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The COVID-19 pandemic has been the most significant health crisis in recent global history. Early studies from Wuhan highlighted COVID-19-associated coagulopathy and a significant association with mortality was soon recognised. As research continues across the world, more evidence is emerging of the cross-talk between the innate immune system, coagulation activation and inflammation. Immunothrombosis has been demonstrated to play a key role in the pathophysiology of severe COVID-19, with extracellular histones and neutrophil extracellular traps detected in the plasma and cardiopulmonary tissues of critically ill patients. Targeting the components of immunothrombosis is becoming an important factor in the treatment of patients with COVID-19 infection. Recent studies report outcomes of intermediate and therapeutic anticoagulation in hospitalised patients with varying severities of COVID-19 disease, including optimal dosing and associated bleeding risks. Immunomodulatory therapies, including corticosteroids and IL-6 receptor antagonists, have been demonstrated to significantly reduce mortality in COVID-19 patients. As the pandemic continues, more studies are required to understand the driving factors and upstream mechanisms for coagulopathy and immunothrombosis in COVID-19, and thus potentially develop more targeted therapies for SARS-CoV-2 infection, both in the acute phase and in those who develop longer-term symptom burden.

BackgroundAdult primary immune thrombocytopenia (ITP) is a rare bleeding disorder of unknown cause. Recent estimates of its incidence and trend over time were acquired for England.MethodThe primary ITP population (using ICD 10 code D693 and excluding secondary ITP cases; positive predictive value: 82.6%) was sourced from NHS Digital inpatient and outpatient. Incidence rate (IR) for England and by age groups, sex, and regions were calculated and trends were assessed using average annual percent change (AAPC).ResultsA total of 25 805 patients (mean age 59 years; females 57.8%) diagnosed between 2003 and 2014 was identified. IRs increased from 4.2/100 000 to 6.4/100 000 over this period (AAPC:4.3%). For all sex-specific age groups, the IRs significantly increased over time, except 18–29 years males. The greatest increase was among females aged 30–39 (AAPC:8.7%). In contrast, among ≥70 years, ITP was more common in males (highest IR among ≥80 years males: 23.9/100 000). England's average annual IR was 6.1/100 000 for 2010–14. An estimated 2.5/100 000 (based on UKITP Registry data) was estimated to require 1st line treatment whereas 2.4/100 000 would have 1st and 2nd line treatments within 6 months from diagnosis. IRs for London and East Midlands were the highest (6.5/100 000).ConclusionsThis study found a rising incidence of primary ITP, with sharp increases among young women and elderly men. These findings put in context the impact of ITP on patients' lives and the healthcare services in England, especially with 17%–50% who may develop chronic ITP and require long-term care.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

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Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.

© 2019 British Society for Haematology and John Wiley & Sons Ltd Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post-thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non-blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3 months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D-dimers. Two-hundred and eighty-one patients were recruited, randomised and followed up for 24 months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P

Background The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. Objectives To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE. Methods We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked or weakly provoked VTE who had completed (IMAGE_)3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies. Results Of 1,123 records identified by the search, 20 studies (17 RCTs) and 8,740 patients were included in the analysis. During 13,011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding (n = 41) and fatal bleeding (n = 7) per 100 person-years was 0.35 (95% confidence interval [CI]: 0.20–0.54) and 0.09 (95% CI: 0.05–0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI: 0.4–2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI: 10.6–31.1%). Conclusion The risk of major bleeding once anticoagulants are discontinued in patients with a first unprovoked VTE is not zero. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE.

Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain. Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5years in patients with a first unprovoked VTE. Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results. Results: Twenty-six studies and 15603 patients were included in the analysis. During 11631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03–1.84) and 0.09 (0.04–0.16), with 5-year cumulative incidences of 7.1% (3.0%–13.2%) and 1.2% (0.4%–4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77–1.44) with direct oral anticoagulants and 1.55 (1.01–2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%–8.7%). Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE. © 2021 International Society on Thrombosis and Haemostasis.

