Rilzabrutinib versus placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study.

Background: Immune thrombocytopenia (ITP) is characterized by primarily autoantibody-mediated platelet destruction and impaired platelet production resulting in thrombocytopenia and an increased risk of bleeding. Other manifestations include increased risk of thrombosis and diminished quality of life. Current treatment approaches are directed toward lowering the rate of platelet destruction or stimulating platelet production to prevent bleeding. Rilzabrutinib is an oral, reversible, potent Bruton tyrosine kinase inhibitor that was specifically designed to treat immune-mediated diseases and mediates its therapeutic effect through a dual mechanism of action: (1) inhibiting B-cell activation and (2) interrupting antibody-coated cell phagocytosis by Fc gamma receptor in spleen and liver. A 24-week dose-finding phase I/II study of rilzabrutinib in patients with ITP showed a 40% platelet response (⩾2 consecutive platelet counts of ⩾50 × 109/L and increase from baseline ⩾20 × 109/L without rescue medication use) and a well-tolerated safety profile with only grade 1/2 transient adverse events across dose levels. Objectives: Assess the efficacy and safety of oral rilzabrutinib in adult and adolescent patients with persistent or chronic ITP. Design: Rilzabrutinib 400 mg BID is being evaluated in the ongoing LUNA 3 multicenter, double-blind, placebo-controlled phase III study. Methods and analysis: The primary endpoint is durable platelet response, defined as achieving platelet counts of ⩾50 × 109/L for at least two-thirds of ⩾8 available weekly scheduled platelet measurements during the last 12 weeks (including ⩾2 available measurements within the last 6 weeks) of the 24-week blinded treatment period in the absence of rescue therapy. Ethics: Ethical guidelines and informed consent are followed. Discussion: The LUNA 3 trial will further investigate rilzabrutinib's safety and efficacy in adult and adolescent patients, with the primary goal of addressing a major objective in treating patients with ITP: durability of platelet response. Trail Registration: ClinicalTrials.gov NCT04562766: https://clinicaltrials.gov/ct2/show/NCT04562766; EU Clinical Trials Register EudraCT 2020-002063-60: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-002063-60.

Complement in immune thrombocytopenia (ITP): The role of complement in refractory ITP.

Immune thrombocytopenia (ITP) is a disorder characterized by low platelets due to increased clearance and decreased platelet production. While ITP has been characterized as an acquired disorder of the adaptive immune system, the resulting platelet autoantibodies provide ancillary links to the innate immune system via antibody interaction with the complement system. Most autoantibodies in patients with ITP are of the IgG1 subclass, which can be potent activators of the classical complement pathway. Antibody-coated platelets can initiate complement activation via the classical pathway leading to both direct platelet destruction and enhanced clearance of C3b-coated platelets by complement receptors. Similar autoantibody interactions with bone marrow megakaryocytes can also result in complement injury and ineffective thrombopoiesis. The development of novel therapeutic complement inhibitors has revived interest in the role of complement in autoantibody-mediated disorders, such as ITP. A recent early-phase clinical trial of a classical complement pathway inhibitor has demonstrated efficacy in a subset of ITP patients refractory to conventional immune modulation. In this review, we will analyse the role of complement in refractory ITP.

The unique diagnostic and management challenge of a patient with concomitant anti-interferon-gamma autoantibody associated immunodeficiency syndrome, IgG4-related disease, and treatment refractory, disseminated mycobacterium avium complex infection.

BACKGROUND: Anti-interferon-gamma autoantibody-associated immunodeficiency syndrome is a rare and underrecognized adult onset immunodeficiency syndrome associated with severe opportunistic infections such as disseminated nontuberculous mycobacterium. Few cases have documented a relationship with IgG4-related disease. Concomitant diagnoses of these diseases present a diagnostic and management challenge. CASE PRESENTATION: A 61 year old man of Southeast Asian descent with pulmonary mycobacterium avium complex infection presented to our hospital system with a new skin rash and worsening lymphadenopathy. He was eventually diagnosed with IgG4-related disease through excisional nodal biopsy. He was managed with immunosuppressive treatment with prednisone, rituximab and cyclophosphamide. He later re-presented with disseminated mycobacterium avium complex infiltration of his joints, bones and prostate. Original titers of anti-interferon-gamma autoantibodies were falsely negative due to being on immunosuppressive therapy for his IgG4-related disease. However, anti-interferon-gamma autoantibody titers were re-sent after immunosuppression was held and returned strongly positive. CONCLUSIONS: This case reviews diagnostic criteria and discusses management strategies with existing challenges in treating a patient with concomitant adult onset immunodeficiency syndrome, IgG4-related disease and a disseminated mycobacterial avium complex infection.

