that rituximab and thrombopoietic agents would likely reduce equity due to cost and uneven insurance coverage. The panel judged that MMF, rituximab, and thrombopoietic agents are probably acceptable and feasible, with cost and insurance coverage being the most significant barriers to their use as initial therapy.

The panel underscored that MMF is contraindicated in pregnancy and that the safety of rituximab and the thrombopoietic agents is not well established in pregnancy.

Conclusions for this recommendation

Results of the panel discussion of the pairwise comparisons informed the multiple-comparison EtD (linked to each intervention) that was used to form the final recommendations. The panel made a conditional recommendation in favor of combination therapy with rituximab plus corticosteroids (with or without IVIG) or a thrombopoietic agent plus corticosteroids (with or without IVIG), rather than corticosteroids (with or without IVIG) alone, primarily because the combination regimens demonstrated greater SRoT at 6 and 12 months, reduced minor bleeding, reduced need for rescue therapy, and improved various dimensions of HRQoL. These benefits were felt to more than offset the greater costs and reduced equity associated with the combination regimens.

An individualized approach to the selection of initial therapy for adults with primary ITP corresponding to recommendation 1 and incorporating patient values, preferences, and treatment availability is recommended and is summarized in Figure 3.

MMF plus corticosteroids (with or without IVIG) was rated less favorably by the guideline panel because there was no evidence regarding the prioritized outcome of SRoT with this regimen. Furthermore, HRQoL was significantly lower in the combination group than the corticosteroid-only group despite a higher rate of platelet count responses in the former.

In the event that neither rituximab nor thrombopoietic agents are available, the panel made a conditional recommendation in favor of initial therapy with corticosteroids (with or without IVIG) alone rather than combination therapy with MMF plus corticosteroids (with or without IVIG). This recommendation was primarily driven by decreased HRQoL, increased costs, and a lack of data on SRoT associated with the combination regimen.

Treatment for adults with primary ITP needing additional treatment after initial therapy with corticosteroids (with or without IVIG)

For adults with primary ITP needing additional treatment after initial therapy with corticosteroids (with or without IVIG), should an anti-CD20 agent, AZA, a BTK inhibitor, MMF, an SYK inhibitor, or a thrombopoietic agent be used, or should corticosteroids (with or without IVIG) be continued?Recommendation 2aFor adults with primary ITP needing additional treatment after initial therapy with corticosteroids (with or without IVIG), the ASH guideline panel recommends a thrombopoietic agent (strong recommendation based on moderate certainty in the evidence of effects ⨁⨁⨁◯) or suggests rituximab (conditional recommendation based on low certainty in the evidence ⨁⨁◯◯).Remarks:•If a thrombopoietic agent is used, any approved thrombopoietic agent at a standard starting dose may be used. Duration of therapy is typically guided by clinical response, toxicity, and platelet count stability.•Rituximab may be preferable for patients who value avoiding chronic medication or who have a contraindication to, are unable to access, or cannot tolerate thrombopoietic agents.•If rituximab is used, the most studied regimen is 375 mg/m2 × 4 weekly doses. However, other doses and schedules of rituximab may be used according to local practice.

Biosimilars to rituximab are suitable substitutes.

Recommendation 2bFor adults with primary ITP needing additional treatment after initial therapy with corticosteroids (with or without IVIG) who are either ineligible for or choose not to receive a thrombopoietic agent or rituximab, the ASH guideline panel suggests a BTK inhibitor, MMF, or an SYK inhibitor (conditional recommendation based on very low certainty in the evidence ⨁◯◯◯).Remarks:•The panel concluded that current evidence in the population of interest is too indirect to definitively rank BTK inhibitors, MMF, or SYK inhibitors. Side effect profiles, cost, availability, and shared decision-making may be considered in selecting an agent.•The panel concluded that AZA has a less favorable benefit-to-harm ratio; therefore, it is not equivalent to the other suggested treatment options. Nevertheless, AZA may be useful in some settings due to its low cost, global availability, and safety profile in pregnancy.

Background

Although the guideline panel suggests a combination of either rituximab or a thrombopoietic agent plus corticosteroids (with or without IVIG) as initial therapy (see “Recommendation 1”), it acknowledges that some patients will still be treated with corticosteroids (with or without IVIG) alone as initial therapy. The panel therefore prioritized the following question: for adults with primary ITP needing additional treatment after initial therapy with corticosteroids (with or without IVIG) alone, should an anti-CD20 agent, AZA, a BTK inhibitor, MMF, an SYK inhibitor, or a thrombopoietic agent be used, or should corticosteroids (with or without IVIG) be continued?

