British Journal of Haematology最新文献

Germline variants in DDX41 (DDX41^MT-germline predisposition syndrome [GPS]) are associated with predisposition to haematological malignancies (HM), including lymphoid and myeloid neoplasms (MN). We retrospectively analysed the clinical and molecular features of 195 patients diagnosed and treated at Mayo Clinic with DDX41^MT-GPS. Patients with germline DDX41 pathogenic variants (42.3%) and variants of unknown significance (VUS, 57.6%) were included. The median age was 68.6 years (16.2–93.4). Ninety-two per cent were Caucasian, 64.1% were male and 30.8% had a family history of HM. There were 92 distinct germline variants among our cohort, and the most common was p.Met1? (15.9%), followed by p.Asp140Glyfs*2 (9.2%). Clinical diagnoses included asymptomatic carriers (10.2%), clonal cytopenia of undetermined significance (CCUS, 6.1%), myeloproliferative neoplasms (6.7%), myelodysplastic syndrome (40.5%), acute myeloid leukaemia (20.5%), lymphoid neoplasms (9.2%), plasma cell dyscrasias (6.1%) and solid tumours (22.5%). Patients with MN were older (median age 70 vs. 63.5 years) and more likely to be male (M:F ratio 2.3 vs. 1.0) and most patients (78.8%) with MN had a normal karyotype. The most common somatic variants involved DDX41 (34.4%), followed by TET2 (11.2%), DNMT3A (9.6%) and ASXL1 (9.2%). In summary, we have comprehensively described the spectrum of clinical phenotypes within the Mayo Clinic DDX41^MT-GPS cohort.

Germline homozygous loss-of-function mutations in TET2 result in significant childhood immunodeficiency that resembles autoimmune lymphoproliferative syndrome and predisposes one to lymphoma. The implications of heterozygous variants are less well understood. We describe four patients with heterozygous germline loss-of-function TET2 mutations who presented with B-cell lymphoma on a background of chronic lymphadenopathy and autoimmune features. This expands the association of germline TET2 mutations with lymphoma and an autoimmune lymphoproliferative syndrome-like phenotype to the heterozygous state. Assessment for TET2 mutations and germline origin should be considered in the appropriate context, as recognition of these variants may have implications on patient care.

Although CD20xCD3 bispecific antibodies (BsAbs) have demonstrated transformational activity in diffuse large B-cell lymphoma (DLBCL), some patients fail to respond and others relapse. To begin to explore possible limitations, we compared the in vitro activity of four CD20xCD3 biosimilar BsAbs against four DLBCL cell lines with CD20 expression ranging over a 100-fold. All four biosimilar BsAbs demonstrated superior in vitro activity to rituximab, with biosimilar glofitamab consistently being the most potent. Moreover, biosimilar glofitamab and odronextamab retained significant activity in the presence of low-level CD20 expression. Finally, one DLBCL cell line exhibited intrinsic resistance to all four CD20xCD3 BsAbs despite inducing marked T-cell and NK-cell activation.

In high-income countries, individuals with sickle cell disease (SCD) almost universally survive into adulthood, but transfer to adult SCD care is fraught. The young adult clinic (YAC) at our sickle cell centre was designed to provide developmentally appropriate, expert SCD care to young adults with SCD aged 18-30 years. In this retrospective cohort study, we measured YAC appointment attendance and scheduling attempts based on patient referral source and demographic characteristics. Between 1 March 2019 and 30 September 2023, 89% (170/192) of referred patients attended a YAC appointment, and 97% (77/79) of patients referred from paediatric SCD care attended a YAC appointment. Most patients attended their first scheduled appointment (61%, 105/170). Among rescheduled patients, the mean number of scheduling attempts before attendance was 2.9 (standard deviation 1.5). During the 55-month study period, this cohort had five deaths (3%) and seven successful haematopoietic stem cell transplants (4%). These results indicate that healthcare systems designed to meet the needs of young adults with SCD enable successful participation in adult SCD care. Resources to build robust adult SCD care systems are desperately needed, alongside research regarding optimal approaches to integrating young people into adult SCD care.