Background: Recent evidence suggests that in patients with immune thrombocytopenia (ITP) with a stable response on thrombopoietin receptor agonists, treatment may be tapered and/or discontinued. Objectives: The objective of this study was to provide a guide for tapering and discontinuation of TPO-RA therapy in patients with ITP, based on hematologist survey results, existing evidence, and expert consensus. Patients/Methods: UK hematologists completed a survey to characterize self-reported practice patterns related to TPO-RA tapering and discontinuation in patients with ITP. Using a modified Delphi panel approach, ITP experts developed consensus statements regarding the use of TPO-RA tapering and discontinuation. Results: Survey respondents estimated that 30–34% of their patients were suitable for tapering or discontinuation and that 29–35% of these patients required treatment re-initiation after an average treatment-free interval of 86–106 days. No clear predictors of patient suitability or response to tapering or discontinuation were identified. The ITP expert consensus was that approximately 30% of patients are eligible for tapering and discontinuation, which may be considered after 6–12 months for patients demonstrating an adequate treatment response (platelet count >50,000/µL at ≥75% of assessments in the preceding 6 months). Treatment re-initiation may be considered if the platelet count decreases or if the patient becomes symptomatic. Individual differences need to be taken into account when considering TPO-RA tapering or discontinuation. Conclusions: Tapering and discontinuation of TPO-RA therapy may be considered for certain patients with ITP. Further study is needed to better predict patients likely to achieve sustained off-treatment responses after tapering and discontinuation.

Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4+ T-helper subset distribution and enhanced production of pro-inflammatory cytokines such as interleukin 17A and interferon gamma. The role of monocytes (MCs) in ITP is less widely described, but innate immune cells have a role in shaping CD4+ T-cell phenotypes. Glucocorticoids (GCs) are commonly used for first-line ITP treatment and modulate a broad range of immune cells including T cells and MCs. Using multiparameter flow cytometry analysis, we demonstrate the expansion of intermediate MCs (CD14++ CD16+ ) in untreated patients with newly diagnosed ITP, with these cells displaying a pro-inflammatory phenotype, characterised by enhanced expression of CD64 and CD80. After 2 weeks of prednisolone treatment (1 mg/kg daily), the proportion of intermediate MCs reduced, with enhanced expression of the anti-inflammatory markers CD206 and CD163. Healthy control MCs were distinctly different than MCs from patients with ITP before and after GC treatment. Furthermore, the GC-induced phenotype was not observed in patients with chronic ITP receiving thrombopoietin receptor agonists. These data suggest a role of MCs in ITP pathogenesis and clinical response to GC therapy.

BACKGROUND The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Venous thrombosis is a frequent complication of coronavirus disease 2019, particularly in patients with severe disease on intensive care units. A high rate of thrombosis is seen despite the use of standard doses of prophylactic low-molecular weight heparin. This has led to the suggestion that increased doses of prophylactic anticoagulation should be tried. There are now several clinical studies in progress of increased intensity anticoagulation and other therapeutic interventions aimed at trying to reduce the rate of thrombosis. While the results of these studies are awaited some units have already introduced increased doses of anticoagulants for primary prevention of venous thrombosis into clinical practice. This article debates whether that is appropriate or whether we should only be using increased doses of anticoagulants within the context of clinical trials.

Abstract When planning a multicentre clinical trial, it can be difficult to predict the time needed to open individual sites, and this in turn impacts on the total number of sites needed, the budget and the time frame for a clinical trial to be delivered successfully. This is of particular importance for funding applications with a limited time frame and budget such as NIHR RfPB. It is more efficient and cost-effective to open the total number of sites needed at the outset of a trial, rather than to respond later to slow site opening and recruitment. Here, we share our experience of successfully delivering a multicentre clinical trial for a rare disease within a limited time frame and budget by approximately doubling the number of sites initially predicted to be needed. We initially predicted 20 sites would be needed to deliver the clinical trial, but early on in the trial, the number of sites was more than doubled to allow successful recruitment of the target sample size within the desired time frame. Of the 48 ethically approved sites, the median time from ethical approval of a site to opening for recruitment was 182 days (95% confidence interval [143 to 245 days]) and ranged from 18 to 613 days. In four (9%) of these sites, part of the delay was due to pharmacy sign off not being given when R&D had issued capacity and capability (C&C). Delays due to pharmacy sign off varied from 10 days to over 3 months delay in two sites (94 days and 102 days). A mathematical solution to the problem of planning a study with a short recruitment window has been given to support the planning and costing of grants with fixed time constraints: number of sites = required sample size divided by (number of eligible patients per site per month times recruitment rate times (the number of months accrual minus 6 months)). We expect these results to help others who are planning multicentre clinical trials in the UK. Ethical approval from NRES Committee South West (IRAS number 225959). Trial registration EudraCT Number 2017-001171-23. Registered on 26 June 2017

Background: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. Methods: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. Conclusion: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.

