Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag

Pretreatment blood counts, particularly an absolute reticulocyte count ≥25×10⁹/L, correlate with response to immunosuppressive therapy in severe aplastic anemia. In recent trials, eltrombopag combined with standard immunosuppressive therapy yielded superior responses than those to immunosuppressive therapy alone. Our single institution retrospective study aimed to elucidate whether historical predictors of response to immunosuppressive therapy alone were also associated with response to immunosuppressive therapy plus eltrombopag. We sought correlations of blood counts, thrombopoietin levels and the presence of paroxysmal nocturnal hemoglobinuria clones with both overall and complete responses in 416 patients with severe aplastic anemia, aged 2-82 years (median, 30 years), initially treated with immunosuppressive therapy plus eltrombopag between 2012 and 2019 (n=176) or with immunosuppressive therapy alone between 1999 and 2010 (n=240). Compared to non-responders, patients in the group of overall responders to immunosuppressive therapy plus eltrombopag had significantly higher pretreatment absolute reticulocyte counts, higher neutrophil counts and reduced thrombopoietin levels, as also observed for the group treated with immunosuppressive therapy alone. Addition of eltrombopag markedly improved the overall response in subjects with an absolute reticulocyte count between 10-30×10⁹/L from 60% (54 of 90) to 91% (62 of 68). Absolute lymphocyte count correlated with complete response in the groups treated with immunosuppressive therapy with or without eltrombopag, especially in adolescents aged ≥10 years and adults, but the correlation was reversed in younger children. Platelet count and the presence of a paroxysmal nocturnal hemoglobinuria clone did not correlate with responses to immunosuppressive therapy. Blood counts remain the best predictors of response to nontransplant therapies in severe aplastic anemia. Addition of eltrombopag to immunosuppressive therapy shifted patients with a lower absolute reticulocyte count into a better prognostic category.     

The Endothelin System: A Critical Player in the Pathophysiology of Preeclampsia

Purpose of Review

Preeclampsia (PE) is a disorder of pregnancy typically characterized by new-onset hypertension and proteinuria after gestational week 20. Although preeclampsia is one of the leading causes of maternal and perinatal morbidity and death worldwide, the mechanisms of the pathogenesis of the disorder remain unclear and treatment options are limited. Placental ischemic events and the release of placental factors appear to play a critical role in the pathophysiology. These factors contribute to a generalized systemic vascular endothelial dysfunction and result in increased systemic vascular resistance and hypertension.

Recent Findings

There is increasing evidence to suggest that endothelin-1 (ET-1) in the maternal vascular endothelium is a critical final common pathway, whereby placental ischemic factors cause cardiovascular and renal dysfunction in the mother. Multiple studies report increased levels of ET-1 in PE. A number of experimental models of PE are also associated with elevated tissue levels of prepro-ET-1 mRNA. Moreover, experimental models of PE (placental ischemia, sFlt-1 excess, TNF-α excess, and AT1-AA infusion) have proven to be responsive to ET type A receptor antagonism. Recent studies also suggest that abnormalities in ET type B receptor signaling may also play a role in PE.

Summary

Although numerous studies highlight the importance of the ET system in the pathogenesis of PE, further work is needed to determine whether ET receptor antagonists could provide an effective therapy for the management of this disease.

     

Long‐term safety and effectiveness of berotralstat for hereditary angioedema: The open‐label APeX‐S study

BackgroundBerotralstat (BCX7353) is an oral, once‐daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long‐term safety study of berotralstat in patients with HAE.MethodsAPeX‐S is an ongoing, phase 2, open‐label study conducted in 22 countries (ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT03472040","term_id":"NCT03472040"}}NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE‐C1‐INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long‐term safety and the secondary objective was to evaluate effectiveness.ResultsEnrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11–540) and 307 (14–429) days for the 150‐mg and 110‐mg groups, respectively. Treatment‐emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug‐related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug‐related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline.ConclusionsIn this analysis, both berotralstat doses, 150  and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE.Trial registrationThe study is registered with ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT03472040","term_id":"NCT03472040"}}NCT03472040).     

Deficit of circulating CD19+CD24hiCD38hi regulatory B cells in severe aplastic anaemia

Immune aplastic anaemia (AA) is caused by cytotoxic T lymphocytes (CTLs) that destroy haematopoietic stem and progenitor cells. Enhanced type 1 T helper (Th1) responses and reduced regulatory T cells (Tregs) are involved in the immune pathophysiology. CD24^hiCD38^hi regulatory B cells (Bregs) suppress CTLs and Th1 responses, and induce Tregs via interleukin 10 (IL-10). We investigated circulating B-cell subpopulations, including CD24^hiCD38^hi Bregs, as well as total B cells, CD4⁺ T cells, CD8⁺ T cells and natural killer cells in 104 untreated patients with severe and very severe AA, aged ≥18 years. All patients were treated with standard immunosuppressive therapy (IST) plus eltrombopag. CD24^hiCD38^hi Bregs were markedly reduced in patients with AA compared to healthy individuals, especially in very severe AA, but residual Bregs remained functional, capable of producing IL-10; total B-cell counts and the other B-cell subpopulations were similar to those of healthy individuals. CD24^hiCD38^hi Bregs did not correlate with responses to IST, and they recovered to levels present in healthy individuals after therapy. Mature naïve B-cell counts were unexpectedly associated with IST response. Markedly reduced CD24^hiCD38^hi Bregs, especially in very severe AA, with recovery after IST suggest Breg deficits may contribute to the pathophysiology of immune AA.     

