British Journal of Haematology最新文献

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzymopathy worldwide. Current neonatal screening, based on enzymatic assays, often fails to identify heterozygous females due to X-chromosome inactivation. This study aimed to characterize by genotype, enzymatic activity and haematological parameters infants carrying pathogenic G6PD variants and to explore genotype-phenotype correlations. Within the NeoGen project, 4067 newborns underwent whole-exome sequencing (WES). Infants with pathogenic or likely pathogenic variants of the G6PD gene were tested for quantitative enzyme activity and haematological indices. Pathogenic or likely pathogenic G6PD variants were found in 123 infants (3.0%); 107 completed full laboratory assessment. Enzymatic deficiency was observed in hemizygous males, while over 60% of heterozygous females showed normal enzyme levels and would have been missed by enzymatic screening. Males exhibited lower G6PD activity, higher reticulocyte counts and lower haemoglobin than females. Enzymatic and haematological variability was greater among females, underscoring the complexity of genotype-phenotype relationships. Enzymatic screening alone misses a significant proportion of affected females. Incorporating molecular testing into neonatal screening improves diagnostic accuracy, supports preventive strategies and promotes equity in early-life healthcare. These findings support the feasibility of combining molecular and enzymatic screening within large-scale genomic screening programmes.

Anti-CD38 monoclonal antibodies dramatically improve the prognosis in immunoglobulin light-chain (AL) amyloidosis, yet patients with end-stage (Mayo 2004 IIIB) disease are typically excluded from prospective trials. To evaluate the daratumumab plus bortezomib and dexamethasone (Dara-VD) regimen in Mayo 2004 stage III patients, we conducted a prospective phase 2 trial including 20 stage IIIA and 20 stage IIIB patients. The long-term follow-up results are reported here. The 24-month haematological complete response (CR) and very good partial response (VGPR) rate were 52.5% and 12.5% respectively. Organ responses improved after 12 months; the 24-month cardiac CR and VGPR rates were 15.0% and 35.0%. After a median follow-up of 50.9 months, 16 patients died and 10 patients had progressive diseases. The median overall survival (OS) had not been reached in either group, with a 4-year OS rate of 60.0% (95% confidence interval [CI]: 45.2%-75.2%). The median event-free survival (EFS) was 33.5 months (95% CI 21.0-46.0 months), with a 4-year EFS rate of 37.5% (95% CI: 24.3-54.7). No significant difference in OS or EFS was observed between stage IIIA and IIIB patients. In conclusion, the strong anti-plasma cell regimen Dara-VD provides comparable long-term responses and prognosis for Mayo stage IIIB patients.

This nutshell review discusses the pathophysiology, diagnostic features, treatment strategies and avenues for future research in a recently identified thrombotic entity, monoclonal gammopathy of thrombotic significance (MGTS). MGTS is an anti-platelet factor 4 (PF4) antibody-mediated disorder distinct from heparin-induced thrombocytopenia (HIT) and vaccine-induced thrombotic thrombocytopenia (VITT), as it involves the production of persistent, monoclonal anti-PF4 antibodies. Several subtypes of MGTS, including 'HIT-like', 'VITT-like' and 'non-HIT/VITT-like', exhibit unique serological profiles that can complicate diagnosis. Recognition of 'HIT-like' MGTS is critical to avoid heparin exposure in these patients, which can result in adverse effects like those seen in heparin-exposed HIT patients. 'Non-HIT/VITT-like' MGTS antibodies have only been detected in PF4-enhanced functional testing; therefore, we recommend using these platelet-based tests as the front-line assay for detecting MGTS antibodies. Mass profiling using mass spectrometry is critical for the 'fingerprinting' of monoclonal antibodies to establish a diagnosis of MGTS. Treatments used in HIT and VITT, such as non-heparin anticoagulants and intravenous immunoglobulin G, are typically insufficient for managing MGTS. Emerging MGTS therapies, such as plasma cell-directed drugs and Bruton tyrosine kinase inhibitors, are discussed. The review concludes with an emphasis on areas of future research in MGTS.

Despite recent advances, treatment outcomes for adults with acute lymphoblastic leukaemia (ALL) remain poor. Although patients often exhibit an initial favourable response to chemotherapy, with substantial clearance of tumour cells, most patients eventually relapse. This indicates the persistence of a chemoresistant ALL subpopulation capable of driving disease regeneration. Growing evidence implicates interactions between leukaemia cells and the bone marrow (BM) niche in this process. Our findings show that BM-derived mesenchymal stem cells (MSCs) and adipocytes (BMAds) promote chemotherapy resistance in ALL cells via activation of the wingless-related integration site (WNT) signalling pathway. Chemotherapy-treated co-cultures of MSCs/BMAds and ALL cells exhibited upregulation of several WNT ligands in the stromal compartment. Notably, pharmacological inhibition of WNT signalling abrogated the stromal-mediated chemoprotection and enhanced ALL cell apoptosis in vitro. In vivo, WNT inhibition in a p185^BCR-ABLArf^-/- B-ALL mouse model sensitised leukaemia cells to chemotherapy, delaying relapse and extending survival. Collectively, these results support the therapeutic potential of WNT inhibitors as a strategy to block the cross-talk between the BM stroma and leukaemic cells and reduce ALL chemoresistance.

Inherited bone marrow failure syndromes (IBMFSs) are genetically heterogeneous with an expanding spectrum of causative genes. Recent molecular advances are thought to have contributed to genetic identification, yet the true gain in diagnostic yield remains unclear. Accordingly, this study aims to investigate the evolving genetic landscape of IBMFSs using data from the Canadian Inherited Marrow Failure Registry by analysing patients enrolled from the 2001-2010 cohort to the 2011-2023 cohort. Among 407 genetically tested patients, 308 (75.7%) underwent molecular diagnosis, with variants identified in 62 distinct genes. These genes encompass diverse cellular pathways, including DNA repair, telomere maintenance, transcription, RNA splicing, ribosome biogenesis, nuclear envelope, Golgi, endoplasmic reticulum and mitochondrial integrity, cell signalling, cytokine receptor activity and cytoskeletal regulation. A total of 453 variants were identified, including pathogenic copy number variants in 12.7% (39/308) of cases, representing 10.4% (47/453) of all variants. Diagnostic yield increased from 51.6% in 2001-2010 to 75.7% in 2001-2023, and genetic testing enabled classification of 17.5% (54/308) of previously unclassified cases. These findings underscore the rapid growth of IBMFS genetic knowledge and the crucial value of comprehensive testing, although 24.3% of cases remain unresolved, likely due to novel syndromes and unrecognised IBMFS-related genes.