BackgroundCorticosteroids remain the first line treatment for patients with Immune Thrombocytopenia (ITP). However, 20-30% of patients do not respond to treatment at tolerable doses. This variation in corticosteroid efficacy is replicated in other autoimmune diseases and may have an adaptive immune basis.ObjectiveTo test the hypothesis that CD4+ T cell responses to corticosteroids are different in patients with clinically defined corticosteroid refractory ITP.MethodsIn this prospective cohort study, CD4+ T cells from patients with ITP were cultured in the presence or absence of dexamethasone (Dex). Intracellular cytokine expression was then quantified by flow cytometry and compared with patients’ clinical response to corticosteroid treatment. A control cohort of patients with autoimmune uveitis was also studied to evaluate whether our findings were limited to ITP or are potentially generalizable across autoimmune diseases. ResultsThe ratio of interleukin (IL)-10 to IL-17 expression following CD4+ T cell culture with Dex was able to discriminate between ITP patients with a clinically defined complete (n=33), partial (n=12) or non-response (n=11) to corticosteroid treatment (p=0.002). These findings were replicated in patients with autoimmune uveitis (complete response n=14, non-response n=22; p=0.01) ConclusionsThere is a relative abrogation of IL-10 and persistence of IL-17 expression in the CD4+ T cells of patients who clinically fail corticosteroid therapy. This observation has potential to inform both our mechanistic understanding of the action of corticosteroids in the treatment of ITP, and as a biomarker for steroid refractory disease, with potential application across a range of haematological and non-haematological conditions.

Background Optimal prophylactic and therapeutic management of thromboembolic disease in patients with COVID-19 remains a major challenge for clinicians. The aim of this study was to define the incidence of thrombotic and haemorrhagic complications in critically ill patients with COVID-19. In addition, we sought to characterise coagulation profiles using thromboelastography and explore possible biological differences between patients with and without thrombotic complications. Methods We conducted a multicentre retrospective observational study evaluating all the COVID-19 patients received in four intensive care units (ICUs) of four tertiary hospitals in the UK between March 15, 2020, and May 05, 2020. Clinical characteristics, laboratory data, thromboelastography profiles and clinical outcome data were evaluated between patients with and without thrombotic complications. Results A total of 187 patients were included. Their median (interquartile (IQR)) age was 57 (49–64) years and 124 (66.3%) patients were male. Eighty-one (43.3%) patients experienced one or more clinically relevant thrombotic complications, which were mainly pulmonary emboli (n = 42 (22.5%)). Arterial embolic complications were reported in 25 (13.3%) patients. ICU length of stay was longer in patients with thrombotic complications when compared with those without. Fifteen (8.0%) patients experienced haemorrhagic complications, of which nine (4.8%) were classified as major bleeding. Thromboelastography demonstrated a hypercoagulable profile in patients tested but lacked discriminatory value between those with and without thrombotic complications. Patients who experienced thrombotic complications had higher D-dimer, ferritin, troponin and white cell count levels at ICU admission compared with those that did not. Conclusion Critically ill patients with COVID-19 experience high rates of venous and arterial thrombotic complications. The rates of bleeding may be higher than previously reported and re-iterate the need for randomised trials to better understand the risk-benefit ratio of different anticoagulation strategies. Graphical abstract

Background: There is clinical need for a laboratory biomarker to identify patients who, following an unprovoked venous thrombosis (VTE), are at low VTE recurrence risk and can discontinue anticoagulation after a limited treatment duration (3–6 m). This secondary analysis of the ExACT study aimed to evaluate whether quantitation of peripheral blood endothelial progenitor cells (EPCs) could improve prediction of VTE recurrence risk. Methods: The ExACT study was a non-blinded, multicentre RCT comparing extended vs discontinued anticoagulation following a first unprovoked VTE. Adult patients were eligible if they had completed ≥3 months anticoagulation and remained anticoagulated. The primary outcome was time to first recurrent VTE from randomisation. Blood samples were taken at baseline and results correlated with clinical outcome over 2 years follow up. (Trial registration: ISRCTN:73819751 and EUDRACT:2101-022119-20) Findings: 281 patients were recruited, randomised (between July 2011 and February 2015) and followed up for 24 months (Male:Female 2:1, mean age 63). Of these, 273 patients were included in the final analysis. Blood samples were received at baseline for Full Blood Count(n = 216), d-dimers(n = 205) and endothelial progenitor cell (EPC) quantitation by flow cytometry(n = 193). VTE recurrence was lower in the extended vs discontinued anticoagulation arms (5% vs 23%, HR 0.20(95%CI:0.09–0.46,p

