Nador G, Vijjhalwar R, Javaid MK
… +2 more, Edwards CM, Ramasamy K
Br J Haematol
· 2026 Jun · PMID 41948808
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Multiple myeloma (MM) is a haematological malignancy characterised by clonal plasma cell accumulation in the bone marrow, frequently resulting in myeloma bone disease. Disruption of bone homeostasis, driven by increased...Multiple myeloma (MM) is a haematological malignancy characterised by clonal plasma cell accumulation in the bone marrow, frequently resulting in myeloma bone disease. Disruption of bone homeostasis, driven by increased osteoclastic resorption and suppressed osteoblastic formation, leads to osteolytic lesions and skeletal-related events, contributing substantially to morbidity and mortality. Bone turnover markers (BTMs) provide a non-invasive means of assessing bone metabolism, with potential applications in disease monitoring, prognostication, risk stratification from monoclonal gammopathy of undetermined significance (MGUS) to MM and evaluation of response to myeloma and osteoporosis therapies. This review examines the clinical relevance of BTMs in plasma cell dyscrasias, including MM, MGUS and smouldering MM. Bone formation markers, such as bone-specific alkaline phosphatase and procollagen type I N-terminal propeptide, reflect osteoblastic activity, while resorption markers, including carboxy-terminal collagen crosslinks and deoxypyridinoline, indicate osteoclastic activity. Although several BTMs correlate with disease burden and progression, their routine clinical use is limited by biological variability, renal impairment and lack of assay standardisation. As myeloma therapies continue to evolve, further research is needed to define the role of BTMs alongside imaging and clinical risk models to optimise bone disease management.
Yamashita N, Kawakami T, Matsuzawa S
… +9 more, Miyairi S, Maruyama M, Kawakami F, Kojima S, Yanagisawa R, Higuchi Y, Makishima H, Nakazawa H, Ishida F
Br J Haematol
· 2026 May · PMID 41943918
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T-cell abnormalities have been implicated in the pathogenesis of acquired pure red cell aplasia (PRCA), particularly in its major subtypes such as idiopathic PRCA, thymoma-associated PRCA and large granular lymphocytic l...T-cell abnormalities have been implicated in the pathogenesis of acquired pure red cell aplasia (PRCA), particularly in its major subtypes such as idiopathic PRCA, thymoma-associated PRCA and large granular lymphocytic leukaemia (LGLL)-associated PRCA, and the precise details remain unclear. Furthermore, signal transducer and activator of transcription 3 (STAT3) mutations are frequently detected in PRCA patients, but their association with cellular immune abnormalities is not well understood. In order to elucidate the immunogenetic backgrounds of PRCA, we conducted human leucocyte antigen (HLA) typing in 39 PRCA patients. The results showed a significantly higher allele frequency of HLA-B*44:03:01, -C*14:03, -DRB1*13:02, compared to HLA database. Additionally, analysis of inferred HLA haplotypes revealed significantly increased frequencies of two haplotypes: HLA-A*24:02-C*07:02-B*07:02-DRB1*01:01 and -A*33:03-C*14:03-B*44:03:01-DRB1*13:02. Clonotypic analyses of T-cell receptor beta (TCRβ) chain revealed that 80% of the PRCA cases possessed mono- or oligoclonally expanded T cells. Particularly among those with STAT3 mutations, the 'QGXG' motif in 15 AA sequences of TCRβ complementarity-determining regions 3 (CDR3) regions was specifically recognized. These findings suggest that a specific immunogenetic background defined by particular HLA alleles, the expansion of somewhat limited T-cell clones and STAT3-mutated T cells are involved in the pathogenesis of chronic acquired PRCA.
Br J Haematol
· 2026 May · PMID 41940437
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Pure red cell aplasia (PRCA) is increasingly recognised as a T-cell-mediated bone marrow failure syndrome, yet its immunogenetic drivers remain poorly defined. In their paper, Yamashita et al. integrate human leucocyte a...Pure red cell aplasia (PRCA) is increasingly recognised as a T-cell-mediated bone marrow failure syndrome, yet its immunogenetic drivers remain poorly defined. In their paper, Yamashita et al. integrate human leucocyte antigen (HLA) typing, T-cell receptor repertoire analysis and mutational profiling to reveal enriched HLA alleles, signal transducer and activator of transcription 3 (STAT3)-mutated T-cell clones and a shared T cell receptor beta (TCRβ) motif in PRCA patients. These findings suggest that antigen-driven cytotoxic T-cell responses represent a central mechanism underlying erythroid suppression. Commentary on: Yamashita et al. Immunological features of acquired pure red cell aplasia: Specific human leucocyte antigen alleles, signal transducer and activator of transcription 3 mutations and a unique T- cell receptor beta motif. Br J Haematol 2026; 208:1797-1805.
