British Journal of Haematology最新文献

Hydroxycarbamide (HC) is the most widely used therapeutic for individuals with sickle cell disease (SCD, including sickle cell anemia and other forms of the disease). HC's clinical benefits are primarily associated with its ability to induce foetal haemoglobin (HbF); this limited view of HC's therapeutic potential may lead to its discontinuation when a modest amount of HbF is induced. A better understanding of the HbF-independent effects of HC on genes and pathways relevant to SCD pathophysiology is therefore needed. In this study, we performed bulk RNA-Seq on whole blood samples collected from a cohort of 25 paediatric patients with SCD to identify genes and pathways that are affected by treatment with HC. At the maximum tolerated dose (MTD) of HC, patients showed altered expression levels of several genes and biological pathways. Pathways related to haeme metabolism, interferon-alpha response, and interferon-gamma response were significantly downregulated at HC MTD relative to the matched pre-HC samples. Pathways linked with IL2-STAT5 signalling and TNFα signalling via NF-Kβ were observed to be up-regulated at HC MTD. These results illustrate the range of effects exerted by HC during therapy for SCD and pave the way for an improved understanding of the HbF induction-independent benefits of HC.

Dissecting the genomic traits and clinical course of secondary myelodysplastic syndrome following aplastic anaemia is a milestone. The report by Li and colleagues investigates determinants of evolution to myelodysplastic syndrome and acute myeloid leukaemia in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria with a specific focus on post-transplant outcomes. Commentary on: Li et al. Clinical and genetic profiles and outcomes of allogeneic haematopoietic stem cell transplantation in secondary myelodysplastic syndrome following aplastic anaemia. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19855.

Many cases of venous thromboembolism (VTE) are idiopathic and clonal haemopoiesis, a risk factor for atherosclerotic vascular disease, may be a contributing factor to VTE. The report by Englisch and colleagues suggests that clonal haemopoiesis is a risk factor for recurrent VTE, especially in people without identifiable thrombotic predisposition. Commentary on: Englisch et al. Association of clonal hematopoiesis with recurrent venous thromboembolism: A case-control study. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19871.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders, manifesting multiple clinical autoimmune inflammatory phenomena, including rarely peripheral neuropathy. Twenty-four patients diagnosed with MDS and 29 healthy subjects were enrolled in this prospective study in a 5-year period. Every subject was assessed by symptoms questionnaire and clinical neurological examination followed by nerve conduction studies, quantitative sensory testing and skin biopsy. Peripheral neuropathy was diagnosed in 12 subjects (50%). Our study indicated that peripheral neuropathy involving large and small nerve fibres, with a symmetrical length-dependent pattern, is not uncommon between patients with MDS.

Human leucocyte antigen (HLA) class II molecules are critically involved in the pathology of acquired aplastic anaemia (AA) by regulating the immune response and autoreactive T cell-mediated haematopoietic cell death. In the study, amino acid residue variation and molecular structure of HLA class II have been initially investigated in 96 patients with AA. The frequencies of residues 9 and 57 in pocket 9 (P9) in DQB1, and amino acid positions 9, 11, 13, 16, 26, 38, 67 and 71 in the P4, P6 and P9 pockets in DRB1 were more prevalent among AA patients. By applying a multivariate recursive approach, the DRβ-Gln-16 (OR = 3.003, 95% CI = 1.468-6.145, p_c = 0.003), DRβ-Ala-71 (OR = 1.924, 95% CI = 1.233-3.002, p_c = 0.004) in P4/P7 and DQβ-Asp-57 (OR = 3.483, 95% CI = 1.079-11.242, p_c = 0.037) in P9, these critical residues were significantly discovered as risk amino acid residues on the onset of AA, as well as associated with PNH-type cells and pathological somatic or cytogenetic mutations. In silico structural model analysis showed that identified DRβ-Ala-71 and DQβ-Asp-57 within the antigen-binding groove interacting with a more variable antigenic segments, may impact the repertoire of peptides presented, influence the interface HLA-antigen-T-cell receptor β (TCR β). These findings provided light on the immunogenetic pathophysiology of AA aetiology and their potential impact on upcoming immunotherapies.

Lin et al. report the long-term follow-up of a phase II trial involving 95 adult patients with Langerhans cell histiocytosis (LCH), investigating the combination of methotrexate and cytarabine (MA). After a median follow-up of 6.5 years, the study showed high response rates, with 90% overall response; 55% of patients free from an event such as disease progression, poor response or death; and 93% of patients were alive, though nearly half experienced febrile neutropenia. This prospective study helps fill gaps in understanding adult LCH treatment, indicating that fixed-duration chemotherapy can yield durable responses despite its associated risks. It emphasizes the importance of personalized treatment decisions, considering both fixed-duration chemotherapy and continuous targeted agents based on patient and disease-specific factors. Commentary on: Lin et al. Long term follow-up of methotrexate and cytarabine in adult patients with Langerhans cell histiocytosis. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19830.

The therapeutic paradigm for patients suffering from chronic lymphocytic leukaemia continues to rapidly evolve. Fixed duration therapies continue to develop using novel-novel non-chemotherapeutic combinations. B-cell lymphoma 2 (BCL2) inhibitors in combination with either anti-CD20 antibody or Bruton tyrosine kinase inhibitors are able to achieve deep responses. Levels of attained 'negative' measurable residual disease (MRD, also known as minimal residual disease) have been shown to predict survival outcomes in a number of settings, including following immunochemotherapy and BCL2-combinations. This review will outline the current data supporting fixed duration treatment approaches, the use of MRD in clinical practice, alongside the challenges and possibilities for MRD utility in the future.

The clonal haematopoiesis risk score (CHRS) was proposed to predict the rate of progression from clonal haemopoiesis of indeterminate potential (CHIP)/clonal cytopenia with unknown significance (CCUS) to myeloid neoplasms in the general population. CHRS encompasses the type and VAF of the mutation, the presence of a single DNMT3A mutation, cytopenia, age, red cell distribution width (RDW) and mean corpuscular volume (MCV). We studied clonal haematopoiesis in a cohort of 55 consecutive patients treated with CD19-directed CAR-T cells: CHIP and CCUS were present in 7% and 33% of patients before CAR-T. Three therapy-related myeloid neoplasms (t-MN) were observed after treatment with CAR-T (2 MDS and 1 AML). Only patients with an intermediate-high baseline CHRS developed a t-MN. Patients with an intermediate-high CHRS had more than a twofold increased risk of developing a t-MN within the first 9 months after CAR-T (odds ratio 2.89, 95% C.I. 1.98-4.19, p < 0.001). Overall, CHRS was able to predict the occurrence of t-MN after CAR-T with good specificity.