Immune thrombocytopenia (ITP) is a rare condition characterized by thrombocytopenia and variable bleeding severity. After acute management with steriods and intravenous immunoglobulin (IVIG), the next line therapies include medical treatments: immunosuppressive therapy such as rituximab, mycophenolate mofetil (MMF), thrombopoietin receptor agonists or surgical treatments. The choice of therapy depends on the time course of the disease, severity, patient choice and comorbidities. The evidence for comparative efficacy between different treatment modalities is lacking in the literature, in particular the immunosuppressive therapies MMF and rituximab. The UK ITP registry is a national registry of primary ITP, capturing demographics, clinical features, treatments and comorbidities. As of July 2021, it has 4402 participants from 90 acute NHS Trusts across the UK. We analyzed data from the UK adult ITP registry to assess responses to rituximab and MMF therapy. All patients entered into the registry from 1st January 2010 were included in this analysis. Internationally recognized definitions of response based on platelet count were used: partial response (PR) platelets >30 x10 9/L and double baseline, complete response (CR) platelets >100 x10 9/L; No response - absence of CR and PR. In addition, we reviewed use of rescue therapy and use of additional therapies following treatment. A total of 844 patients were included in the analysis, of these 486 had received rituximab and 358 had received MMF since 2010. The median follow up before treatment was 230.5 weeks for rituximab and 195 weeks for MMF. At the time of commencing rituximab (and within 4 weeks of starting), 26.1% patients were receiving prednisolone, 10% IVIG, 3% dexamethasone, 3.2% MMF, 2.95% romiplostim and 2.36% eltrombopag. At the time of commencing MMF (and within 4 weeks of starting), 39.2% patients were receiving prednisolone, 12.74 IVIG, 3.86% dexamethasone, 3.6 rituximab, 5.6% romiplostim and 3.86% eltrombopag. The total number of patients achieving platelet response at each time response are listed in table 1. Of those receiving rituximab with baseline platelets The median duration of response was 44 weeks for rituximab and 27 weeks for MMF. Where new therapies were required, the median number of weeks until therapy was switched was 18 weeks for rituximab and 15 weeks for MMF. 77% patients and 80.7% patients who received rituximab and MMF respectively changed treatment during their follow up. Overall 284 (58.4%) patients received rescue medication during follow up, of those that received MMF 234 (65.36%) received rescue medication. The main rescue therapies were prednisolone (589 episodes in rituximab group and 520 in MMF group) and IVIG (482 in rituximab group and 321 in MMF group). In conclusion, this is one of the first studies, using real world data and long term follow up, to compare outcomes after immunosuppression. Both rituximab and MMF are often administered with additional therapies at the outset, predominantly steroids and IVIG, but also other therapies such as the thrombopoietin receptor agonists. The use of rescue therapies during follow up, suggesting treatment failure or a need to augment the response, is common with most patients in both groups ultimately having treatment change during follow up. Extension of this study to include other therapies and identifying groups most likely to respond will support optimization of treatment for patients with ITP. Figure 1 Figure 1. Disclosures McDonald: Bayer, Sobi, Novartis, Amgen, argenx: Honoraria; Grifols: Research Funding. Loughlin: FIECON: Current Employment. Laws: FIECON: Current Employment. Stacey: Grifols: Current Employment. Spears: Grifols: Current Employment. Hill: Apellis: Consultancy, Honoraria; Argenx: Consultancy; Novartis: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; Sanofi: Consultancy; ReAlta: Consultancy; Alexion: Honoraria; Amgen: Honoraria. Cooper: UCB: Honoraria; Sanofi: Honoraria; Novartis: Honoraria, Other: Research support; Rigel: Honoraria, Other: Research support; Principia: Honoraria; Amgen: Honoraria; Grifols: Honoraria; Sobi: Honoraria. Makris: Freeline: Consultancy. Bradbury: BMS Pfizer: Honoraria, Speakers Bureau; Bayer: Honoraria, Other: support to attend conferences, Speakers Bureau; Amgen: Honoraria, Other: support to attend conferences, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support to attend conferences, Speakers Bureau; Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees; Ablynx: Membership on an entity's Board of Directors or advisory committees. Newland: Octapharma: Research Funding; Roche: Speakers Bureau; UCB Biosciences: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; GSK: Consultancy, Research Funding, Speakers Bureau; BMS: Research Funding; Argenx: Consultancy, Speakers Bureau; Angle: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: rituximab - immune thrombocytopenia mycophenolate - immune thrombocytopenia