Adults with immune thrombocytopenia who switched to avatrombopag following prior treatment with eltrombopag or romiplostim: A multicentre US study.

Patients with immune thrombocytopenia (ITP) may respond to one thrombopoietin receptor agonist (TPO-RA) but not another. Limited data are available describing outcomes in patients who switched from romiplostim or eltrombopag to avatrombopag, a newer oral TPO-RA. We performed a retrospective observational study of adults with ITP who switched from eltrombopag or romiplostim to avatrombopag at four US tertiary ITP referral centres. Forty-four patients were included, with a mean ITP duration of 8.3 years and a median (range) of four prior ITP treatments. On avatrombopag, 41/44 patients (93%) achieved a platelet response (≥50 × 109 /l) and 38/44 patients (86%) achieved a complete response (≥100 × 109 /l). In all patients, the median platelet count on eltrombopag or romiplostim was 45 × 109 /l vs 114 × 109 /l on avatrombopag (p < 0.0001); in patients switched for ineffectiveness of romiplostim/eltrombopag, it was 28 × 109 /l on romiplostim/eltrombopag vs 88 × 109 /l on avatrombopag (p = 0.025). Fifty-seven percent of patients receiving concomitant ITP medications before switching discontinued them after switching, including 63% of patients receiving chronic corticosteroids. In a heavily pretreated chronic ITP population, avatrombopag was effective following therapy with romiplostim or eltrombopag, with high response rates even in patients with inadequate response to a prior TPO-RA.

SARS-CoV-2 vaccination and ITP in patients with de novo or preexisting ITP.

Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.

Corticosteroid overuse in adults with immune thrombocytopenia: Cause for concern.

Corticosteroids remain a crucial component of first-line therapy for immune thrombocytopenia (ITP) due to low cost, high initial response rates, and acceptable short-term tolerability. However, extended and recurrent use of corticosteroids is associated with substantial toxicity. Survey studies indicate that >95% of patients with ITP treated with corticosteroids report adverse effects, more than one-third of whom require reduction or discontinuation of treatment. In light of the heavy treatment burden of prolonged corticosteroid exposure, clinical practice guidelines recommend limiting corticosteroid treatment to no more than 6 weeks in adults with ITP receiving initial therapy. For patients who require subsequent therapy, clinical practice guidelines recommend treatments more suitable for long-term disease control such as thrombopoietin receptor agonists, rituximab, other immune-modulating medications, or splenectomy, rather than repeated courses of corticosteroids. Despite these recommendations, real-world evidence suggests that corticosteroids remain the most frequently used treatment for adults with ITP, not only in the first line, but also in the second and third line. In this review, we summarize evidence on the efficacy, safety, and tolerability of corticosteroids; discuss the problem of overuse; and suggest strategies for curtailing the excessive use of corticosteroids in adults with ITP.

Understanding Immune Thrombocytopenia: Looking Out of the Box.

The pathogenesis of immune thrombocytopenia (ITP) is increasingly being elucidated, and its etiology is becoming more frequently identified, leading to a diagnostic shift from primary to secondary ITP. The overlap between autoimmunity, immunodeficiency, and cancer is evident, implying more interdisciplinarity in daily care. This mini-review is based on an expert meeting on ITP organized by the Intercontinental Cooperative ITP Study Group and presents the challenges of hematologists in understanding and investigating "out of the box" concepts associated with ITP.

Nattokinase atherothrombotic prevention study: A randomized controlled trial.

BACKGROUND: Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. OBJECTIVE: To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. METHODS: In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers. RESULTS: After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. CONCLUSIONS: Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Tapering thrombopoietin receptor agonists in primary immune thrombocytopenia: Expert consensus based on the RAND/UCLA modified Delphi panel method.

BACKGROUND: Thrombopoietin receptor agonists (TPO-RAs) are used to treat primary immune thrombocytopenia (ITP). Some patients have discontinued treatment while maintaining a hemostatic platelet count. OBJECTIVES: To develop expert consensus on when it is appropriate to consider tapering TPO-RAs in ITP, how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy. METHODS: We used a RAND/UCLA modified Delphi panel method. Ratings were completed independently by each expert before and after a meeting. Second-round ratings were used to develop the panel's guidance. The panel was double-blinded: The sponsor and nonchair experts did not know each other's identities. RESULTS: Guidance on when it is appropriate to taper TPO-RAs in children and adults was developed based on patient platelet count, history of bleeding, intensification of treatment, trauma risk, and use of anticoagulants/platelet inhibitors. For example, it is appropriate to taper TPO-RAs in patients who have normal/above-normal platelet counts, have no history of major bleeding, and have not required an intensification of treatment in the past 6 months; it is inappropriate to taper TPO-RAs in patients with low platelet counts. Duration of ITP, months on TPO-RA, or timing of platelet response to TPO-RA did not have an impact on the panel's guidance on appropriateness to taper. Guidance on how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy is also provided. CONCLUSION: This guidance could support clinical decision making and the development of clinical trials that prospectively test the safety of tapering TPO-RAs.