Summary of the evidence

This multiple-comparison question compared 6 different interventions (MMF, thrombopoietic agent, anti-CD20, SYK inhibitor, BTK inhibitor, or AZA) to a uniform SOC, which was defined as corticosteroids with or without IVIG. Supplement 8a presents the characteristics of all included studies for PICO 2 for MMF, thrombopoietic agent, anti-CD20, SYK inhibitor, BTK inhibitor, and AZA. Supplement 8b presents study-level data for thrombopoietic and anti-CD20 agents for SRoT, durable response, and HRQoL outcomes.

MMF

We found 1 prospective 1-armed study39 that addressed this question. The study included adults with primary ITP needing additional therapy after treatment with corticosteroids (with or without IVIG) and was considered indirect evidence because 15% of the study participants underwent splenectomy. The prospective 1-armed study reported SRoT at 6 months, durable response at 6 months, and overall GI symptoms.39

The evidence profile and EtD framework for this intervention are available online at https://guidelines.ash.gradepro.org/profile/wTP6UBZ2lXQ.

THROMBOPOIETIC AGENTS

We found 14 studies, including 3 RCTs,40, 41, 42 1 retrospective cohort study,43 3 RCTs treated as prospective 1-armed studies due to crossover at 6 to 10 weeks,25,44,45 6 prospective 1-armed studies,32,46, 47, 48, 49, 50 and 1 retrospective 1-armed study,51 that addressed this question. Three studies also had an ancillary publication that contained prioritized outcomes (primary/ancillary: Kuter et al40/George et al52; Kuter et al41/Kuter et al53; Mei et al25/Mei et al54). Four studies were classified as direct evidence43,47,48,50 because no patients had undergone splenectomy, and 10 studies were classified as indirect evidence25,32,40, 41, 42,44, 45, 46,49,51 because up to 20% of patients had undergone splenectomy.

Because our population of interest was patients who had previously received only initial therapy (with corticosteroids with or without IVIG) and not patients who had received multiple prior lines of therapy, we excluded studies with ≥20% of patients who had undergone splenectomy (with no ability to separate patients who had undergone splenectomy from those who had not). Data from the studies without a comparator arm were reported in the evidence tables, assessed by the panel, and informed the recommendations but are only reported in the text if no evidence from controlled studies was available.

Four studies reported SRoT at 6 months,46, 47, 48,51 3 studies reported SRoT at 12 months,48, 49, 50 5 studies assessed durable response at 6 months,25,32,40,43,44 3 studies assessed durable response at 12 months,41,49,54 6 studies assessed major bleeding,32,42,44,48,50,54 8 studies assessed minor bleeding,25,32,41,42,44,46,47,50 4 studies assessed infection,25,41,42,45 3 studies assessed overall GI symptoms,25,41,44 6 studies assessed thrombosis,25,32,41,42,44,47 4 studies assessed nausea,25,32,47,50 2 studies assessed vomiting,32,50 2 studies reported HRQoL,52,53 1 study reported fatigue,32 1 study reported diarrhea,47 6 studies reported the need for rescue therapy,25,40,42,44, 45, 46 and 4 studies reported time to response.25,43,46,49

The evidence profile and EtD framework for this intervention are available online at https://guidelines.ash.gradepro.org/profile/hSqNgVFmvAg.

ANTI-CD20

We found 5 studies, 3 RCTs,55, 56, 57 1 retrospective cohort study,43 and 1 prospective 1-armed cohort study,58 that addressed this question. All studies included adults with a diagnosis of primary ITP for 6 months or longer needing additional therapy after treatment with corticosteroids (with or without IVIG or platelet transfusions). Three studies were classified as direct evidence43,56,58 because no patients had undergone splenectomy, and 2 studies were classified as indirect evidence55,57 because up to 20% of patients had undergone splenectomy.

Studies with ≥20% of patients who had undergone splenectomy (with no ability to separate patients who had undergone splenectomy from those who had not) were excluded.

One study reported SRoT at 6 months,55 2 studies reported SRoT at 12 months,55,58 3 studies assessed durable response at 6 months,43,56,57 1 study assessed durable response at 12 months,56 2 studies assessed major bleeding,55,57 1 study assessed minor bleeding,56 2 studies assessed thrombosis,56,58 4 studies assessed infection,55, 56, 57, 58 2 studies assessed overall GI symptoms,57,58 1 study reported the need for rescue therapy,57 1 study reported fatigue,57 and 2 studies reported time to response.43,58

The evidence profile and EtD framework for this intervention are available online at https://guidelines.ash.gradepro.org/profile/jHfWCOEkAqI.