e13598 Background: The impact on cancer outcomes from the Covid-19 pandemic has yet to be determined. Concerns persist on screening, delays in diagnosis, treatment interruptions and outcomes of infection in the immunosuppressed. The need for agile working has been exemplified by establishment of Nightingale Hospitals, staff redeployment and sudden integration of virtual consultations into clinical working. With most cancer clinical trials halted, recruitment into COVID-19 research became essential and embedded into the everyday. Here we present how rapid implementation of COVID-19 randomised clinical trials within an NHS organisation during the pandemic was achieved. Methods: A COVID-19 senior facilitation committee was set up to provide oversight, maximise staff capacity and resource and prioritise studies. Specific strategies to maximise access and clinical trials recruitment for patients including children and those with solid tumours were designed. These included presence of a research nurse at clinical ward rounds and team meetings, the promotion of protocol and informed consent training to all including doctors in the acute settings and weekly research meetings to share-best practice. Reflecting on learnings from this time provide an opportunity to consider how we adjust working for our patients in the future. Results: The integration of research into the everyday working of clinical teams looking after patients with COVID-19 has become the norm. The provision of protocol and informed consent training for all levels of staff and the consideration of all patients for trials during clinical ward rounds and multi-disciplinary meetings, have ensured access to trials has become embedded. The integration of research nurses working, upskilling and prompting clinical colleagues has ensured equity of access and provided a research presence and focus during the busy clinical day. The adoption of cross-disciplinary working, sharing best practice and a culture of commitment and support to the trials ensures no patient is denied the opportunity to participate. Three RTCs opened over 7 weeks. At one site 1904 patients were screened for one of the randomised-controlled trials and over 18% of these patients (351) were recruited and 175 patients declined. Conclusions: The pandemic has had a devastating impact across the UK. However, a coordinated and collaborative multi-disciplinary approach has supported high recruitment and equity of access for patients into COVID-19 trials. Learnings from this work may lead to embedding clinical trials and access to translational research for cancer patients in the future as we recover from the full impact of the pandemic. COVID-19 research has demonstrated how increased recruitment accelerates access and implementation of new innovations and novel drug combinations.The full impact of improved access to cancer research in the future during COVID recovery is worthy of more research.

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Intravenous immunoglobulin (IVIg) is a common therapy for patients with immune thrombocytopenia (ITP). The initial response rate for IVIg is 80%[1][1] and is typically rapid, with some patients responding in 24 hours, although usually in 2–4 days.[2][2] When IVIg is used alone, the response is

Methodology This Good Practice Paper was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. The BSH produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org.

Multiple myeloma is associated with a significant risk of venous thromboembolism (VTE), causing substantial levels of morbidity and mortality. The thrombogenicity of myeloma is multifactorial, with disease- and treatment-related factors playing important roles. Immunomodulatory drugs (IMiDs) and high-dose dexamethasone, in particular, are known to enhance the thrombotic potential of myeloma. For this reason, assessment of the VTE risk has long been advocated prior to treatment initiation in patients with myeloma requiring IMiD-based regimens. However, despite routine use of thromboprophylaxis, these patients can still develop VTE and its sequelae. The optimum choice and dose of thromboprophylactic drug is not entirely clear, and with this, there is growing interest regarding use of the direct oral anticoagulants (DOACs) in this setting. In this review we discuss the pathogenesis of thrombosis in multiple myeloma, its relation to some of the commonly used chemotherapeutic regimens, current risk stratification and the evidence supporting the different anticoagulants used as thromboprophylaxis. We propose an amended risk stratification, and consider management of challenging patients including those with renal impairment and recurrent thrombosis.

