89 results found
Kuter DJ, Efraim M, Mayer J, et al., 2022, Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia., N Engl J Med, Vol: 386, Pages: 1421-1431
BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic eff
Grainger J, Bussel JB, Tarantino MD, et al., 2022, A Single-Arm, Long-Term Efficacy and Safety Study of Subcutaneous Romiplostim in Children with Immune Thrombocytopenia., Blood Adv
Romiplostim is a thrombopoietin receptor agonist approved for children/adults with immune thrombocytopenia (ITP) for >/=6 months, recommended as second-line treatment. This phase 3b, single-arm, multicenter study investigated long term efficacy/safety of romiplostim in children >/=1-<18 years old with >/=6 months ITP duration and platelet counts </=30×109/L. Children received weekly subcutaneous romiplostim (1 μg/kg titrated to 10 μg/kg) to maintain platelets within 50-200×109/L. A subset underwent bone marrow examinations. Primary endpoint was percent of time with platelet response during the first 6 months' treatment (counts >/=50×109/L without rescue medication within the preceding 4 weeks). Overall, 203 patients (median age, 10.0 years) received >/=1 dose of romiplostim, median treatment duration was approximately 3 years, median average weekly dose was 6.9 μg/kg. Ninety-five (46.8%) discontinued (lack of efficacy, n=43 [21.2%]). Platelet responses were achieved a median (IQR) of 50.0% (16.7%-83.3%) of the time during the first 6 months, increasing to 78.2% (26.7%-90.4%) during the overall 36 month treatment period. Eleven patients (5.4%) achieved sustained responses (consecutive counts >/=50×109/L without ITP medications for >/=24 weeks). Treatment-related adverse events (AEs) occurred in 56 patients (27.6%), with 8 (3.9%) experiencing serious treatment-related AEs; all of these led to discontinuation, including 4 cases of neutralizing antibodies (romiplostim, n=3; thrombopoietin, n=1). Bleeding occurred in 141 patients (69.5%), decreasing over time; grade >/=3 bleeding events occurred in 20 (9.9%). At year 2, 8/63 evaluable patients (12.7%) had grade 2 reticulin. Long-term romiplostim resulted in sustained on-treatment platelet responses with an overall safety profile consistent with previous studies.
Joyce KE, Onabanjo E, Brownlow S, et al., 2022, Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variants, Blood Advances, ISSN: 2473-9529
The abnormal vascular structures of hereditary hemorrhagic telangiectasia (HHT) often cause severe anemia due to recurrent hemorrhage, but HHT-causal genes do not predict the severity of hematological complications. We tested for chance inheritance and clinical associations of rare deleterious variants where loss-of-function causes bleeding or hemolytic disorders in the general population. In double-blinded analyses, all 104 HHT patients from a single reference centre recruited to the 100,000 Genomes Project were categorised on new MALO (more/as-expected/less/opposite) sub-phenotype severity scales, and whole genome sequencing data tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, platelet, hemoglobin, erythrocyte enzyme and erythrocyte membrane constituents. Rare variants (all GnomAD allele frequencies <0.003) were identified in 56 (75%) of these 75 HHT-unrelated genes, and in 38/104 (36.5%) of the HHT patients. Likely deleteriousness assignments by Combined Annotation Dependent Depletion (CADD) scores >15 were supported by gene-level mutation significance cutoff (MSC) scores. CADD>15 variants were found for 1 in 10 patients within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to HHT vessels had more CADD-deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. However, the HHT cohort had 60% fewer deleterious variants in platelet and coagulation genes than expected (Mann Whitney p=0.021). In conclusion, HHT patients commonly have rare variants in genes of relevance to their phenotype, offering new therapeutic targets and opportunities for informed, personalised medicine strategies.
