Secondary central nervous system lymphoma (SCNSL) remains a rare but challenging manifestation of aggressive lymphomas, with limited prospective data to guide treatment decisions in the modern therapeutic era. We conduct...Secondary central nervous system lymphoma (SCNSL) remains a rare but challenging manifestation of aggressive lymphomas, with limited prospective data to guide treatment decisions in the modern therapeutic era. We conducted a multicentre retrospective cohort study of 105 consecutively treated adult patients diagnosed with SCNSL between 2016 and 2024 across four German academic centres, capturing detailed treatment sequencing, response dynamics and outcome data. Median progression-free survival (PFS) was 7.62 months (95% CI 5.34-9.90), and median overall survival (OS) was 16.62 months (95% CI 5.91-27.33). Consolidation with high-dose chemotherapy and autologous haematopoietic stem cell transplantation (HDT-AHSCT) was associated with significantly improved OS and PFS in univariate and multivariate analyses. Achieving complete remission prior to HDT-AHSCT conferred with superior outcomes. In a small subset of patients with relapsed/refractory (rr) SCNSL, CD19-directed chimeric antigen receptor T-cell (CAR T) therapy showed favourable outcomes compared with non-transplant salvage therapy in exploratory univariate analysis (OS HR 0.28, 95% CI 0.08-0.94, p = 0.039; PFS HR 0.37, 95% CI 0.16-0.88, p = 0.025). In this contemporary multicentre real-world cohort, early response and consolidative HDT-AHSCT emerged as key determinants of durable disease control, while CAR T therapy may represent a salvage strategy for selected patients. These findings provide clinically relevant benchmarks to inform risk-adapted treatment sequencing in SCNSL.
Bruton's tyrosine kinase inhibitors (BTKi) are widely used in B-cell malignancies. Ibrutinib is associated with atrial fibrillation (AF), but comparative real-world evidence on AF risk across BTKi remains limited. We con...Bruton's tyrosine kinase inhibitors (BTKi) are widely used in B-cell malignancies. Ibrutinib is associated with atrial fibrillation (AF), but comparative real-world evidence on AF risk across BTKi remains limited. We conducted a nationwide new-user population study using the French national health insurance database (2015-2024). Adults initiating ibrutinib, acalabrutinib, zanubrutinib or venetoclax were included, excluding those with prior AF or non-overlapping BTKi indications. The primary outcome was AF requiring hospitalization. Hazard ratios (HRs) were estimated using Cox models with inverse probability of treatment weighting (IPTW). Among 26 393 patients, median follow-up ranged from 167 days in the zanubrutinib cohort to 526 days in the ibrutinib cohort. One-year incidence of hospitalized AF was highest with ibrutinib (2.3%) versus acalabrutinib (0.9%), zanubrutinib (0.7%) and venetoclax (0.5%). Ibrutinib was associated with a significantly higher AF risk versus acalabrutinib (HR 3.03, 95% confidence interval [CI] 1.84-5.00), zanubrutinib (HR 7.58, 95% CI 2.05-28.06) and venetoclax (HR 9.04, 95% CI 5.81-14.04). No significant differences in AF risk were observed between second-generation BTKi and venetoclax. Ibrutinib was associated with a substantially higher risk of hospitalized AF than second-generation BTKi, supporting closer cardiac monitoring in ibrutinib-treated patients.
Anaemia is a common global health problem affecting more than 500 million people worldwide. While N6-methyladenosine (mA) methylation is recognized as the most abundant internal (messenger ribonucleic acid (mRNA) modific...Anaemia is a common global health problem affecting more than 500 million people worldwide. While N6-methyladenosine (mA) methylation is recognized as the most abundant internal (messenger ribonucleic acid (mRNA) modification that governs haematopoiesis, its specific function in erythropoiesis remains poorly understood. Here, we demonstrate that Wilms tumour 1-associating protein (WTAP), a core component of the mA methyltransferase complex, is highly expressed in erythroid progenitors and is expressed at low levels during differentiation. Depletion of WTAP compromises erythropoiesis both in vivo and in vitro, characterized by a profound reduction in erythroid progenitors and increased erythroblast apoptosis. Mechanistically, our findings demonstrate that WTAP-mediated mA modification is indispensable for maintaining normal erythropoiesis, orchestrating a broader regulatory network in which the signal transducer and activator of transcription 5 (STAT5) pathway acts as a critical, albeit not exclusive, downstream effector.
