British Journal of Haematology最新文献

When the World Health Organization (WHO) declared the global COVID-19 pandemic, it was recognised that patients with haematological cancers would be more susceptible to severe disease. Set within a UK population of ~4 million (https://hmrn.org/), all patients diagnosed with haematological neoplasms 2005-2019 who were alive on 1 January 2020 were followed up until March 2023. For comparative purposes, a similar age- and sex-matched general population cohort was also constructed. COVID-19 deaths were classified using ICD-10 codes and a multiple cause of death analysis was undertaken using a competing risk approach. Deaths of 486/18 883 haematology patients were attributed to COVID-19, yielding a cumulative incidence of 2.59% (95% confidence interval [CI]: 2.37-2.82) that was significantly higher than that of the general population (1.65; 95% CI: 1.58-1.72). In both cohorts, risks were higher in men, older people and those with co-morbidities. Within the patient cohort, excess mortality was largely concentrated in those suffering from more indolent conditions. Patients with the premalignancy MBL suffered from the highest excess mortality in the early phase of the pandemic when, unlike patients with malignancies, they were not advised to shield. Effects of shielding were evident and a clear vaccination benefit was demonstrated, with the exception of CLL and MCL; findings that warrant consideration in relation to other viruses.

To investigate T-cell glucose metabolism dysfunction in primary immune thrombocytopenia (ITP) and the role of mammalian target of rapamycin complex 1 (mTORC1) in regulatory T-cell (Treg) suppression function. Gene set enrichment analysis (GSEA) assessed glycolysis and mTORC1 pathways in dysfunctional Tregs from patients with systemic lupus erythematosus (SLE). CD4⁺ effector T cells (Teffs) were isolated from peripheral blood mononuclear cells (PBMCs) pre- and post-dexamethasone treatment and from healthy controls. The extracellular acidification rate (ECAR) of Tregs and Teffs was measured using the Agilent Seahorse XF96 platform. Flow cytometry evaluated glucose transporter 1 (GLUT1) and phosphorylated S6 (p-S6) expression. The immune suppression function of Tregs was assessed by mTORC1 inhibiting test. GSEA revealed a possible relation of glycolysis and mTORC1 signalling in dysfunctional Tregs. Both Tregs and Teffs from ITP patients showed elevated ECAR, with Teff ECAR normalizing post-glucocorticoid treatment. Treg ECAR decreased after treatment, but remained higher than normal level. GLUT1 and p-S6 expression was significantly higher in ITP Tregs and Teffs, normalizing GLUT1 levels after glucocorticoid therapy. Inhibiting mTORC1 could recover the suppression of ITP Tregs. Dysregulated CD4⁺ T-cell glucose metabolism contributes to ITP pathogenesis. Targeting mTORC1 signal may offer a novel therapeutic approach for ITP.

Bispecific T-cell-engaging antibodies (TCEs) are a significant advance in the treatment of diffuse large B-cell lymphoma (DLBCL), demonstrating robust clinical activity with manageable toxicity profiles. Their integration into third line as monotherapy, and now second line in combination, as well as recent data in the first line underscores their therapeutic potential. The efficacy of bispecific antibodies depends on sustained target antigen expression and preserved T-cell function; the loss of either of these factors, or intrinsic tumour and microenvironment biology, contributes to therapeutic resistance. Combination strategies aim to overcome these resistance mechanisms, enhance anti-tumour efficacy and potentially reduce treatment-related adverse events. In this review, we critically examine the current understanding of TCE resistance and discuss how this informs combination strategies. We explore approaches to bispecific antibody-based combination therapies in DLBCL and review emerging clinical trial results, with a view on potential future strategies for TCE-based combinations.

Immune thrombocytopenia (ITP) is an autoimmune disease where premature destruction of platelets as well as inhibition of platelet production leads to thrombocytopenia and associated bleeding. It has long been considered a disease primarily caused by B cells, but the role of T lymphocytes in its pathogenesis is now better understood and deserves elucidation. Two types of T cells will be discussed: (1) splenic T follicular helper cells (TFH) that participate in differentiation of B cells within germinal centres (GC) and stimulate the production of antiplatelet antibodies, thus supporting the humoral autoimmune response; and (2) antibody-independent mechanisms of action of cytotoxic T lymphocytes (CTL) that may directly participate in platelet destruction as well as inhibit their production by targeting megakaryocytes. To date, most novel therapies target antibody-mediated disease, but targeting either TFH or CTL may provide new therapeutic opportunities.

Outcomes for patients with multiple myeloma have improved markedly in recent years due to the introduction of highly effective immune-mediated anti-myeloma therapies in both newly diagnosed and relapsed patients. Conversely, while patients are living longer, myeloma bone disease continues to contribute significantly to morbidity and mortality. Routine incorporation of anti-resorptive therapies into patient management is recommended by consensus guidelines; however, patients continue to sustain skeletal-related events, including pathological fractures. In this review, we discuss the diagnosis and pathogenesis of myeloma bone disease and the evidence underpinning guideline recommendations for the use of bisphosphonates in patients with myeloma. We consider novel approaches to reducing bone disease presented by targeting osteoblastic activity, the impact of anti-myeloma therapies themselves on bone disease and the role of biomarkers to monitor disease activity and guide the intensity and duration of bone-targeted therapy.

Standard pomalidomide dosing (4 mg/day for 21 of 28 days) achieved the most robust pharmacokinetic (PK) and pharmacodynamic (PD) effects. Daily dosing with pomalidomide 2 mg is a safe alternative for patients at risk of toxicity; alternate-day dosing was less effective.