Prediction and Prevention of Cancer-Associated Thromboembolism.

Venous and arterial thromboembolism are prevalent, highly burdensome, and associated with risk of worse outcomes for patients with cancer. Risk for venous thromboembolism (VTE) varies widely across specific cancer subpopulations. The ability to predict risk of cancer-associated VTE is critical because an optimal thromboprophylaxis strategy is best achieved by targeting high-risk patients with cancer and avoiding prophylaxis in patients with cancer at low risk for VTE. A validated risk tool for solid tumors has been available for a decade. Newer tools have focused on specific populations, such as patients with multiple myeloma. Emerging studies continue to optimize risk prediction approaches in patients with cancer. Recent randomized trials have specifically addressed risk-adapted thromboprophylaxis using direct oral anticoagulants, and revised guidelines have included these new data to formulate recommendations for outpatient thromboprophylaxis. Implementation science approaches to enhance use of outpatient prophylaxis in the context of these guideline changes are under way. However, major knowledge gaps remain, including a lack of data for inpatient thromboprophylaxis in the cancer setting and a lack of formal tools for identifying risk of bleeding. This review describes optimal approaches to risk prediction and patient selection for primary pharmacologic thromboprophylaxis of cancer-associated VTE, addresses barriers to implementing these practices, and highlights strategies to overcome them. IMPLICATIONS FOR PRACTICE: Risk for venous thromboembolism (VTE) varies widely among patients with cancer. Individual risk can be determined using validated approaches. Inpatient and postsurgical thromboprophylaxis is more widely accepted. However, most patients with cancer develop VTE in the outpatient setting. Recent randomized trials have demonstrated benefit to risk-adapted outpatient thromboprophylaxis. High-risk patients may therefore be considered for outpatient thromboprophylaxis as recommended by recently updated guidelines. System-wide implementation approaches are necessary to improve compliance with prophylaxis.

Acute dilated cardiomyopathy in the setting of catastrophic antiphospholipid syndrome and thrombotic microangiopathy: A case series and review.

Catastrophic antiphospholipid antibody syndrome (CAPS) is a rare form of antiphospholipid syndrome, an autoimmune condition characterized by vascular thromboses, pregnancy loss, and antiphospholipid (aPL) antibodies. Diagnosis of CAPS relies on thrombosis of at least three different organs systems over 1 week, histopathological evidence of small vessel occlusion, and high aPL antibody titers. In a subset of precipitating circumstances, activation or disruption of endothelial cells in the microvasculature may occur along with cardiomyopathy. We present two cases of CAPS-associated dilated cardiomyopathy at our institution, focusing on disease management, pathophysiology, and treatment. These patients were of Southeastern Asian descent, raising the possibility of genetic polymorphisms contributing to the development of cardiomyopathy. Both met CAPS criteria and both demonstrated clinicopathologic thrombotic microangiopathy (TMA) and complement activation and developed severe dilated cardiomyopathy with shock. Complement activation plays an important role in the development of CAPS and may be important in the pathogenesis of CAPS-associated cardiomyopathy. Clinical suspicion for TMA as a pathophysiologic mechanism of unexplained heart failure in CAPS is important and increased awareness of cardiac side effects is necessary so that early treatment can be initiated to halt further cardiac and systemic complications.

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update.

PURPOSE: To provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. METHODS: PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs published from August 1, 2014, through December 4, 2018. ASCO convened an Expert Panel to review the evidence and revise previous recommendations as needed. RESULTS: The systematic review included 35 publications on VTE prophylaxis and treatment and 18 publications on VTE risk assessment. Two RCTs of direct oral anticoagulants (DOACs) for the treatment of VTE in patients with cancer reported that edoxaban and rivaroxaban are effective but are linked with a higher risk of bleeding compared with low-molecular-weight heparin (LMWH) in patients with GI and potentially genitourinary cancers. Two additional RCTs reported on DOACs for thromboprophylaxis in ambulatory patients with cancer at increased risk of VTE. RECOMMENDATIONS: Changes to previous recommendations: Clinicians may offer thromboprophylaxis with apixaban, rivaroxaban, or LMWH to selected high-risk outpatients with cancer; rivaroxaban and edoxaban have been added as options for VTE treatment; patients with brain metastases are now addressed in the VTE treatment section; and the recommendation regarding long-term postoperative LMWH has been expanded. Re-affirmed recommendations: Most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for all outpatients with cancer. Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Patients with cancer should be periodically assessed for VTE risk, and oncology professionals should provide patient education about the signs and symptoms of VTE.Additional information is available at www.asco.org/supportive-care-guidelines.

Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder, characterized by a low platelet count (<100 × 109 /L) in the absence of other causes associated with thrombocytopenia. In most patients, IgG autoantibodies directed against platelet receptors can be detected. They accelerate platelet clearance and destruction, inhibit platelet production, and impair platelet function, resulting in increased risk of bleeding and impaired quality of life. Efgartigimod is a human IgG1 antibody Fc-fragment, a natural ligand of the neonatal Fc receptor (FcRn), engineered for increased affinity to FcRn, while preserving its characteristic pH-dependent binding. Efgartigimod blocks FcRn, preventing IgG recycling, and causing targeted IgG degradation. In this Phase 2 study, 38 patients were randomized 1:1:1 to receive four weekly intravenous infusions of either placebo (N = 12) or efgartigimod at a dose of 5 mg/kg (N = 13) or 10 mg/kg (N = 13). This short treatment cycle of efgartigimod in patients with ITP, predominantly refractory to previous lines of therapy, was shown to be well tolerated, and demonstrated a favorable safety profile consistent with Phase 1 data. Efgartigimod induced a rapid reduction of total IgG levels (up to 63.7% mean change from baseline), which was associated with clinically relevant increases in platelet counts (46% patients on efgartigimod vs 25% on placebo achieved a platelet count of ≥50 × 109 /L on at least two occasions, and 38% vs 0% achieved ≥50 × 109 /L for at least 10 cumulative days), and a reduced proportion of patients with bleeding. Taken together, these data warrant further evaluation of FcRn antagonism as a novel therapeutic approach in ITP.

A Retrospective Study of the Combination of Rituximab, Cyclophosphamide and Dexamethasone for the Treatment of Relapsed/Refractory Warm Antibody Autoimmune Hemolytic Anemia.

The combination of rituximab, cyclophosphamide, and dexamethasone (RCD) is highly effective in the treatment of warm autoimmune hemolytic anemia (WAIHA) associated with chronic lymphocytic leukemia (CLL). We treated a cohort of patients with relapsed/refractory WAIHA, without CLL, with RCD. The primary objective was to evaluate the overall response (OR) of RCD therapy. Complete response (CR) was defined as a hemoglobin (Hgb) ≥12 g/dL. Partial response (PR) was defined as Hgb 10-11.9 g/dL or ≥2 g/dL increase in Hgb. Sustained response was defined as Hgb ≥10 g/dL with no treatment changes. A total of 16 patients with relapsed/refractory WAIHA received RCD (7 primary WAIHA, 9 secondary WAIHA) for a median of 4 cycles (range: 2-6). The median pretreatment Hgb was 10.0 g/dL (range: 4.3-12.2). The median best Hgb achieved was 12.5 g/dL (range: 10.6-15.1) with a median of 2 cycles until best Hgb response. The OR was 94% (11 CR, 4 PR). Two immunocompromised patients were admitted for infections during RCD treatment. There were no deaths during the treatment or follow-up period. Following a response to RCD, 4 patients received noncorticosteroid immune modulation therapy and 4 patients continued on corticosteroid therapy. Seven patients received no additional treatment.

A systematic literature review on the use of platelet transfusions in patients with thrombocytopenia.

Objective: Investigate globally, current treatment patterns, benefit-risk assessments, humanistic, societal and economic burden of platelet transfusion (PT). Methods: Publications from 1998 to June 27, 2018 were identified, based on databases searches including MEDLINE®; Embase and Cochrane Database of Systematic Reviews. Data from studies meeting pre-specified criteria were extracted and validated by independent reviewers. Data were obtained for efficacy and safety from randomized controlled trials (RCTs); data for epidemiology, treatment patterns, effectiveness, safety, humanistic and societal burden from real-world evidence (RWE) studies; and economic data from both. Results: A total of 3425 abstracts, 194 publications (190 studies) were included. PT use varied widely, from 0%-100% of TCP patients; 1.7%-24.5% in large studies (>1000 patients). Most were used prophylactically rather than therapeutically. 5 of 43 RCTs compared prophylactic PT with no intervention, with mixed results. In RWE studies PT generally increased platelet count (PC). This increase varied by patient characteristics and hence did not always translate into a clinically significant reduction in bleeding risk. Safety concerns included infection risk, alloimmunization and refractoriness with associated cost burden. Discussion: In RCTs and RWE studies there was significant heterogeneity in study design and outcome measures. In RWE studies, patients receiving PT may have been at higher risk than those not receiving PT creating potential bias. There were limited data on humanistic and societal burden. Conclusion: Although PTs are used widely for increasing PC in TCP, it is important to understand the limitations of PTs, and to explore the use of alternative treatment options where available.