SYK INHIBITOR

We found 4 studies, including 1 1-armed post hoc analysis of 2 RCTs59 and 3 retrospective 1-armed studies,60, 61, 62 that addressed this question. All studies included adults with a diagnosis of primary ITP for ≥6 months needing additional therapy after treatment with corticosteroids (with or without IVIG or platelet transfusions). One study was classified as direct evidence59 because no patients had undergone splenectomy, and 3 studies were classified as indirect evidence60, 61, 62 because up to 20% of patients had undergone splenectomy.

Studies including ≥20% patients who had undergone splenectomy (with no ability to separate patients who had undergone splenectomy from those who had not) were excluded.

One study reported SRoT at 6 months,60 4 studies assessed durable response at 6 months,59, 60, 61, 62 2 studies assessed durable response at 12 months,59,61 1 study assessed minor bleeding,60 1 study assessed thrombosis,60 3 studies assessed diarrhea,60, 61, 62 2 studies assessed time to response,60,61 2 studies reported the need for rescue therapy,59,61 1 study reported depression,60 and 1 study reported nausea.60

The evidence profile and EtD framework for this intervention are available online at https://guidelines.ash.gradepro.org/profile/XraioI1rAYY.

BTK INHIBITORS

We found 4 studies, including 1 RCT with a SOC comparison group,63 1 RCT comparing doses with no SOC comparison group (dose groups combined and reported together),64 1 dose-finding phase 1/2 clinical trial,65 and 1 prospective 1-armed cohort study,66 that addressed this question. All studies included adults with a diagnosis of primary ITP for ≥6 months needing additional therapy after treatment with corticosteroids (with or without IVIG or platelet transfusions). No studies were classified as direct evidence, and 4 studies were classified as indirect evidence63, 64, 65, 66 because up to 20% of patients had undergone splenectomy.

Studies including ≥20% patients who had undergone splenectomy (with no ability to separate patients who had undergone splenectomy from those who had not) were excluded.

One study reported SRoT at 6 months,66 2 studies assessed durable response at 6 months,63,64 1 study assessed major bleeding,66 3 studies assessed minor bleeding,64, 65, 66 2 studies assessed thrombosis,64,65 3 studies assessed infection,64, 65, 66 1 study assessed nausea,66 2 studies assessed diarrhea,65,66 1 study assessed vomiting,66 2 studies assessed HRQoL,64,65 3 studies reported the need for rescue therapy,64, 65, 66 and 2 studies reported time to response.64,66

The evidence profile and EtD framework for this intervention are available online at https://guidelines.ash.gradepro.org/profile/ov13DGGMco8.

AZA

We found 5 studies, including 1 RCT with a SOC comparator,27 1 retrospective cohort study,67 1 RCT with no SOC comparators68 (only AZA arm reported), and 2 retrospective 1-armed studies,69,70 that addressed this question. All studies included adults with a diagnosis of primary ITP for ≥6 months who required additional therapy after treatment with corticosteroids (with or without IVIG or platelet transfusions). Three studies were classified as direct evidence27,67,69 because no patients had undergone splenectomy, and 2 studies were classified as indirect evidence68,70 because up to 20% of patients had undergone splenectomy.

Studies including ≥20% patients who had undergone splenectomy (with no ability to separate patients who had undergone splenectomy from those who had not undergone splenectomy) were excluded.

Two studies reported SRoT at 6 months,27,69 2 studies assessed durable response at 6 months,67,68 1 study assessed major bleeding,70 2 studies assessed minor bleeding,27,70 1 study assessed thrombosis,27 4 studies assessed infection,27,67,69,70 1 study assessed overall GI symptoms,70 2 studies assessed nausea,67,68 1 study assessed diarrhea,68 1 study assessed anxiety,27 1 study assessed depression,27 1 study reported fatigue,27 1 study reported the need for rescue therapy,27 and 1 study reported time to response.70

The evidence profile and EtD framework for this intervention are available online at https://guidelines.ash.gradepro.org/profile/gV_jlnhKT44.

Benefits

MMF

Only 1 indirect, single-arm prospective study was identified. The reported SRoT at 6 months was 45% (9/20), and durable response at 6 months was 65% (13/20) for MMF. The panel judged the desirable effects of MMF to be small because there was only 1 eligible study, which did not include a control arm.

The desirable effects from PICO 1 (increased durable response) were used as indirect evidence to assist in decisions related to desirable effects of this agent. Overall, the certainty in the evidence for these estimated effects was very low because of serious inconsistency and serious imprecision related to the inclusion of only 1 prospective single-arm study. There was also serious indirectness because 15% of patients had undergone splenectomy.