Glomeruloid haemangiomas and extensive angiomas occurred in a small subset of Erdheim-Chester disease patients, all showing markedly elevated vascular endothelial growth factor-A (VEGF-A) levels despite the absence of PO...Glomeruloid haemangiomas and extensive angiomas occurred in a small subset of Erdheim-Chester disease patients, all showing markedly elevated vascular endothelial growth factor-A (VEGF-A) levels despite the absence of POEMS (polyneuropathy, organomegaly, M-spike, and skin disease) syndrome. Molecular analyses demonstrated mitogen-activated protein kinase (MAPK)-activated histiocytes without endothelial mutations, supporting a paracrine VEGF-A-driven angiogenesis mechanism underlying these atypical cutaneous lesions.
Interpretation of rare non-canonical MPL and CALR variants in myeloproliferative neoplasms (MPNs) remains challenging and frequently results in variants of uncertain significance (VUS). We explored whether these variants...Interpretation of rare non-canonical MPL and CALR variants in myeloproliferative neoplasms (MPNs) remains challenging and frequently results in variants of uncertain significance (VUS). We explored whether these variants share structural or electrostatic features with established MPN driver mutations. We studied 179 patients with BCR::ABL1-negative MPNs using targeted next-generation sequencing (NGS), structural modelling, in silico pathogenicity assessment and unsupervised phenotypic clustering. MPL variants were mapped according to transmembrane helical orientation, while CALR exon 9 variants were evaluated according to predicted C-terminal charge profiles. Eight patients (4.5%) harboured atypical molecular signatures, including non-canonical MPL and CALR variants. MPL V501A mapped to the same transmembrane activation face as the canonical W515 hotspot, whereas MPL R592Q localized away from this region. Rare CALR 34-bp deletions generated positively charged C-terminal tails similar to canonical pathogenic frameshifts, while a 12-bp in-frame deletion preserved the native acidic profile despite high variant allele frequency. Atypical cases showed clinical overlap with canonical MPN cohorts and clustered within related phenotypic groups on unsupervised analysis. Rare MPL and CALR variants may share structural and electrostatic features with established MPN drivers. Integrating receptor structure, charge effects and clinical phenotype may help contextualize atypical variants detected on routine NGS panels.
Puertas B, Padilla I, Alejo E
… +22 more, Serra-Toral F, García-Mateo A, López-López R, Bárez A, Alonso-Alonso JM, Aguilar-Franco C, de Cabo E, Cantalapiedra-Diez A, García-Coca A, Hernández R, Rey-Búa B, Fonseca-Santos M, López-Parra M, López-Corral L, Gutiérrez NC, Vidriales-Vicente MB, Pérez JJ, González-Calle V, Mateos MV, Escalante F, Flores-Montero J, Puig N
While measurable residual disease (MRD) in bone marrow (bmMRD) is a validated surrogate biomarker in multiple myeloma (MM), the clinical relevance of MRD in the apheresis product (aMRD) remains unclear. We retrospectivel...While measurable residual disease (MRD) in bone marrow (bmMRD) is a validated surrogate biomarker in multiple myeloma (MM), the clinical relevance of MRD in the apheresis product (aMRD) remains unclear. We retrospectively analysed 422 MM patients who underwent autologous stem cell transplantation (ASCT) between 2005 and 2023 at the University Hospital of Salamanca, all evaluated for aMRD by 8-colour flow cytometry. Overall, 45 patients (10%) were aMRD+ve and 377 (90%) were aMRD-ve, with similar baseline characteristics except for a higher frequency of t(11;14) in aMRD+ve cases. Patients with responses worse than a very good partial response before apheresis were six times more likely to be aMRD+ve (odds ratio [OR] 6.6, p = 0.006), and notably, no patients with bmMRD-ve status prior to apheresis were aMRD+ve. After ASCT, patients with aMRD+ve exhibited lower rates of complete response and bmMRD-ve than patients with aMRD-ve, leading to a shorter progression-free survival (hazard ratio 1.7, p = 0.006), and aMRD+ve status was identified as an independent predictor of early relapse (OR 9.75, p = 0.007). These findings may suggest that aMRD+ve serves as a critical early biomarker to identify suboptimal treatment responses, reflecting bmMRD persistence and predicting inferior clinical outcomes.