Chauss D, Freiwald T, McGregor R, et al., 2021, Autocrine vitamin D signaling switches off pro-inflammatory programs of T(H)1 cells, NATURE IMMUNOLOGY, Vol: 23, Pages: 62-+, ISSN: 1529-2908
Bye AP, Hoepel W, Mitchell JL, et al., 2021, Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets, BLOOD, Vol: 138, Pages: 1481-1489, ISSN: 0006-4971
Vergis N, Phillips R, Cornelius V, et al., 2021, Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial, Trials, Vol: 22, ISSN: 1745-6215
OBJECTIVES: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. TRIAL DESIGN: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. PARTICIPANTS: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease C
Rosas IO, Brau N, Waters M, et al., 2021, Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 384, Pages: 1503-1516, ISSN: 0028-4793
Cooper N, Morrison MA, Vladescu C, et al., 2020, Identification of occult cerebral microbleeds in adults with immune thrombocytopenia, Blood, Vol: 136, Pages: 2875-2880, ISSN: 0006-4971
Management of symptoms and prevention of life-threatening hemorrhage in immune thrombocytopenia (ITP) must be balanced against adverse effects of therapies. Because current treatment guidelines based on platelet count are confounded by variable bleeding phenotypes, there is a need to identify new objective markers of disease severity for treatment stratification. In this cross-sectional prospective study of 49 patients with ITP and nadir platelet counts <30 × 109/L and 18 aged-matched healthy controls, we used susceptibility-weighted magnetic resonance imaging to detect cerebral microbleeds (CMBs) as a marker of occult hemorrhage. CMBs were detected using a semiautomated method and correlated with clinical metadata using multivariate regression analysis. No CMBs were detected in health controls. In contrast, lobar CMBs were identified in 43% (21 of 49) of patients with ITP; prevalence increased with decreasing nadir platelet count (0/4, ≥15 × 109/L; 2/9, 10-14 × 109/L; 4/11, 5-9 × 109/L; 15/25 <5 × 109/L) and was associated with longer disease duration (P = 7 × 10−6), lower nadir platelet count (P = .005), lower platelet count at time of neuroimaging (P = .029), and higher organ bleeding scores (P = .028). Mucosal and skin bleeding scores, number of previous treatments, age, and sex were not associated with CMBs. Occult cerebral microhemorrhage is common in patients with moderate to severe ITP. Strong associations with ITP duration may reflect CMB accrual over time or more refractory disease. Further longitudinal studies in children and adults will allow greater understanding of the natural history and clinical and prognostic significance of CMBs.
Ghanima W, Provan D, Cooper N, et al., 2020, ITP World Impact Survey (I-WISh) 2.0: Further Exploration of the Impact of ITP on Patients, Blood, Vol: 136, Pages: 2-3, ISSN: 0006-4971
<jats:p>Immune thrombocytopenia (ITP) is an acquired autoimmune disorder defined by a platelet count &lt; 100 × 109/L without explanation, and an increased risk of bleeding. ITP itself as well as its treatments have multifaceted, often poorly understood impacts on patients' quality of life (QoL). These effects include impact on activities of daily living, emotional health, energy, ability to think well and clearly, and productivity in the workplace. There are limited data on which individual aspects of ITP are perceived both by patients and physicians as having the greatest impact on QoL. Understanding patients' perspectives is vital to optimize their QoL by specifying particular areas in need of therapy.</jats:p> <jats:p>I-WISh 1.0 was an exploratory, cross-sectional survey in which 1507 patients with ITP and 472 physicians across 13 countries completed separate, but related, online surveys that included assessments of ITP signs and symptoms, impact of symptoms, and patient-physician relationships. These findings have been presented at previous ASH and EHA congresses, and manuscripts are currently in preparation. However, although I-WISh 1.0 provided considerable insights into unexplored facets of the effects of ITP, an all-too-large number of gaps in understanding still remain. In response to this, I-WISh 2.0 is currently being developed.</jats:p> <jats:p>The objectives of the I-WISh 2.0 patient and physician cross-sectional surveys include: (1) to further explore the burden of fatigue and how it affects patients' lives, including what makes it better or worse; (2) to assess the emotional impact of living with chronic ITP, especially in relation to depression; (3) to assess how treatments for ITP can impact activities of daily living (positively and negatively); (4) to further relate effects of treatment to patients' QoL; and (5) to explore how telemedicine affects healthcare delivery for pati
Tarantino MD, Despotovic J, Roy J, et al., 2020, Romiplostim treatment for children with immune thrombocytopenia: Results of an integrated database of five clinical trials, PEDIATRIC BLOOD & CANCER, Vol: 67, ISSN: 1545-5009
Thaventhiran JED, Lango Allen H, Burren OS, et al., 2020, Whole-genome sequencing of a sporadic primary immunodeficiency cohort (vol 583, pg 90, 2020), Nature, Vol: 584, Pages: E2-E2, ISSN: 0028-0836
Thaventhiran JED, Lango Allen H, Burren OS, et al., 2020, Whole-genome sequencing of a sporadic primary immunodeficiency cohort., Nature, Vol: 583, Pages: 90-95
Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
Sharrack B, Saccardi R, Alexander T, et al., 2020, Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)., Bone Marrow Transplantation, Vol: 55, Pages: 283-306, ISSN: 0268-3369
These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
Neunert C, Terrell DR, Arnold DM, et al., 2019, American Society of Hematology 2019 guidelines for immune thrombocytopenia, Blood Advances, Vol: 3, Pages: 3829-3866, ISSN: 2473-9529
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background:</jats:title> <jats:p>Despite an increase in the number of therapies available to treat patients with immune thrombocytopenia (ITP), there are minimal data from randomized trials to assist physicians with the management of patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the management of ITP.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>In 2015, ASH formed a multidisciplinary guideline panel that included 8 adult clinical experts, 5 pediatric clinical experts, 2 methodologists with expertise in ITP, and 2 patient representatives. The panel was balanced to minimize potential bias from conflicts of interest. The panel reviewed the ASH 2011 guideline recommendations and prioritized questions. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence-to-decision frameworks, to appraise evidence (up to May 2017) and formulate recommendations.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>The panel agreed on 21 recommendations covering management of ITP in adults and children with newly diagnosed, persistent, and chronic disease refractory to first-line therapy who have non–life-threatening bleeding. Management approaches included: observation, corticosteroids, IV immunoglobulin, anti-D immuno
Downes K, Megy K, Duarte D, et al., 2019, Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders, Blood, Vol: 134, Pages: 2082-2091, ISSN: 1528-0020
A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multi-disciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2,396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbour variants associated with rare bleeding, thrombotic or platelet disorders (BTPD). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number and intronic variants, as Pathogenic, Likely Pathogenic or Variants of Uncertain Significance. Half (50.9%) of these variants are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPD. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.