THROMBOPOIETIC AGENTS

The studies, both direct and indirect combined, showed SRoT at 6 months of 30% (59/195) and SRoT at 12 months of 27% (43/158). Thrombopoietic agents overall increased the odds of durable response at 6 months (direct: 10/11 [91%] thrombopoietic agent vs 34/41 [83%] SOC; OR, 2.06; 95% CI, 0.23-18.78; indirect: 27/41 [66%] thrombopoietic agent vs 3/21 [14%] SOC; OR, 11.57; 95% CI, 2.90-46.10) and durable response at 12 months (indirect: 139/157 [89%] thrombopoietic agent vs 54/77 [70%] SOC; OR, 3.29; 95% CI, 1.65-6.57). Thrombopoietic agents decreased the odds of the need for rescue therapy (indirect: 10/89 [11%] thrombopoietic agent vs 17/45 [38%] SOC; OR, 0.18; 95% CI, 0.07-0.47).

The studies found no meaningful difference between those receiving a thrombopoietic agent and those receiving SOC for minor bleeding (indirect: 97/202 [48%] thrombopoietic agent vs 48/99 [49%] SOC; OR, 0.94; 95% CI, 0.47-1.89), overall GI symptoms (indirect: 18/202 [9%] thrombopoietic agent vs 8/101 [8%] SOC; OR, 0.86; 95% CI, 0.11-6.57), or nausea (indirect: 3/48 [6%] thrombopoietic agent vs 1/26 [4%] SOC; OR, 1.67; 95% CI, 0.16-16.88). Time to response may be longer with thrombopoietic agents than with SOC (direct: median, 1.5 days longer for thrombopoietic agent), and HRQoL may be greater with thrombopoietic agents (indirect: mean difference, 3.67 higher; 95% CI, −5.06 to 12.39), but the estimates were imprecise, and the CIs include no effect. The panel judged the desirable effects of thrombopoietic agents to be large, mainly driven by durable response at 6 and 12 months and SRoT at 6 and 12 months.

In addition, there was a reduction in the need for rescue therapy and improvement in various HRQoL domains. The panel noted that the duration of treatment with a thrombopoietic agent was variable, as was dosing among included studies. Overall, the certainty the evidence for these estimated effects was deemed moderate based on 3 critically important outcomes (durable response at 6 months, durable response at 12 months, and need for rescue therapy).

ANTI-CD20

Anti-CD20 increased the odds of SRoT at 6 months (indirect: 24/31 [77%] anti-CD20 vs 12/31 [39%] SOC; OR, 5.43; 95% CI, 1.79-16.47) and SRoT at 12 months (indirect: 21/31 [68%] anti-CD20 vs 6/31 [19%] SOC; OR, 8.75; 95% CI, 2.72-28.10). Anti-CD20 may increase the odds of durable response at 6 months (direct: 79/90 [88%] anti-CD20 vs 74/95 [78%] SOC; OR, 1.12; 95% CI, 0.95-1.28; indirect: 20/32 [63%] anti-CD20 vs 19/26 [73%] SOC; OR, 0.86; 95% CI, 0.60-1.25) and durable response at 12 months (direct: 35/55 [64%] anti-CD20 vs 28/54 [52%] SOC; OR, 1.63; 95% CI, 0.76-3.60) and may decrease the odds of the need for rescue therapy (14/32 [44%] anti-CD20 vs 17/26 [65%] SOC; OR, 0.41; 95% CI, 0.14-1.20), overall GI symptoms (direct: 0/32 [0%] anti-CD20 vs 4/26 [15%] SOC; OR, 0.08; 95% CI, 0.00-1.50), and minor bleeding (21/55 [38%] anti-CD20 vs 27/54 [59%] SOC; OR, 0.62; 95% CI, 0.29-1.32), but the estimates were imprecise, and the CIs include no effect. The panel judged the desirable effects of anti-CD20 agents to be small, driven primarily by SRoT with rituximab at 6 and 12 months, although the panel noted that SRoT was likely a surrogate for durable response, given that small amounts of treatment (eg, prednisone <7.5 mg daily) were permitted in the largest randomized trial.56 The panel noted that the effect of anti-CD20 on B-cell depletion can last for many months; consequently, “exposure” to the pharmacodynamic effects of the drug persists well after treatment is completed.

Overall, the certainty the evidence for these estimated effects is deemed low because of serious inconsistency, serious imprecision, and serious indirectness. The decision to assign low certainty in the evidence was also influenced by differences in anti-CD20 dosing.

SYK INHIBITOR

Only single-arm studies were identified. The reported SRoT at 6 months was 3% (4/122), durable response at 6 months was 53% (125/238), and durable response at 12 months was 38% (24/63). The panel judged the desirable effects of SYK inhibitors to be small, driven primarily by durable response at 6 and 12 months.

Some studies included patients with refractory disease. The panel noted that because there was efficacy in a patient population with more refractory disease (indirect), response in the population of interest would be expected to be at least as high. Overall, the certainty in the evidence for these estimated effects was very low because of very serious to serious risk of bias, serious inconsistency, serious indirectness, and single-arm study design.