Amerikanou R, Munir T, Bowles K
… +13 more, McNamara C, Chavda N, Price E, Adiyodi J, Coles A, Kelsey P, Smith J, Adams R, Hussein H, Zhao R, Nguyen T, Collin M, Gohil S
Trametinib (MEK inhibitor) shows efficacy in refractory and high-risk adult histiocytic neoplasms. At a median follow-up of 21.4 months, the clinical response rate was 81% (30/37) and the radiological response was 68% (2...Trametinib (MEK inhibitor) shows efficacy in refractory and high-risk adult histiocytic neoplasms. At a median follow-up of 21.4 months, the clinical response rate was 81% (30/37) and the radiological response was 68% (25/37) (n = 37).
Early identification of patients at risk of failing first-line therapy remains a key challenge in primary mediastinal B-cell lymphoma (PMBCL). This study assessed whether positron emission tomography (PET) radiomics coul...Early identification of patients at risk of failing first-line therapy remains a key challenge in primary mediastinal B-cell lymphoma (PMBCL). This study assessed whether positron emission tomography (PET) radiomics could predict treatment outcomes in PMBCL. Baseline PET/computed tomography (CT) scans from 501 patients enrolled in the International Extranodal Lymphoma Study Group 37 (IELSG37) trial and treated with rituximab- and doxorubicin-based immunochemotherapy were analysed. Functional PET parameters reflecting tumour burden (metabolic tumour volume, MTV), glucose consumption (total lesion glycolysis, TLG) and metabolic heterogeneity (MH) were calculated using a 25% maximum standard uptake value (SUVmax) segmentation threshold. Radiomic analysis was performed in 495 patients, extracting 107 features; 74 features uncorrelated with SUVmax and MTV were selected and analysed using a recursive-partitioning classification tree (Ctree) approach. Ctree identified grey-level run-length matrix run variance (GLRLM-RV), a marker of MH, as the most significant prognostic feature. Patients with low MH (GLRLM-RV <0.136) had a 5-year progression-free survival (PFS) of 93%, compared with 65% in those with high MH (p < 0.0001). Five-year overall survival (OS) was 96% vs. 80% respectively (p < 0.0001). A subsequent Ctree model integrating GLRLM-RV and TLG further improved prognostic stratification for PFS and OS (p < 0.0001), outperforming established prognostic indices (International Prognostic Index [IPI], revised-IPI and age-adjusted IPI).
Silent cerebral infarctions (SCIs) are present in patients with a diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) at a younger age and with a higher prevalence than in the general population. Prio...Silent cerebral infarctions (SCIs) are present in patients with a diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) at a younger age and with a higher prevalence than in the general population. Prior history of stroke, cardiovascular disease and diabetes are risk factors for SCI in patients with a prior diagnosis of iTTP. Commentary on: Javed et al. Risk factors for silent cerebral infarction in immune-mediated thrombotic thrombocytopenic survivors. Br J Haematol 2026;208(2):654-660.