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It is postulated that disease relapse in patients with acute myeloid leukemia (AML) is consequent upon chemoresistance within leukemic stem/progenitor cell (LSC) populations from which bulk blasts arise1. In adults with high risk AML, allogeneic hematopoietic cell transplantation (HCT) has become a central component of the treatment algorithm to overcome this chemoresistance as it delivers maximal anti-leukemic activity through both dose intensification and by the genesis of a potent graft-versus-leukemia (GVL) effect2-4. However relapse still occurs in a significant proportion of allografted patients and now represents the major cause of treatment failure particularly with reduced intensity conditioning (RIC) regimens5. Whilst minimal residual disease (MRD) from the bulk leukemic population is known to be prognostic, more accurate predictors of relapse risk might be developed from detection of putative LSC populations pre- or post-transplant. However, to date an association between LSC and transplant outcome remains uncertain.

Evaluation of coagulopathy before and during induction chemotherapy for acute lymphoblastic leukaemia, including assessment of global clotting tests

Histones are subject to a wide variety of post-translational modifications that play a central role in gene activation and silencing. We have used histone modification-specific antibodies to demonstrate that two histone modifications involved in gene activation, histone H3 acetylation and H3 lysine 4 methylation, are functionally linked. This interaction, in which the extent of histone H3 acetylation determines both the abundance and the "degree" of H3K4 methylation, plays a major role in the epigenetic response to histone deacetylase inhibitors. A combination of in vivo knockdown experiments and in vitro methyltransferase assays shows that the abundance of H3K4 methylation is regulated by the activities of two opposing enzyme activities, the methyltransferase MLL4, which is stimulated by acetylated substrates, and a novel and as yet unidentified H3K4me3 demethylase.

l-Asparaginase is a potent antileukemia agent and an essential part of treatment protocols for acute lymphoblastic leukemia. However, toxicity limits dose escalation, especially in adults. This includes a significant risk of thrombosis, which remains an important source of avoidable morbidity and mortality. Here, we provide a detailed report of 10 cases of cerebral thrombotic complications that occurred over a 5-year period at 4 large tertiary referral hospitals. To our knowledge, this is the first report of this type in the published literature.

Histone deacetylase inhibitors (HDIs) are a new class of drugs with significant antileukemic activity. To explore mechanisms of disease-specific HDI activity in acute myeloid leukaemia (AML), we have characterised expression of all 18 members of the histone deacetylase family in primary AML blasts and in four control cell types, namely CD34+ progenitors from umbilical cord, either quiescent or cycling (post-culture), cycling CD34+ progenitors from GCSF-stimulated adult donors and peripheral blood mononuclear cells. Only SIRT1 was consistently overexpressed (>2 fold) in AML samples compared with all controls, while HDAC6 was overexpressed relative to adult, but not neo-natal cells. HDAC5 and SIRT4 were consistently underexpressed. AML blasts and cell lines, exposed to HDIs in culture, showed both histone hyperacetylation and, unexpectedly, specific hypermethylation of H3 lysine 4. Such treatment also modulated the pattern of HDAC expression, with strong induction of HDAC11 in all myeloid cells tested and with all inhibitors (valproate, butyrate, TSA, SAHA), and lesser, more selective, induction of HDAC9 and SIRT4. The distinct pattern of HDAC expression in AML and its response to HDIs is of relevance to the development of HDI-based therapeutic strategies and may contribute to observed patterns of clinical response and development of drug resistance.

Summary Histone deacetylase inhibitors (HDIs) are emerging as valuable new agents in the treatment of acute myeloid leukaemia (AML). However, since response rates to these agents alone are low, we sought to identify markers associated with responsiveness. In a trial of 20 patients treated with the HDI sodium valproate (VPA) in combination with all trans retinoic acid and theophylline, three patients responded clinically with one complete remission (CR) and two partial remissions. The in vivo response of the CR patient was mirrored by high in vitro sensitivity of their blasts to VPA, indicating that similar factors determine both in vivo and in vitro sensitivity. Microarray analysis of the primary AMLs and a panel of haemato-lymphoid cell lines, with a similar range of VPA sensitivities as the primary leukaemic blasts, identified elevated FOSB-expression as a potential marker of VPA sensitivity. Quantitative polymerase chain reaction confirmed overexpression of FOSB in the CR patient blasts compared to patients failing to achieve CR, and in a subset of a larger panel of AML samples. Overexpression of FOSB in K562 myeloid cells significantly increased in vitro sensitivity to VPA. Thus, we propose that FOSB is a novel, potential marker of VPA sensitivity in AML.