BTK INHIBITOR

BTK inhibitors increased the odds of durable response at 6 months (26/96 [27%] BTK vs 0/50 [0%] SOC; OR, 37.96; 95% CI, 2.26-637.61), but the CI was very wide. The reported SRoT at 6 months was 35% (7/20). Increases in HRQoL were also reported (average increase of 21.2 points in physical well-being and 10.3 points in emotional well-being using the 36-Item Short Form Health Survey scores measured at week 24).

The panel judged the desirable effects of BTK inhibitors to be small, driven primarily by increased durable response at 6 months. Some studies included patients with refractory disease. The panel noted that because there was efficacy in a patient population with more refractory disease (indirect), response in the population of interest would be expected to be at least as high.

Overall, the certainty in the evidence for these estimated effects was very low because of very serious to serious risk of bias, serious inconsistency, serious indirectness, and single-arm study design.

AZA

AZA may decrease the odds of anxiety (direct: 86/110 [78%] AZA vs 94/105 [90%] SOC; OR, 0.42; 95% CI, 0.19-0.91), may increase the odds of durable response at 6 months (direct: 10/15 [67%] AZA vs 9/18 [50%] SOC; OR, 2.00; 95% CI, 0.49-8.24), may decrease the odds of depression (direct: 93/110 [85%] AZA vs 99/105 [95%] SOC; OR, 0.33; 95% CI, 0.193-0.88), and may decrease fatigue (direct: 74/110 [67%] AZA vs 81/105 [77%] SOC; OR, 0.61; 95% CI, 0.33-1.12), but the estimates were imprecise, and the CIs include no effect. Studies found no meaningful difference between those receiving AZA and SOC for the need for rescue therapy (direct: 19/110 [17%] AZA vs 15/105 [14%] SOC; OR, 1.25; 95% CI, 0.16-2.62). The reported percentage of patients experiencing major bleeding who received AZA was low (2% [1/63]).

The panel judged the desirable effects of AZA to be trivial, driven primarily by a small improvement in durable response at 6 months and improvements in various domains of HRQoL. The panel noted that many patients in the included studies had refractory disease (indirect) and that response rates would be expected to be at least as high in the population of interest. Overall, the certainty in the evidence for these estimated effects was very low because of serious risk of bias, serious inconsistency, and serious indirectness.

Harms and burden

MMF

For MMF, overall GI symptoms occurred in 7 of 20 (35%) patients. There was very low certainty in the estimate of the risk of adverse effects because of serious inconsistency and serious imprecision related to the inclusion of only 1 prospective single-arm study. There was also serious indirectness because 15% of patients had undergone splenectomy.

However, given the available evidence, the guideline panel considered the risk of adverse effects most likely to be small, primarily driven by GI symptoms. Some panel members noted that the undesirable effects could be considered moderate. The undesirable effects were extrapolated from an indirect population; however, undesirable effects were not expected to be substantially different in the population of interest.

THROMBOPOIETIC AGENTS

Thrombopoietic agents may increase the odds of infection (23/202 [11%] thrombopoietic agent vs 5/101 [5%] SOC; OR, 2.43; 95% CI, 0.49-12.05) and thrombosis (indirect: 6/202 [3%] thrombopoietic agent vs 2/101 [2%] SOC; OR, 1.48; 95% CI, 0.29-7.51), but the estimates were imprecise and the CIs include no effect. There was low certainty in the estimate of the risk of adverse effects because of serious indirectness and serious imprecision. However, given the available evidence, the guideline panel considered the risk of adverse effects most likely to be small, primarily driven by thrombosis.

Patients may be adversely affected by dietary restrictions associated with certain thrombopoietic agents (ie, eltrombopag) or the need for weekly injections in a health care setting (ie, romiplostim). The panel also noted other side effects that were not prioritized, including musculoskeletal pain and liver injury (with eltrombopag).

ANTI-CD20

Anti-CD20 may increase the odds of thrombosis (direct: 2/55 [4%] anti-CD20 vs 0/54 [0%] SOC; OR, 5.09; 95% CI, 0.24-108.60), infection (direct: 22/55 [40%] anti-CD20 vs 13/54 [24%] SOC; OR, 2.10; 95% CI, 0.92-4.80; indirect: 7/63 [11%] anti-CD20 vs 7/57 [12%]; OR, 1.26; 95% CI, 0.38-4.23), fatigue (7/32 [22%] anti-CD20 vs 2/26 [8%] SOC; OR, 3.36; 95% CI, 0.63-17.82), and major bleeding (9/63 [14%] anti-CD20 vs 6/57 [11%] SOC; OR, 1.25; 95% CI, 0.34-24.52), but the estimates were imprecise, and the CIs include no effect. Time to response was a median of 1.5 days longer in the anti-CD20 arm than in the SOC arm. There was low certainty in the estimate of the risk of adverse effects because of serious inconsistency, serious imprecision, and serious indirectness.

