Investigational drugs for immune thrombocytopenia.

INTRODUCTION: Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease of unknown cause. Autoantibodies, self-reactive T cells and other immune abnormalities, with impairment of platelet production, lead to a reduced platelet count. Until recently, therapy was largely empirical using immune suppressants (none of which have undergone randomized clinical trials). These therapies have variable efficacy and are associated with predictable unwanted effects which impact patient quality-of-life. With greater understanding of the underlying pathophysiology, better, more targeted therapies have been developed; however, there is still an urgent need for additional classes of treatment. AREAS COVERED: This article covers new TPO receptor agonists, Syk inhibitors, Fcγ receptor antagonists, BTK and complement inhibitors, and other therapies. Insights into the most promising therapies are offered. Novel ITP treatments currently in clinical trials and those recently approved come under the spotlight. EXPERT OPINION: Thrombopoietin receptor agonists remain the most effective treatment for ITP and have changed the ITP therapeutic landscape remarkably. Other new molecules such as Fcγ receptor blockers, Bruton tyrosine kinase, complement inhibitors, and others are unlikely to enjoy the same success rate as the TPO-RAs, but nonetheless they will find a place in the management of patients with ITP.

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.

Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic.

This document aims to provide practical guidance for the assessment and management of patients with thrombocytopenia, with a particular focus on immune thrombocytopenia (ITP), during the COVID-19 pandemic. The intention is to support clinicians and, although recommendations have been provided, it is not a formal guideline. Nor is there sufficient evidence base to conclude that alternative approaches to treatment are incorrect. Instead, it is a consensus written by clinicians with an interest in ITP or coagulation disorders and reviewed by members of the UK ITP forum.

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.

Updated international consensus report on the investigation and management of primary immune thrombocytopenia.

Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.

A distinct plasmablast and naïve B-cell phenotype in primary immune thrombocytopenia.

Primary immune thrombocytopenia is an autoimmune disorder in which platelet destruction is a consequence of both B- and T-cell dysregulation. Flow cytometry was used to further characterize the B- and T-cell compartments in a cross-sectional cohort of 26 immune thrombocytopenia patients including antiplatelet antibody positive (n=14) and negative (n=12) patients exposed to a range of therapies, and a cohort of matched healthy volunteers. Markers for B-cell activating factor and its receptors, relevant B-cell activation markers (CD95 and CD21) and markers for CD4(+) T-cell subsets, including circulating T-follicular helper-like cells, were included. Our results indicate that an expanded population of CD95(+) naïve B cells correlated with disease activity in immune thrombocytopenia patients regardless of treatment status. A population of CD21-naïve B cells was specifically expanded in autoantibody-positive immune thrombocytopenia patients. Furthermore, the B-cell maturation antigen, a receptor for B-cell activating factor, was consistently and strongly up-regulated on plasmablasts from immune thrombocytopenia patients. These observations have parallels in other autoantibody-mediated diseases and suggest that loss of peripheral tolerance in naïve B cells may be an important component of immune thrombocytopenia pathogenesis. Moreover, the B-cell maturation antigen represents a potential target for plasma cell directed therapies in immune thrombocytopenia.

Current Management of Primary Immune Thrombocytopenia.

Primary immune thrombocytopenia is an autoimmune disorder of unknown cause affecting both children and adults. The low peripheral blood platelet count is caused by premature platelet destruction by self-reacting antibodies in addition to an impairment of platelet production. The disease is heterogeneous in its pathophysiology, clinical features and responses to treatment. To date, most of the treatments used have been immune-modulating drugs and these contribute to increased morbidity and mortality in patients. A new class of drugs, the thrombopoietin receptor agonists, has been developed for use in ITP. These have gone through randomised controlled trials in large numbers of patients with ITP. These drugs have high efficacy and are well tolerated. In addition, around 30% of patients receiving these drugs are able to stop them and maintain a safe or normal platelet count. Older treatments such as splenectomy are being used less than before, largely because of the introduction of the thrombopoietin receptor agonists. Currently there are trials underway evaluating novel therapies for ITP that will become available over the next few years once the trials are complete.

Fatigue in immune thrombocytopenia.

Fatigue is an important aspect of health-related quality of life from the patient perspective and can have significant socio-economic consequences. It is a common feature of chronic illnesses and a significant number of both adults and children with immune thrombocytopenia (ITP) suffer from fatigue. Reliable, validated fatigue scales have been developed for use in ITP. These will facilitate future investigation of its pathogenesis and the effectiveness of intervention. Acute inflammation acts on neural and endocrine systems resulting in 'sickness behaviour', an adaptive response to infection and injury. Inflammation is also thought to cause fatigue in chronic disease and immune dysregulation in ITP appears to have a number of pro-inflammatory components. Clinicians should consider fatigue when assessing the burden of disease. Although effective ITP-directed therapy can improve fatigue, a number of fatigue-directed strategies may also need to be considered.