Education and social inclusion of people with disabilities in five countries in West Africa: a literature review

Abstract

Purpose: An estimated 1 billion people worldwide live with some form of disability. With the adoption of the Sustainable Development Goals and the “Leave no one behind” agenda, there is a global momentum to ensure that disadvantaged groups, not least people with disabilities, are included and accounted for, in mainstream development efforts. However, in many low-income settings little is known about disability and the policies and programs in place to improve the lives of those affected.

Method: This literature review describes the extent and quality of published and unpublished literature on education and social inclusion of people with disabilities in five West African countries: Cameroon, Liberia, Mali, Sierra Leone and Senegal.

Results: Fifty-four unique documents met inclusion criteria of the review and described related policy and legislation; national and international stakeholders; intervention programs and primary research related to disability and inclusion. The majority of documents were from Sierra Leone (19); and four described more than one country. Primary research included mainly qualitative studies and cross-sectional surveys; 33 sources were critically appraised with the majority being attributed unclear risk of bias (20).

Conclusions: The findings call for (i) standardized tools for monitoring the implementation of programs and policies at national level; (ii) improved stakeholder coordination mechanisms; (iii) development and adoption of coordinated approaches to measuring disability and social exclusion; (iv) rigorous evaluations of the effectiveness of disability programs and (v) disaggregation of routine data by disability.

• Implication for Rehabilitation

• There is a need for standardized tools for monitoring the implementation of programs and policies at national level.

• Countries that have not yet ratified the UNCRPD or the protocol should be supported to do so.

• Stakeholder coordination mechanisms need to be improved.

• Improved coordination between stakeholders involved in disability at the country level could help improve the quality of services delivered.

• Development and adoption of coordinated approaches is key to measuring disability and social exclusion.

• There are few, if any, rigorous evaluation of the effectiveness of disability-specific evaluations in the five countries.

• There is a need for disaggregation of routine data from development programs by disability to inform implementation.

     

New guidance on codes of practice, standardized methods and regulations for cell-based therapeutics

Consultations with members of the UK regenerative medicine community have identified the need for greater overall clarity regarding the current legislation, guidance and standards to be used. To facilitate this, the UK Department of Trade and Industry commissioned the British Standards Institution to develop guidance on the product pathway from cell/tissue donation to clinical trial for cell-based therapies within the UK and outline the accompanying legislation, codes of practice, guidance documents and standards for this process. This document will be aimed at a cross-section of end users from academic groups through to small and medium enterprises, larger industrial companies and the general public.     

Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity

Background Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo.Methods In this study, using advanced proteomic techniques, we have significantly expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line. USP18-dependent effects were explored further in CML and colorectal carcinoma cellular models.Results Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation.Conclusions Our results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target.Subject terms: Cancer immunotherapy, Ubiquitylation, RIG-I-like receptors, Radiotherapy, Mechanisms of disease     

Utility of plasma cell-free DNA for de novo detection and quantification of clonal hematopoiesis

Although cell-free DNA (cfDNA) tests have emerged as a potential non-invasive alternative to bone marrow biopsies for monitoring clonal hematopoiesis in hematologic diseases, whether commercial cfDNA assays can be implemented for the detection and quantification of de novo clonal hematopoiesis in place of blood cells is uncertain. In this study, peripheral plasma cfDNA samples available from patients with aplastic anemia (n=25) or myelodysplastic syndromes (n=27) and a healthy cohort (n=107) were screened for somatic variants in genes related to hematologic malignancies using a Clinical Laboratory Improvement Amendments-certified panel. Results were further compared to DNA sequencing of matched blood cells. In reported results, 85% of healthy subjects, 36% of patients with aplastic anemia and 74% of patients with myelodysplastic syndromes were found to have somatic cfDNA variants, most frequently in DNMT3A, TET2, ASXL1 and SF3B1. However, concordance between cfDNA and blood cell findings was poor for the detection of clonal hematopoiesis when the allele frequency of the variants was <10%, which was mostly observed in the healthy and aplastic anemia cohorts but not in patients with myelodysplastic syndromes. After filtering data for potential artifacts due to low variant allele frequency and sequencing depth, the frequency of clonal hematopoiesis in cfDNA from healthy individuals and patients with aplastic anemia decreased to 52% and 20%, respectively. cfDNA and matched blood cells were not interchangeable for tracking changes in allele burdens as their agreement by Bland-Altman analysis was poor. A commercial cfDNA assay had good performance for de novo detection of clonal hematopoiesis in myelodysplastic syndromes, but showed no advantage over blood cells in diseases with low allele burdens or in healthy individuals.