Histones are subject to a wide variety of post-translational modifications that play a central role in gene activation and silencing. We have used histone modification-specific antibodies to demonstrate that two histone modifications involved in gene activation, histone H3 acetylation and H3 lysine 4 methylation, are functionally linked. This interaction, in which the extent of histone H3 acetylation determines both the abundance and the "degree" of H3K4 methylation, plays a major role in the epigenetic response to histone deacetylase inhibitors. A combination of in vivo knockdown experiments and in vitro methyltransferase assays shows that the abundance of H3K4 methylation is regulated by the activities of two opposing enzyme activities, the methyltransferase MLL4, which is stimulated by acetylated substrates, and a novel and as yet unidentified H3K4me3 demethylase.

This article discusses the most common causes of incidental thrombocytopenia and provides advice on the relevant investigations

Abstract 4098 Relapse after allogeneic hematopoietic cell transplantation (HCT) is usually incurable for acute myeloid leukemic (AML) patients. Residual disease (MRD) monitoring pre- and post-HCT may improve relapse prediction, allowing the targeted implementation of post-HCT interventions to at risk patients when disease burden is sufficiently low for these to be effective. Previous studies have shown that MRD detection by multiparameter flow cytometry (MRD MFC) at either pre- (Leung et al 2012, Walter et al 2011) or post- transplant (Yan et al 2012) timepoints is prognostic for myeloablative HCT outcome in AML. Quantification of hematopoietic populations enriched for leukemic stem cells such as CD34+CD38low or lymphoid-primed multi-potential progenitor-like (LMPP-like) (Lin-CD34+CD38lowCD90-CD45RA+) (Goardon et al 2011) may improve the specificity of MFC MRD assays. In this study we retrospectively evaluated the predictive value of MRD MFC at both pre- and post- HCT timepoints in a cohort of unselected AML/high risk myelodysplasia (MDS) patients (n=44) who underwent reduced intensity conditioning (RI n= 32, median age 59, range 34–70) or myeloablative (MA n=12, median age 28, range 19–47) HCT between June 2010 and November 2011 (Table 1). MFC MRD was assessed both by detection of standard leukemic- aberrant-immunophenotypes (LAIPs) (identified at presentation and/or relapse) and quantification of CD34+CD38low and LMPP-like progenitors (LSC-enriched progenitors, LSC-EP). Pre HCT, 37 patients (MA = 11, RI = 26) were assessable for MFC MRD. 15 (41%) were MRD positive (LAIP MRD+) and 47% (7/15) (MA = 37.5%, 3/8; RI = 57%, 4/7) of these relapsed post HCT compared to 8% (MA = 0%, RI = 9%) of MRD negative patients (LAIP-MRD-), (Fig 1 p 0.03). Post HCT, 34 patients (MA = 9, RI =25) were assessable for MFC MRD. 10 (37%) had detectable LAIP MRD positivity between 2 and 9 months post HCT. 80% of these relapsed (MA = 60%; RI = 100%) with a median disease free survival (DFS) post HCT of 5 months (MA = 4 months; RI = 5 months); there were no relapses in the 17 patients who remained LAIP MRD- at a median follow-up of 20 months (range 9–26). (p=0.0006, Figure 2a). Presence of MRD post-transplant was associated with significantly poorer overall survival (p=0.005). Although 1 patient with high MRD (in CR, LAIP >1%, LSC-EP +) pre HCT relapsed 1 month (median time to relapse from MRD detection of 1.5 months, range 1–6; OS, median 4 months, range 1 - not reached). CD34+CD38low progenitors (34+38low) were < 0.03% of bone marrow nucleated cells in the majority of patients. Detectable 34+38low were mainly CD45RA+ so in most cases correlated with LMPP-like quantitation. Pre HCT, 34+38low were detectable in 40% of patients who went on to relapse and in only 9% of those who have not yet relapsed. Post HCT, 34+38lowpositivity preceded frank relapse by ≥1 month in 60% of patients who relapsed. Only 6% of patients who have not yet relapsed had detectable 34+38low. LSC-LEP positivity appears prognostic for DFS and OS (Figure 2b) but for a lower frequency of relapses compared to LAIP MRD positivity (60% v 80%). Conclusions: These data suggest that post HCT MFC detection of LAIP MRD is predictive of relapse in RI as well as MA HCT. LSC-LEP quantitation may be prognostic in a subset of patients. Pre HCT MRD might be more predictive of relapse in RI than MA HCT. However, post HCT MRD positivity precedes most clinical relapses by a time window which may be sufficient for interventions such as azacytidine or donor lymphocyte infusion (DLI) when disease burden is still low. These results provide a basis for the use of MFC residual disease detection pre and post HCT to inform treatment decisions in reduced intensity as well as myeloablative HCT. Disclosures: No relevant conflicts of interest to declare.