Hall A, Croft J, Walker K
… +12 more, Boyd K, Roberts S, Holroyd A, Garg M, Ferris E, Cook G, Pierceall WE, Thakurta A, Gandhi A, Pawlyn C, Brown SR, Kaiser M
There is an ongoing need for accessible combination therapies for patients with relapsed-refractory multiple myeloma (RRMM), alongside a growing interest in understanding their immunological effects, particularly on T-ce...There is an ongoing need for accessible combination therapies for patients with relapsed-refractory multiple myeloma (RRMM), alongside a growing interest in understanding their immunological effects, particularly on T-cell populations. Myeloma UK (MUK) MUKseven (NCT02406222) was an academic, UK multicentre randomized controlled, open-label phase 2 trial. The planned sample size was 250 patients but recruitment was stopped early due to changes in standard of care. Between 2016 and 2018, 104 RRMM patients from 26 UK hospitals were recruited and randomized to receive cyclophosphamide, pomalidomide, and dexamethasone (CPd) or pomalidomide and dexamethasone (Pd) using minimization. Fifty-four participants in each arm were analysed. The primary end-point, progression-free survival (PFS) was not met with median 6.9 months (95% Confidence Interval (CI): 5.7-10.4) for CPd versus 4.6 months for Pd (95% CI: 3.5-7.4), although not significant; reflecting underpowering from early closure. CPd showed a higher overall response rate, and toxicity was comparable to previously reported Pd regimens. Peripheral blood T-cell analysis revealed stronger and more sustained enrichment of CD3+ T cells, HLA-DR-positive CD8+ and CD8+ effector memory cells in the CPd arm. Pretreatment CD4+ T-cell levels were identified as a prognostic PFS marker. In summary, our results demonstrate significant effects of cycloaddition to Pd on response and T-cell composition.
Itonaga H, Fukushima T, Kato K
… +20 more, Muranushi H, Tokunaga M, Miyazono T, Ito A, Eto T, Suehiro Y, Kato T, Fujioka M, Kawakita T, Uchida N, Mori Y, Yoshimitsu M, Nakamae H, Morichika K, Ishitsuka K, Kanda J, Fukuda T, Atsuta Y, Fuji S, ATL working groups of the Japanese Society for Transplantation and Cellular Therapy
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers potentially curative outcomes for adult T-cell leukaemia/lymphoma (ATL), but post-transplant refractory/relapsed (R/R) ATL is associated with poor ou...Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers potentially curative outcomes for adult T-cell leukaemia/lymphoma (ATL), but post-transplant refractory/relapsed (R/R) ATL is associated with poor outcomes. Advances have been made in transplant modalities, novel targeted agents and supportive care; however, it remains unclear whether these advances have improved survival outcomes of post-transplant R/R ATL. To clarify changes in survival after post-transplant R/R, we evaluated the survival outcomes in 1146 patients over a 24-year period, using a nationwide database. The period was divided into three groups: 1999-2010 (early period, as reference), 2011-2016 (middle period) and 2017-2022 (late period). In patients with refractory ATL, multivariate analyses showed no significant difference in overall mortality (OM) after post-transplant refractory in the early and middle periods, but a significantly lower OM in the late period than in the early period (hazard ratio [HR], 0.73 [95% confidence interval, 0.55-0.96]). In patients with relapsed ATL, OM after post-transplant relapse was significantly lower in the middle (HR 0.62 [0.48-0.80]) and late periods (HR 0.68 [0.52-0.90]) than in the early period. Thus, recent advances appear to have contributed to increased opportunities for therapeutic interventions, leading to improved survival outcomes in patients with post-transplant R/R ATL.
Xu Y, Wang Y, Wang N
… +27 more, He L, Ling J, Jin M, Xie B, Le S, Huang M, Peng J, Cheng H, Jin J, Zhou L, Zhou Z, Gai C, Zhang Y, Sun M, Li X, Yin J, Cheng Y, Xue A, Xu W, Han H, Zhang F, Zhu W, He S, Zhou H, Zhang L, Xue F, Yang R
Emicizumab is an established prophylactic therapy for haemophilia A (HA). However, real-world multicentre evidence on long-term outcomes, particularly in a resource-constrained setting, remains limited. We aimed to evalu...Emicizumab is an established prophylactic therapy for haemophilia A (HA). However, real-world multicentre evidence on long-term outcomes, particularly in a resource-constrained setting, remains limited. We aimed to evaluate real-world outcomes in patients with HA receiving emicizumab prophylaxis across multiple centres with extended follow-up. We conducted a multicentre retrospective study of patients with HA who received emicizumab prophylaxis for ≥1 year across 25 centres. Outcomes included annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), bleeding events, target joint status and adverse events. A total of 132 patients (131 males and 1 female) were included, with a median age at switch of 2.0 years (interquartile range [IQR], 1.0-4.8). Over a median follow-up of 26 months (IQR: 16.0-40.0), the negative binomial regression model-based ABR for all bleeds was 0.81 (95% confidence interval [CI], 0.62-1.07). Across 12-month intervals, both calculated mean and negative binomial regression model-based AJBR remained between 0.1 and 0.3. Of the 74 baseline target joints, 95.9% (n = 71) resolved and no new target joints developed. Forty-two patients (31.8%) received factor concentrates during emicizumab treatment. Injection-site reactions occurred in 7.6% of patients, with no thromboembolic or fatal events observed. Long-term emicizumab prophylaxis provides sustained bleeding control, joint protection and a favourable safety profile.