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.

BACKGROUND: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain. METHODS: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding. RESULTS: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49). CONCLUSIONS: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).

Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer.

BACKGROUND: Protein disulfide isomerase (PDI) is a thiol isomerase secreted by vascular cells that is required for thrombus formation. Quercetin flavonoids inhibit PDI activity and block platelet accumulation and fibrin generation at the site of a vascular injury in mouse models, but the clinical effect of targeting extracellular PDI in humans has not been studied. METHODS: We conducted a multicenter phase II trial of sequential dosing cohorts to evaluate the efficacy of targeting PDI with isoquercetin to reduce hypercoagulability in cancer patients at high risk for thrombosis. Patients received isoquercetin at 500 mg (cohort A, n = 28) or 1000 mg (cohort B, n = 29) daily for 56 days, with laboratory assays performed at baseline and the end of the study, along with bilateral lower extremity compression ultrasound. The primary efficacy endpoint was a reduction in D-dimer, and the primary clinical endpoint included pulmonary embolism or proximal deep vein thrombosis. RESULTS: The administration of 1000 mg isoquercetin decreased D-dimer plasma concentrations by a median of -21.9% (P = 0.0002). There were no primary VTE events or major hemorrhages observed in either cohort. Isoquercetin increased PDI inhibitory activity in plasma (37.0% in cohort A, n = 25, P < 0.001; 73.3% in cohort B, n = 22, P < 0.001, respectively). Corroborating the antithrombotic efficacy, we also observed a significant decrease in platelet-dependent thrombin generation (cohort A median decrease -31.1%, P = 0.007; cohort B median decrease -57.2%, P = 0.004) and circulating soluble P selectin at the 1000 mg isoquercetin dose (median decrease -57.9%, P < 0.0001). CONCLUSIONS: Isoquercetin targets extracellular PDI and improves markers of coagulation in advanced cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02195232. FUNDING: Quercegen Pharmaceuticals; National Heart, Lung, and Blood Institute (NHLBI; U54HL112302, R35HL135775, and T32HL007917); and NHLBI Consortium Linking Oncology and Thrombosis (U01HL143365).

Ethnic and racial difference in Helicobacter pylori infection in patients with immune thrombocytopenia treated at a major urban medical center.

Immune thrombocytopenia (ITP) is an autoimmune disorder with a complex immunopathology and pathogenesis characterized by thrombocytopenia and bleeding manifestations. The disorder is separated into primary (idiopathic) ITP and secondary ITP, when associated with other immune or lymphoproliferative disorders and certain chronic infections. Helicobacter pylori (H. pylori) is a recognized bacterial cause of ITP. In regions with high prevalence of infection, bacterial eradication has resulted in improvement in platelet count. However, the prevalence of H. pylori infection and response to antimicrobial therapy in North American ITP patients is reportedly low. We evaluated the prevalence of H. pylori infection in ITP patients diagnosed and treated at a large urban medical center. Eighty-two patients were screened for H. pylori, by stool antigen (n = 54), H. pylori breath test (n = 11), and H. pylori antibodies (n = 16), of which 15 (18.3%) were white non-Hispanic (WNH), 55 (67%) Hispanic (H), 8 (9.8%) Asian (A), and 4 (4.9%) African-American (AA). Of the screened patients, 36/82 (43.9%) tested positive for H. pylori. The prevalence of H. pylori infection within the represented ethnic groups was 2/15 (13%) WNH, 29/55 (52.7%) H, 3/8 (37.5%) A, and 2/4 (50%) AA. There was a significant difference in prevalence of infection comparing WNH and H patients (p = 0.007). There were 36 treated patients, with H. pylori eradication documented in 26 patients. Fifteen of the 26 patients were evaluable for response with 8 of 15 (53%) having clinical responses, 6 complete responses, and 2 partial responses. Our study demonstrates an increased prevalence of H. pylori infection in the Hispanic ITP population with a reasonable platelet response among patients with H. pylori eradication.