The peripheral blood lymphocyte-to-monocyte ratio (LMR) has been shown to predict outcomes in follicular lymphoma (FL). Among 1018 patients from the RELEVANCE trial (for previously untreated, high tumour burden FL), the median LMR was 2.5 (range, 0.3-93.5) and an LMR cut-off of 2 was mostly associated with survival end-points. Patients with an LMR ≤2 (n = 372; 37%) were older and had higher risk disease. An LMR ≤2 was associated with a shorter progression-free survival (PFS) (hazard ratio [HR] = 1.39, p = 0.002) and overall survival (OS) (HR = 1.44, p = 0.049). The association of the LMR with PFS was significant in the rituximab plus chemotherapy arm (p = 0.01) and inconclusive in the rituximab plus lenalidomide arm (p = 0.08). Within the three Follicular Lymphoma International Prognostic Index risk categories, the LMR retained its association with PFS only in the low-risk group (p = 0.03). An LMR ≤2 was also associated with a higher risk of progression of disease within 24 months of treatment initiation (univariable odds ratio (OR) = 1.84, p < 0.001; multivariable OR = 1.58, p = 0.02). In conclusion, the LMR is an easily accessible parameter informative of outcomes in FL patients in need of treatment, being especially helpful in otherwise low-risk patients. Whether the incorporation of immunomodulators such as lenalidomide will reduce its negative prognostic value needs to be further investigated.

The outcome of B-cell non-Hodgkin lymphoma (B-NHL) in children and adolescents has improved significantly over recent decades due to risk-adapted strategies and the use of immunotherapy. However, refractory or relapsed (R/R) B-NHL remains extremely difficult to cure (<30%). This retrospective study of 45 patients with R/R B-NHL reflects the limited benefit associated with reintroducing rituximab in second-line strategies, the importance of achieving complete remission before stem cell transplantation and the potential role of TP53 as a biomarker in R/R B-NHL. TP53 mutations were identified in 44% of tumours and associated with a worse 3-year overall survival (15% vs. 80%; p = 0.048).

Iron is required for key physiological processes, like oxygen transport, energy production and cell proliferation. Body iron homeostasis is regulated by the erythroferrone-hepcidin-ferroportin (FPN) axis, which mainly acts on absorptive duodenal cells and macrophages involved in iron recycling from red blood cell breakdown. In addition to systemic iron regulation, macrophages are also involved in local iron release to neighbouring cells. Similarly, bone marrow (BM)-resident macrophages could represent promptly available local sources of iron for developing haematopoietic cells. To study the impact of macrophage-released iron on BM haematopoietic stem and progenitor cells, we employed mice with targeted deletion of Fpn in the myeloid lineage (Fpn conditional knockout or Fpn-cKO). Fpn-cKO mice develop age-related anaemia and microcytaemia, reduction of BM erythroblasts and preferential megakaryopoiesis at the expenses of erythropoiesis, suggesting that red cells are mostly affected by the lack of myeloid-derived iron delivery. Transferrin receptor 1 surface expression is higher in Fpn-cKO mice than littermate controls in all the BM subpopulation analysed, starting from haematopoietic stem cells, indicating a broad BM sensitivity to lower iron availability. Last, Fpn-cKO mice activate systemic compensatory mechanisms, such as extramedullary haematopoiesis and erythroferrone upregulation, albeit not sufficient to overcome anaemia.

Erythropoiesis, the process of red blood cell (RBC) development from haematopoietic stem cells, is crucial in haematology research due to its intricate regulation and implications in various pathologies such as anaemia and haemoglobinopathies. Humanized mice, created by introducing human cells or tissues into immunodeficient mice, offer a promising avenue in vivo approach. However, challenges persist in fully replicating human erythropoiesis in these models, particularly in generating mature human RBCs capable of sustained circulation. This review discusses the differences between human and mouse erythropoiesis, recent progress made using refined humanized mouse models for studying human erythropoiesis and erythropoietic disorders, the challenges that impede a faithful mimicking of human phenotypes in these mice and recommendations for future research improvements. Despite progress being made, enhancing the translational potential of humanized mouse models for human erythropoiesis research remains a priority.