British Journal of Haematology最新文献

Polyradiculoneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a rare plasma cell dyscrasia. Questions remain regarding the use of induction therapy, given the known efficacy of melphalan autologous stem cell transplant (ASCT), as well as the optimal management of transplant-ineligible patients. We describe the outcomes of 105 patients with POEMS syndrome and systemic disease, with a median follow-up of 68 months. Median age at diagnosis was 55 years and 75 were male. Front-line ASCT was performed in 67 patients, 61 melphalan 200 mg/m² and six 140 mg/m². Upfront ASCT was delivered in 28 and 39 patients received prior induction. ASCT was highly efficacious, with a median overall survival (OS) not reached; 5- and 10-year OS of 100% and 90.7%, respectively, with progression-free survival (PFS) of 76.5% and 60.0%. No significant difference was seen in OS, PFS, depth of response or improvement in mobility status with induction therapy. Outcomes were inferior for non-ASCT patients with a median OS of 11.4 years, 5-year OS of 72.8% and 10-year OS of 64.7%. Median PFS for this cohort was 5.6 years, with 5- and 10-year PFS of 57.2% and 31.8% respectively. Attainment of complete vascular endothelial growth factor (p < 0.001) and/or haematological response (p = 0.01) following front-line therapy was associated with a lower risk of relapse.

Lymphoma-associated haemophagocytic lymphohistiocytosis (LA-HLH) is associated with a high mortality rate, making early diagnosis and appropriate treatment critical for improving patient outcomes. In this study, we enrolled 126 patients diagnosed with LA-HLH and 254 with non-LA-HLH. A machine learning-based predictive model was developed and validated to enable timely differentiation of LA-HLH from other HLH subtypes. The model incorporated 11 predictive variables for early LA-HLH prediction, among which the top five most influential were age, ferritin, monocyte percentage, haemoglobin and platelet count. Among seven machine learning algorithms evaluated, the random forest model demonstrated the best performance, achieving an area under the curve (AUC) of 0.946 on the training set and 0.794 on the validation set. We subsequently evaluated combined models that incorporated disease-specific indicators such as soluble interleukin-2 receptor (sCD25) and PET-CT SUVmax, which resulted in a non-significant increase in AUC on the validation set. Finally, the optimal model was deployed as a web-based tool to support early aetiological differentiation. This may facilitate prompt initiation of targeted examination and appropriate treatment for patients with LA-HLH.

Constitutional pathogenic variants in DDX41 predispose to myelodysplasia and acute myeloid leukaemia. Acquisition of subsequent somatic hits in the second allele is frequent, with notable recurrent variants at key hotspots. Sequencing of Deoxyribonucleic acid from blood/marrow of 239 patients with suspected/confirmed haematological malignancies at a single centre within a 4-year period identified 136 unique DDX41 variants. Among those with co-occurring somatic and likely/confirmed germline variants, 54.8% of likely/confirmed germline variants were pathogenic when classified according to current Cancer Variant Interpretation Group UK (CanVIG-UK) guidelines (incorporating American College of Medical Genetics [ACMG] criteria), while 45.2% were deemed variants of uncertain significance (VUS). Classification of variants as uncertain poses challenges, as it then calls into question the underlying aetiology of the malignancy, as well as the significance of any subsequent somatic DDX41 variants. As carrier relatives of suspected deleterious DDX41 variants will not usually be considered as donors for bone marrow transplantation, classification of variants of likely germline origin will have immediate treatment implications. Current ACMG and CanVIG-UK guidelines do not permit co-occurrence with recurrent somatic driver variants as evidence favouring pathogenicity, despite this being a convincing finding. This study proposes modifying certain rules as a basis for developing DDX41-specific guidance, as it will significantly impact decisions surrounding bone marrow transplantation.

Evidence for an association between insulin-like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF-I concentrations and risk of MM by combining baseline serological data among UK Biobank participants (n = 444 187; 732 incident MM) with a two-sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF-I and IGF-binding protein 3 (IGFBP-3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF-I level was positively associated with MM risk Hazard ratio-HR-per one standard deviation-SD-increase (HR_1-SD = 1.11, 95% confidence interval [CI]: 1.01-1.22; p-value = 0.03), especially closer to diagnosis. Genetically inferred IGF-I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05-1.54) but not with any other LNs. Genetically inferred IGFBP-3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF-I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR_{1-SD in obese male} = 1.36, 95% CI: 1.14-1.61). Our serological and MR analyses suggest a contributing role of IGF-I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex-specific adiposity.

The clinical impact of immunosuppression termination (IST) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains to be fully elucidated. This study was aimed at assessing the impact of IST within 2 years after transplantation on subsequent clinical outcomes. We analysed data for patients from the Transplant Registry Unified Management Program 2 (TRUMP 2) database who survived without progression for at least 2 years after allo-HSCT. Of the 5061 patients whose median age was 48 (range: 0-79) years, 2320 discontinued immunosuppressive therapy within 2 years (IST group), while 2741 did not (non-IST group). The 4-year overall survival (OS) rate was significantly higher in the IST group than in the non-IST group (95.3% vs. 90.8%; p < 0.01). The 4-year cumulative incidence of non-relapse mortality (NRM) was significantly lower in the IST group than in the non-IST group (3.5% vs. 8.6%; p < 0.01). This reduction in NRM was consistent across major causes, including graft-versus-host disease (GVHD)-related mortality, infection-related mortality and organ failure-related mortality. Immunosuppressive therapy beyond 2 years after allo-HSCT was associated with inferior OS. Our findings suggest that the optimal transplant strategy is necessary to avoid long-term immunosuppression for improving clinical outcomes in allo-HSCT recipients.

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.