Bussel JB, Ghanima W, Tomiyama Y, et al., 2019, Physicians' and Patients' Perspectives on Treatments in ITP - a Multi-Country Perspective: Results from the ITP World Impact Survey (I-WISh), 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Grainger J, Bussel JB, Tarantino MD, et al., 2019, Updated Results from the Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP), 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Sayed AAA, Cooper N, Malik A, et al., 2019, Eltrombopag: more than just a thrombopoietin receptor agonist (TPO-RA) in immune thrombocytopenia (ITP), 61st Annual Meeting and exposition of the American Society for Hematology (ASH), Publisher: American Society of Hematology, ISSN: 0006-4971
Griffiths P, Grant L, Bonner N, et al., 2019, The Psychometric Properties of the ITP Life Quality Index Assessed in a Large Multinational "Real-World" Cohort of Immune Thrombocytopaenia Patients, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Kuter DJ, Boccia RV, Lee E-J, et al., 2019, Phase I/II, Open-Label, Adaptive Study of Oral Bruton Tyrosine Kinase Inhibitor PRN1008 in Patients with Relapsed/Refractory Primary or Secondary Immune Thrombocytopenia, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Cooper N, Ghanima W, 2019, Immune Thrombocytopenia, New England Journal of Medicine, Vol: 381, Pages: 945-955, ISSN: 0028-4793
Vandrovcova J, Salzer U, Grimbacher B, et al., 2019, FAS mutations are an uncommon cause of immune thrombocytopenia in children and adults without additional features of immunodeficiency., Br J Haematol
Cooper N, Bird R, Hato T, et al., 2019, PF709 TAPERING AND DISCONTINUATION OF THROMBOPOIETIN RECEPTOR AGONISTS IN ITP: EXPERT CONSENSUS OPINIONS, HemaSphere, Vol: 3, Pages: 309-310
Alwan F, Vendramin C, Liesner R, et al., 2019, Characterization and treatment of congenital thrombotic thrombocytopenic purpura, BLOOD, Vol: 133, Pages: 1644-1651, ISSN: 0006-4971
Teraz-Orosz A, Nichola C, Crawley J, et al., 2019, Detection of anti-platelet antibodies in immune thrombocytopenia by flow cytometry, British Journal of Haematology, Vol: 184, Pages: 844-847, ISSN: 1365-2141
Povoleri GAM, Nova-Lamperti E, Scotta C, et al., 2018, Human retinoic acid-regulated CD161(+) regulatory T cells support wound repair in intestinal mucosa, Nature Immunology, Vol: 19, Pages: 1403-1414, ISSN: 1529-2908
Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161+ regulatory T (Treg) cells as a distinct, highly suppressive population of Treg cells that mediate wound healing. These Treg cells were enriched in intestinal lamina propria, particularly in Crohn’s disease. CD161+ Treg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on Treg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161+ Treg cell signature in Crohn’s disease mucosa associated with reduced inflammation. These findings identify CD161+ Treg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.
Lucchini E, Fanin R, Cooper N, et al., 2018, Management of immune thrombocytopenia in elderly patients, European Journal of Internal Medicine, Vol: 58, Pages: 70-76, ISSN: 0953-6205
Tarantino MD, Despotovic JM, Roy J, et al., 2018, Safety and Efficacy of Romiplostim in over 200 Children with Immune Thrombocytopenia (ITP): Results of an Integrated Database of 5 Clinical Trials, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Adams G, Gosztolai A, Lucchini E, et al., 2018, Bayesian Analysis of TPO Levels in Immune Thrombocytopenia, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Duliege A-M, Arnold DM, Boccia R, et al., 2018, Two-Year Safety and Efficacy Outcomes with Fostamatinib in Adult Patients with Immune Thrombocytopenia (ITP): Open-Label Extension to Phase 3 Trial Program, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
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