There is increasing evidence that perturbations in chromatin structure contribute to the pathogenesis of AML raising the possibility that modulators of chromatin structure may be of therapeutic benefit. Sodium valproate (VPA) is a potent histone deacetylase inhibitor (HDI) and in conjunction with ATRA induces apoptosis of primary AML blasts in vitro. It has been postulated that induction of pro-apoptotic genes including p21 and TRAIL play a critical role in determining the tumor selectivity of HDIs. We have therefore conducted a Phase I/II study of combined VPA/ATRA therapy in patients with high risk AML ineligible for chemotherapy and correlated clinical response with alterations in chromatin structure, induction of pro-apoptotic genes and in vitro sensitivity to VPA. In light of evidence that modulating cAMP levels may increase rexinoid responsiveness theophylline was added in patients who had failed to respond to 28 days combined VPA/ATRA therapy. A total of 20 patients (median age 72 yrs) have been treated to date including 12 patients with relapsed AML, 6 with previously untreated disease and 2 with primary refractory disease. Nine patients completed treatment for at least 8 weeks. Four patients (all with relapsed AML) demonstrated a haematological response. One patient achieved a complete remission and two a partial remission. Myeloblasts isolated from trial patients prior to the commencement of therapy demonstrated varying sensitivity to VPA and ATRA in vitro which correlated with clinical response. Combined treatment with VPA and ATRA resulted in increased levels of histone acetylation and methylation and induced expression of p15, p16 and p21 in myeloblasts from treated patients. Induction of TRAIL was documented in three patients-two of whom demonstrated a clinical response. p21 induction was documented in all responding patients. Induction of p21 and TRAIL was most marked in the patient who achieved a CR. There was no apparent correlation between induction of p15 or p16 and response. We have previously documented that exposure of AML cell lines to HDIs results in specific changes in HDAC expression patterns with selective up-regulation of HDAC11 and to a lesser extent HDAC9 and SIRT4. Similar changes in HDAC expression were documented in myeloblasts from patients after 28 days treatment with VPA/ATRA. This study demonstrates that VPA, in combination with ATRA and theophylline, has significant clinical and biological activity and identifies possible mechanisms underlying the tumor-specific activity of VPA in AML in vivo.

Post-translational modifications of chromatin structure are recognised as having a potential role in the pathogenesis of acute myeloid leukaemia (AML). Histone deacetylases play a central role in determining the acetylation status of histones and are emerging as novel targets in AML therapy. Histone deacetylase inhibitors (HDIs) inhibit growth of primary AML blasts in vitro and demonstrate clinical activity in patients with relapsed AML. To date, three major classes of HDACs have been characterised which differ in their susceptibility to HDIs. However, little is known of the pattern of HDAC expression in AML and this limits the rational use of HDIs in this disease. We have analysed the pattern of class I, II and III HDAC expression in AML cell lines, primary AML blasts and CD34+ selected progenitors from cord blood and normal donors by real time quantitative PCR(RT-PCR). RT-PCR analyses demonstrated consistently increased expression in AML blasts of two HDACs compared with proliferating CD34+ve cells from cord blood (n=5) . HDAC2 (class I HDAC) was more highly expressed in 3/3 myeloid cell lines and 20/24 primary AML samples, compared to cord blood CD 34+ve cells. SIRT1 (class III HDAC) was also more highly expressed in 3/3 myeloid cell lines and 24/24 primary AMLs. In contrast, no marked differences were detected in expression of HDAC1, 3, 4, 5, 6, 7, 9, 10, 11 and SIRT 2–6. We therefore studied the impact of sodium valproate (SV), an HDI with reported activity in AML, on HDAC activity and expression. SV treatment resulted in time and dose dependent increases in histone acetylation and specific methylation at H3K4, in both AML cell lines and primary AML cells. We have shown that the mechanism of the increased methylation at H3K4 is partly a result of the preference of the methyltransferase enzyme for acetylated histones. Using quantitative RT-PCR we found that SV treatment of HL-60 cells resulted in increased expression of the gene for MLL, an enzyme known to be capable of methylating H3K4. These changes in chromatin were associated with dose dependent cell killing. Significant (p

Importance Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (–1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support–free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.