However, given the available evidence, the guideline panel considered the risk of adverse effects to be small, primarily driven by increased risk of infection. The panel noted that serious infections (eg, progressive multifocal leukoencephalopathy) are very rare in ITP but have been reported in other clinical settings, typically when anti-CD20 agents were given in combination with other immunosuppressive agents. The panel noted that treatment with anti-CD20 attenuates the response to vaccinations for ≥6 months.

The panel noted that there are other important adverse effects that were not prioritized, such as hepatitis B reactivation, neutropenia, serum sickness, and infusion reactions.

SYK INHIBITOR

Only single-arm studies were identified. The reported need for rescue therapy was 44% (28/63), minor bleeding 15% (20/138), and diarrhea 18% (38/209). The reported risk of thrombosis (1% [2/138]), depression (1% [2/138]), and nausea (1% [1/138]) was low.

The panel judged the undesirable effects of SYK inhibitors to be small, primarily driven by diarrhea. In addition, there was a low percentage of patients who reported thrombosis. Panel members discussed that the undesirable effects could be considered moderate; however, they settled on small because most toxicities were tolerable and mild and responded to symptomatic treatment.

Other unprioritized side effects noted by the panel include hypertension, neutropenia, and liver injury.

BTK INHIBITOR

Only single-arm studies were identified. The adverse events of thrombosis (2% [1/49]) and vomiting (5% [1/20]) were reported in ≤5% of the time. The reported rate of major bleeding was 10% (2/20), minor bleeding was 13% (9/69), infection was 20% (14/69), nausea was 10% (2/20), diarrhea was 17% (6/36), the need for rescue therapy was 33% (23/69), and the median time to response was 14 days.

The panel judged the undesirable effects of BTK inhibitors to be small. This was primarily driven by the need for rescue therapy, infection, diarrhea, and minor bleeding.

AZA

AZA may increase the odds of minor bleeding (direct: 86/110 [78%] AZA vs 62/105 [59%] SOC; OR, 2.49; 95% CI, 1.37-4.51), may decrease the odds of SRoT at 6 months (direct: 13/72 [18%] AZA vs 23/79 [29%] SOC; OR, 0.54; 95% CI, 0.25-1.16), but the estimate is imprecise, and the CI includes no effect. Studies found no meaningful difference between those receiving AZA and SOC for the outcomes of thrombosis (direct: 0/110 [0%] vs 0/105 [0%]; not pooled), infection (direct: 15/125 [12%] AZA vs 18/123 [15%] SOC; OR, 0.78; 95% CI, 0.37-1.64), and nausea (direct: 1/15 [7%] AZA vs 1/18 [6%] SOC; OR, 1.21; 95% CI, 0.07-21.22). There is very low certainty in the estimate of the risk of adverse effects because of serious risk of bias, serious inconsistency, and serious indirectness.

However, given the available evidence, the guideline panel considered the risk of adverse effects most likely to be moderate. This was primarily driven by the delayed time to response (up to 3 months) and reduced SRoT at 6 months relative to the comparator arm. In addition, panel members discussed that some patients do not tolerate this medication well and that treatment can be complicated by drug-drug interactions.

Important potential side effects that were not prioritized include cytopenias, transaminitis, myalgias, and rash.

Other EtD criteria and considerations

The guideline panel noted that the cost of MMF and AZA is negligible, the cost of rituximab is moderate, and the cost of BTK inhibitors, SYK inhibitors, and thrombopoietic agents is large. The panel noted that the cost of thrombopoietic agents is highly variable, depending on the agent used, as well as the dose, duration, and jurisdiction. The panel emphasized that ∼30% of patients treated with a thrombopoietic agent are ultimately able to achieve SRoT, which mitigates the cost of this class of medications.71

The panel determined that BTK inhibitors, SYK inhibitors, thrombopoietic agents, and rituximab would reduce or probably reduce equity due to cost, uneven insurance coverage, and lack of availability in certain jurisdictions for some agents. They noted that MMF would probably reduce equity because it is contraindicated in pregnancy. Conversely, they emphasized that AZA is inexpensive, is available globally, and can be used safely in pregnancy.

The panel judged that BTK inhibitors, SYK inhibitors, MMF, rituximab, and thrombopoietic agents are probably acceptable and probably feasible, with cost and insurance coverage being the most significant barriers, particularly for BTK inhibitors, SYK inhibitors, and thrombopoietic agents. The panel judged AZA to be probably acceptable and feasible, given its low cost and broad availability.