United Kingdom immune thrombocytopenia registry: retrospective evaluation of bone marrow fibrosis in adult patients with primary immune thrombocytopenia and correlation with clinical findings.

Fibrosis has been reported in some patients with immune thrombocytopenia (ITP) treated with thrombopoietin receptor agonists (TPO-RA). However, fibrosis has also been reported in patients with various stages of ITP, who were TPO-RA treatment-naïve. In our study, we looked for fibrosis in bone marrow trephine biopsies taken at initial diagnosis from 32 adult patients with ITP. Ten of the 32 evaluated samples (31·25%) showed increased reticulin (Grade 1-2 on Bauermeister scale and Grade 0-1 on the European Consensus scale), which showed a positive correlation with ethnicity (0·3%) but did not correlate with disease severity, any clinical features or co-morbidities.

Immune thrombocytopenia -- what are the new treatment options?

INTRODUCTION: Primary immune thrombocytopenia (ITP) is a minor disease for many patients; however, the natural history is variable and unpredictable. Many patients who are in otherwise good health can be left untreated, especially if their platelet counts are close to 20 × 10(9)/l. The overall mortality rate for ITP is < 1%, and the morbidity and mortality associated with treatment can be worse than the disease. AREAS COVERED: ITP is not purely due to platelet destruction and in a significant proportion platelet production is sub-optimal; the review will cover the newer developments with the thrombopoietin receptor agonists (TPOrAs) of which two agents, romiplostim and eltrombopag, are now licensed and these will be placed in context to conventional treatment. EXPERT OPINION: There is an increasing understanding of the natural history of ITP and an increasing evidence-based approach to the disease and its management. Treatment should be aimed at the patient with a bleeding risk and should minimise the risk of adverse effects while maximising the chances of response. Few, if any, treatments are curative and treatment strategies need to be designed in ITP that manage patients with what can be a life-long condition with periodic relapses.

Differential and tumor-specific expression of CD160 in B-cell malignancies.

CD160 is a human natural killer (NK)-cell-activating receptor that is also expressed on T-cell subsets. In the present study, we examined 811 consecutive cases of B-cell lymphoproliferative disorders (B-LPDs), and demonstrated CD160 expression in 98% (590 of 600) of chronic lymphocytic leukemia (CLL) cases, 100% (32 of 32) of hairy cell leukemia (HCL) cases, 15% (5 of 34) of mantle cell lymphoma (MCL) in the leukemic phase, and 16% (23 of 145) of other B-LPD cases. CD160 transcript and protein were absent in the normal B-cell hierarchy, from stem cells, B-cell precursors, maturing B cells in the germinal center, and circulating B cells, including CD5(+)CD19(+) B1 cells in umbilical cord. CD160 positivity was significantly higher in CLL and HCL in terms of percentage (65.9% and 67.8%, respectively, P < .0001) and median fluorescence intensity (552 and 857, respectively, P < .0001) compared with all other B-LPD cases. Lymph node CLL samples were also CD160(+). Using the disease-specific expression of CD5, CD23, and CD160, a score of 3 characterized CLL (diagnostic odds ratio, 1430); a score of 0 excluded CLL, MCL, and HCL; and the CD23/CD5 ratio differentiated CLL from leukemic CD23(+) MCL. In the B-cell lineage, CD160 is a tumor-specific antigen known to mediate cellular activation signals in CLL, and is a novel target for therapeutic manipulation and monitoring of minimal residual disease.

Single nucleotide polymorphism (SNP) analysis demonstrates a significant association of tumour necrosis factor-alpha (TNFA) with primary immune thrombocytopenia among Caucasian adults.

T-helper 1 polarization in patients with primary immune thrombocytopenia (ITP) is well documented. However, the genetic contribution to this imbalance remains unclear. To address this question, we selected six candidate single nucleotide polymorphisms within cytokine or cytokine receptor genes for association testing among Caucasian adults. Patients from the United Kingdom Adult ITP Registry were gender-matched (1:3) with healthy controls from the Wellcome Trust Case Control Consortium. Variants IL10 -819 c>t, TNFA -308 g>a, TGFB1 -509 c>t, IL1A -889 c>t, IL10 -592 c>t, and IL4R q576r were measured in cases and retrieved for controls from the European Genome-phenome Archive. Associations were evaluated using logistic regression models. In total, 206 patients with primary ITP were matched with 618 controls. A significant per allele odds ratio of 1·34 (95% confidence interval, 1·03-1·75; P = 0·03) was observed for TNFA -308 g>a, implicating an increased disease susceptibility among Caucasian carriers of the rare allele.