Response assessment in diffuse large B-cell lymphoma (DLBCL) has traditionally relied on anatomical and metabolic imaging, with fluorodeoxyglucose positron emission tomography (FDG-PET)-defined complete metabolic remissi...Response assessment in diffuse large B-cell lymphoma (DLBCL) has traditionally relied on anatomical and metabolic imaging, with fluorodeoxyglucose positron emission tomography (FDG-PET)-defined complete metabolic remission representing the principal end-point of first-line therapy. However, growing evidence indicates that metabolic control does not necessarily correspond to clonal eradication. Circulating tumour deoxyribonucleic acid (ctDNA)-based minimal residual disease (MRD) assessment offers a complementary perspective by detecting systemic clonal persistence rather than localized tumour burden. In this review, we synthesize biological, methodological and clinical evidence showing that PET and MRD capture distinct and only partially overlapping dimensions of treatment response. We discuss biological implications of PET-negative/MRD-positive status, which may represent occult residual disease driven by subthreshold metabolic activity, diffuse low-volume dissemination or microenvironment-mediated resistance. MRD may therefore refine prognostic stratification beyond PET, particularly among patients achieving complete metabolic responses. Nevertheless, technical variability, limited standardization and insufficient prospective validation currently limit its use as a routine therapeutic decision trigger. Emerging frameworks integrating PET and MRD, especially within adaptive clinical trials, conceptualize response as a dynamic biological process rather than a static classification. Overall, metabolic remission likely reflects control of dominant tumour compartments, whereas MRD detection identifies persisting therapy-resistant clones. Integrating both dimensions may improve interpretation and guide therapeutic strategies.
Wang et al. Ibrutinib plus venetoclax for relapsed/refractory mantle cell lymphoma: Final analysis of the phase 3 SYMPATICO study. Br J Haematol (Online ahead of print).Wang et al. Ibrutinib plus venetoclax for relapsed/refractory mantle cell lymphoma: Final analysis of the phase 3 SYMPATICO study. Br J Haematol (Online ahead of print).
To identify key cytokines for the differentiation and treatment monitoring of haemophagocytic lymphohistiocytosis (HLH). We retrospectively analysed the clinical data and cytokine profiles from 66 patients with HLH, seps...To identify key cytokines for the differentiation and treatment monitoring of haemophagocytic lymphohistiocytosis (HLH). We retrospectively analysed the clinical data and cytokine profiles from 66 patients with HLH, sepsis, Kawasaki disease (KD) and infectious mononucleosis (IM). Hierarchical clustering analysis was performed among those diseases. The diagnostic value of the markers was assessed using logistic regression and receiver operating characteristic (ROC) curves. Longitudinal changes in cytokines were detected in HLH patients. Cluster analysis revealed substantial overlap in the cytokine profiles between HLH and IM, characterized by high levels of C-X-C motif chemokine ligand 9 (CXCL9), C-X-C motif chemokine ligand 10 (CXCL10), interferon-gamma (IFN-γ), soluble cluster of differentiation 25 (sCD25) and interleukin-18 (IL-18). The cytokine profiles differed from sepsis and KD patients. The combined detection of CXCL9 and haemoglobin (Hb) achieved an area under the curve (AUC) of 0.943 for distinguishing Epstein-Barr virus-related HLH (EBV-HLH) from IM. CXCL9 was significantly correlated with aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in HLH patients. Moreover, high levels of CXCL9 were associated with more severe clinical manifestations. During the monitoring of HLH cases, trends in CXCL9 and LDH levels correlated with disease progression.In conclusion, differences in cytokine profiles contribute to disease differentiation, and detection of CXCL9 holds promise for HLH diagnosis and longitudinal monitoring.