Conclusions for this recommendation

Results of the panel discussion of the pairwise comparisons informed the multiple-comparison EtD that was used to form the final recommendations. The shared multiple-comparison EtD for PICO 2 is available in the EtD framework tab of the relevant agent-specific evidence profiles linked in each agent’s subsection in “Summary of the evidence.”

The panel issued a strong recommendation in favor of thrombopoietic agents, primarily driven by large benefits in the form of greater SRoT and durable response at 6 and 12 months, decreased need for rescue therapy, and improvement in various dimensions of HRQoL. These desirable effects were considered to more than offset the small undesirable effects (driven mainly by thrombotic risk), large costs, and probably reduced equity associated with this class of agents.

For patients who place a high value on avoiding chronic medication or who have a contraindication to, are unable to access, or cannot tolerate thrombopoietic agents, the panel issued a conditional recommendation in favor of rituximab. The panel judged the benefits of rituximab to be small (driven mainly by greater SRoT at 6 and 12 months) and determined that the benefits outweigh the small harms (driven mainly by infection), moderate costs, and probable reduction in equity associated with this agent.

For patients who are unable or unwilling to be treated with a thrombopoietic agent or rituximab, the panel issued a conditional recommendation in favor of a BTK inhibitor, SYK inhibitor, or MMF. Although there is more abundant evidence with these agents in patients with chronic and/or more heavily pretreated ITP, the panel determined that the evidence in the population of interest is insufficient to rank order them and noted that consideration of side effect profiles, cost, and availability may be useful in selecting an agent through a shared decision-making approach.

These considerations support an individualized approach to selection of second-line therapy for adults with primary ITP corresponding to recommendation 2 and incorporating patient values, preferences, and treatment availability, as summarized in Figure 3.

Finally, the panel concluded that AZA has a less favorable benefit-to-harm ratio and should therefore be deprioritized compared with the other options. This conclusion was based on the panel’s judgment that the moderate undesirable effects of AZA (driven mainly by delayed time to response, reduced SRoT at 6 months, and well-known toxicity profile) outweigh its trivial benefits (driven mainly by small increased durable response at 6 months). Nevertheless, the panel noted that AZA may be useful in some settings owing to its low cost, global availability, and safety profile in pregnancy.

Good practice statements

Splenectomy

BACKGROUND

Splenectomy is an appropriate consideration for adults with primary ITP in the following circumstances: (1) patients who are intolerant to or have failed multiple lines of medical therapy at optimal doses and durations, (2) patients who wish to avoid long-term medical treatment, and (3) patients with severe thrombocytopenia who need emergent treatment and have an inadequate response to medical therapies.

Indium-labeled autologous platelet scintigraphy predicts the likelihood of response to splenectomy. In a systematic review and meta-analysis, the response rate was 87.1%, 47.1%, and 25.5% in patients with a splenic, mixed, and hepatic sequestration pattern, respectively.72 Indium-labeled autologous platelet scintigraphy is currently only offered at a small number of centers around the world.

Normalization of the platelet count after splenectomy does not prevent transplacental passage of maternal anti-platelet antibodies during pregnancy, which can cause neonatal thrombocytopenia.Good practice statementIf feasible, splenectomy should be delayed for ≥1 year after diagnosis because of the potential for remission.

Good practice statementThe treating clinician should ensure that patients receive appropriate immunizations ≥2 weeks before splenectomy, when feasible, and counseling regarding antibiotic prophylaxis and lifelong risk of sepsis and thrombosis after splenectomy. The treating clinician should educate the patient on prompt recognition and management of fever with antibiotics. After splenectomy, patients should be followed at least annually for platelet count monitoring and counseling and to ensure adherence to recommended immunization schedules.

Thrombopoietic agent switching

BACKGROUND

Patients differ in their response to and tolerance of individual thrombopoietic agents. Patients who have failed to respond to 1 agent may respond to a different one.73Good practice statementSwitching to a different thrombopoietic agent may be considered based on insufficient response, adverse effects, comorbidities, poor adherence, or patient preference.

Good practice statementShared decision-making with the patient, documentation of the rationale for switching, avoidance of treatment gaps, and close monitoring around the time of switching are good practices to ensure optimal outcomes and continuity of care.

What are others saying, and what is new in these guidelines?

The 2026 ASH ITP guidelines include both methodological innovations and novel recommendations. In recognition of the growing number of treatment options available for ITP, these guidelines are the first to use the GRADE EtD framework for multiple comparisons,18 whereas past ITP guidelines, including the 2019 ASH ITP guideline, were limited to pairwise comparisons.15

With respect to initial therapy, previously published guidelines, including the 2019 ASH ITP guidelines, the 2019 International Consensus Report, and national guidelines, advocate for corticosteroids alone in the first-line setting.15,74, 75, 76 In contrast, our guidelines suggest rituximab or a thrombopoietic agent plus corticosteroids as initial therapy (see “Recommendation 1”), a recommendation driven mainly by greater SRoT at 6 and 12 months, reduced need for rescue therapy, and improvement in various dimensions of HRQoL with combination therapy.