ITP: a historical perspective.

A clinical syndrome of bleeding and purpura consistent with a diagnosis of immune thrombocytopenia (ITP) was described by Werlhof long before platelets were identified as the cellular component of blood playing an essential role in primary haemostasis. Although a role for the spleen was suggested nearly a century ago, the pathophysiology of ITP has remained elusive for many decades. During this time Werlhof's disease was renamed idiopathic thrombocytopenic purpura, from which the acronym ITP originally derives. The second half of the 20th century brought recognition of the autoimmune components of ITP, and hence the need for a new standard nomenclature, which has recently been accepted. ITP currently stands for Immune Thrombocytopenia, a name that more appropriately reflects the low platelet count rather than purpura as the main feature of the disease, as well as to defining its underlying nature. Advances in our knowledge of the disease have paralleled the availability of new therapeutic agents, and we are now entering an era of pathophysiologically-based treatment options.

Autologous 111 In-labelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy: a report from the United Kingdom ITP Registry.

While splenectomy is an effective therapy for primary immune thrombocytopenia (ITP), possible complications and observed non-complete response (CR) in one-third of patients demonstrate the need for further research into potential pre-surgical predictors of outcomes. Past investigations into platelet sequestration studies, a hypothesized predictive test, have adopted heterogeneous methods and varied widely with regard to power. By studying patients with primary ITP who underwent autologous (111) In-labelled platelet sequestration studies at Barts and The London NHS Trust between 1994 and 2008, we evaluated the effectiveness of sequestration site in predicting short, medium, and long-term CR (platelet count >100 × 10(9) /l) to splenectomy through multivariate (gender, age at splenectomy, and mean platelet lifespan) logistic regression modelling. In total, 256 patients with primary ITP underwent scans; 91 (35·5%) proceeded to splenectomy. Logistic regression revealed significant adjusted odds ratios for CR of 7·47 (95% confidence interval [CI], 1·89-29·43) at 1-3 months post-splenectomy, 4·85 (95% CI, 1·04-22·54) at 6-12 months post-splenectomy, and 5·39 (95% CI, 1·34-21·65) at last follow-up (median: 3·8 years [range: 0·5-13·1 years]) in patients with purely or predominantly splenic versus mixed or hepatic sequestration. These findings demonstrate the utility of autologous (111) In-labelled platelet sequestration studies as an adjunct predictive instrument prior to splenectomy.

Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database.

BACKGROUND: The risk of thromboembolic events in adults with primary immune thrombocytopenia has been little investigated despite findings of increased susceptibility in other thrombocytopenic autoimmune conditions. The objective of this study was to evaluate the risk of thromboembolic events among adult patients with and without primary immune thrombocytopenia in the UK General Practice Research Database. DESIGN AND METHODS: Using the General Practice Research Database, 1,070 adults (>or=18 years) with coded records for primary immune thrombocytopenia first referenced between January 1(st) 1992 and November 30(th) 2007, and having at least one year pre-diagnosis and three months post-diagnosis medical history were matched (1:4 ratio) with 4,280 primary immune thrombocytopenia disease free patients by age, gender, primary care practice, and pre-diagnosis observation time. The baseline prevalence and incidence rate of thromboembolic events were quantified, with comparative risk modelled by Cox's proportional hazards regression. RESULTS: Over a median 47.6 months of follow-up (range: 3.0-192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01-2.48), 1.37 (95% CI, 0.94-2.00), and 1.41 (95% CI, 1.04-1.91) were found for venous, arterial, and combined (arterial and venous) thromboembolic events, respectively, when comparing the primary immune thrombocytopenia cohort with the primary immune thrombocytopenia disease free cohort. Further event categorization revealed an elevated incidence rate for each occurring venous thromboembolic subtype among the adult patients with primary immune thrombocytopenia. CONCLUSIONS: Patients with primary immune thrombocytopenia are at increased risk for venous thromboembolic events compared with patients without primary immune thrombocytopenia.

International consensus report on the investigation and management of primary immune thrombocytopenia.

Previously published guidelines for the diagnosis and management of primary immune thrombocytopenia (ITP) require updating largely due to the introduction of new classes of therapeutic agents, and a greater understanding of the disease pathophysiology. However, treatment-related decisions still remain principally dependent on clinical expertise or patient preference rather than high-quality clinical trial evidence. This consensus document aims to report on new data and provide consensus-based recommendations relating to diagnosis and treatment of ITP in adults, in children, and during pregnancy. The inclusion of summary tables within this document, supported by information tables in the online appendices, is intended to aid in clinical decision making.