Among patients who require treatment beyond an initial course of corticosteroids, recommendation 2 in these guidelines ranks second-line therapy options as follows: (1) thrombopoietic agents, (2) rituximab, (3) BTK inhibitor or MMF or SYK inhibitor, and (4) AZA. As a recently approved treatment for ITP in 2025, BTK inhibitors are not addressed in previously published guidelines. The other treatment options are addressed but not explicitly rank ordered in other guidelines or consensus articles.15,74, 75, 76

Limitations of these guidelines

A key limitation of these guidelines is inherent in the low or very low certainty in the evidence we identified for many of the questions and interventions. Indeed, we were able to issue only 1 strong recommendation, highlighting the need for further randomized controlled trials comparing different active treatment strategies. For some questions and interventions, the panel relied on indirect evidence, especially when direct evidence was lacking.

We specify in the text where indirect evidence was applied.

Another key limitation of these guidelines is their restricted scope. We undertook a focused revision of the 2019 ASH ITP guidelines, specifically centered on management of primary ITP in adults requiring initial or second-line therapy. Other important aspects of ITP, including diagnosis, indications for treatment, management in children, management of ITP in pregnancy, management of secondary ITP, management of chronic and/or refractory ITP, and management of critical bleeding, are addressed elsewhere.15,74,77

In accordance with the GRADE framework for multiple comparisons, we were limited to ≤7 interventions per question. The guideline panel prioritized which interventions to include but was not able to consider some of the many ITP treatments used around the world, including cyclosporine, danazol, dapsone, sirolimus, tacrolimus, and others.

Finally, there may be confusion about how recommendations 1 and 2 align. Recommendation 1 suggests initial treatment with either rituximab or a thrombopoietic agent plus corticosteroids (with or without IVIG), rather than corticosteroids (with or without IVIG) alone. Notwithstanding this recommendation, the guideline panel acknowledged that many clinicians will continue to prescribe corticosteroids (with or without IVIG) alone as initial therapy.

Recommendation 2 provides guidance on how to manage such patients if they require treatment beyond corticosteroids.

Revision or adaptation of the guidelines

Plans for updating these guidelines

After publication of these guidelines, ASH will maintain them through surveillance for new evidence, ongoing review by experts, and regular revisions.

Updating or adapting recommendations locally

Adaptation of these guidelines will be necessary in many circumstances. These adaptations should be based on the associated EtD frameworks.78

Priorities for research

On the basis of gaps in evidence identified during the guideline development process, the panel makes the following recommendations for further research:•Determination of the optimal thrombopoietic agent, dose, and duration of initial therapy;•Determination of the optimal rituximab dose and schedule for initial therapy;•Randomized controlled trials comparing rituximab plus corticosteroids (with or without IVIG) vs a thrombopoietic agent plus corticosteroids (with or without IVIG) as initial therapy;•Long-term follow-up to determine SRoT beyond 12 months after initial combination therapy and to determine whether these regimens “cure” patients or merely postpone relapse;•Studies of other potential combination regimens for initial therapy, such as SYK inhibitors, BTK inhibitors, B-cell activating factor receptor inhibitors, or anti-CD38 agents plus corticosteroids (with or without IVIG);•Studies of the interval between diagnosis and commencement of initial therapy and its potential impact on outcomes;•Studies of corticosteroid regimens other than high-dose dexamethasone as the corticosteroid component of initial combination therapy;•More and higher-quality evidence on second-line treatment with AZA, BTK inhibitors, MMF, and SYK inhibitors;•Clinical trials of other agents in the second-line setting, including anti-CD38 agents, B-cell activating factor receptor inhibitors, neonatal Fc receptor antagonists, and complement inhibitors;•Studies to define the optimal timing of initiation of second-line therapy;•Identification of clinical predictors and/or biomarkers to guide prioritization and sequencing of specific therapies for individual patients;•Evaluation of the efficacy and safety of ITP therapies in pregnancy; and•Evaluation of AZA, BTK inhibitors, MMF, and SYK inhibitors in the refractory setting, both as monotherapy and as a component of combination therapy.

Conflict-of-interest disclosure: All authors were members of the guideline panel or the systematic review team or both. As such, they completed a disclosure-of-interest form that was reviewed by the American Society of Hematology and is available in supplements 2 and 3.

Douglas B. Cines died on 7 December 2025.