Le Louet S, Brunaud C, Barkaoui M
… +22 more, Chevallier A, Chalard F, Mansuy L, Salmon A, Buchbinder N, Azarnoush S, Pertuisel S, Thomas C, Kuhle J, Maleska A, Desplantes C, Marec-Bérard P, Pagnier A, Isfan F, Aladjidi N, Saultier P, Jeziorski E, Thalhammer J, Idbaih A, Emile JF, Heritier S, Donadieu J
Neurodegeneration (ND) is a severe complication of Langerhans cell histiocytosis (LCH), often leading to progressive neurological decline. We evaluated the usefulness of using plasma and cerebrospinal fluid neurofilament...Neurodegeneration (ND) is a severe complication of Langerhans cell histiocytosis (LCH), often leading to progressive neurological decline. We evaluated the usefulness of using plasma and cerebrospinal fluid neurofilament light chain (p- and CSF-NFL) levels as biomarkers to identify and monitor ND-LCH. NFL levels were measured using the single-molecule array for a subset of patients from the French National LCH Registry. NFL levels in 692 plasma and 115 CSF samples from 273 registry-enrolled children were analysed. Based on 84 paired plasma and CSF samples from 67 patients, p- and CSF-NFL levels were strongly correlated (p < 0.0001). The areas under the receiver operating characteristics curves for ND-LCH were 72% (95% confidence interval [CI], 64%-78%) for p-NFL and 94% (95% CI, 88%-98%) for CSF-NFL. The highest p-NFL (13.7 vs. 7.2 pg/mL; z-score 2.3 vs. 0.6) and CSF-NFL (436.9 vs. 65.2 pg/mL) levels were significantly higher for ND-LCH than in no-ND-LCH patients, respectively (p < 0.0001). Plasma NFL levels were not elevated at LCH diagnosis. At LCH diagnosis, p-NFL was not predictive of ND, but it may serve as a minimally invasive screening tool for ND in LCH, although optimal timing remains to be determined.
Cerebrovascular accidents are serious complications of sickle cell disease (SCD). Children with abnormal transcranial Doppler (TCD) readings are at higher risk for stroke, and those with prior strokes have increased risk...Cerebrovascular accidents are serious complications of sickle cell disease (SCD). Children with abnormal transcranial Doppler (TCD) readings are at higher risk for stroke, and those with prior strokes have increased risk of recurrence. Chronic blood transfusion therapy (BTT) is the standard treatment for stroke prevention; hydroxyurea (hydroxycarbamide [HU]), a recommended alternative, is less effective. This study explores the use of modified short BTT combined with HU for stroke prevention in SCD. We reviewed medical records of 170 children (ages 2-16) with abnormal TCD or prior stroke treated with monthly BTT for 6-8 months and HU. TCD results and stroke incidence were assessed 1 year after discontinuing BTT. Among the children, 136 (80%) had abnormal TCD, 15 (11.2%) had current stroke and 19 (8.8%) had prior stroke. After discontinuation of BTT, abnormal TCD readings decreased significantly to 18.7% and 16.9% (p < 0.05); those with normal TCD increased significantly from 38.8% to 52.8% (p < 0.05) after 1 year. TCD velocity decreased significantly during the same period (p < 0.05). Only 2 (1.5%) children with abnormal TCD experienced stroke. Overall, 13 (7.8%) had stroke by 1-year post BTT. In conclusion, the combination of short-course BTT and HU significantly reduced stroke risk and incidence of stroke in children with SCD.
Itonaga H, Miyazaki Y, Tachi N
… +21 more, Kurosawa S, Marumo A, Konuma T, Ebina T, Doki N, Uchida N, Fukuda T, Nishida T, Katayama Y, Asada N, Sakurai M, Maeda T, Eto T, Tanaka M, Nakamae H, Onizuka M, Kawamura K, Kanda Y, Atsuta Y, Tachibana T, adult MDS and CML/MPN working groups of the Japanese Society for Transplantation and Cellular Therapy
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers a curative potential for myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN). We examined survival trends using...Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers a curative potential for myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN). We examined survival trends using a nationwide database of 7175 patients who underwent their first allo-HSCT between 1998 and 2022. Overall mortality decreased over time in patients with early MDS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.65-0.97, p = 0.026 in 2013-2017; HR 0.54, 95% CI 0.42-0.70, p < 0.001 in 2018-2022), advanced MDS (HR 0.80, 95% CI 0.71-0.90, p < 0.001 in 2013-2017; HR 0.74, 95% CI 0.65-0.85, p < 0.001 in 2018-2022), chronic myelomonocytic leukaemia (HR 0.45, 95% CI 0.32-0.64, p < 0.001 in 2013-2017; HR 0.53, 95% CI 0.37-0.74, p < 0.001 in 2018-2022) and atypical chronic myeloid leukaemia (HR 0.32, 95% CI 0.13-0.80, p = 0.016 in 2013-2017; HR 0.26, 95% CI 0.10-0.68, p = 0.006 in 2018-2022). These decreases in overall mortality were mainly attributable to reductions in non-relapse mortality. Meanwhile, no significant difference in overall mortality was observed in patients with MDS/MPN-unclassified and therapy-related myeloid neoplasm. Across all disease subtypes, relapse incidence did not significantly decrease over time, highlighting persistent challenges in reducing the risk of post-transplant relapse.
Pregnancy complicated by aplastic anaemia (AA) is rare but high risk, with historically poor maternal-fetal outcomes. Contemporary multidisciplinary management may improve prognosis, underscoring the need to clarify curr...Pregnancy complicated by aplastic anaemia (AA) is rare but high risk, with historically poor maternal-fetal outcomes. Contemporary multidisciplinary management may improve prognosis, underscoring the need to clarify current outcomes and risk factors. We conducted a single-centre retrospective cohort study of 54 women with AA who had a total of 65 pregnancies, including those diagnosed with AA during pregnancy (n = 8) and those with a pre-existing AA diagnosis (n = 57). Most patients with new-onset AA presented with severe cytopenia at diagnosis. Although none responded to therapy during pregnancy, all six who continued their pregnancies had live births; two opted out due to severe cytopenia. In the pre-existing AA group, 88% of pregnancies resulted in live births, with a 47% rate of severe maternal or fetal complications. Pre-delivery haemoglobin and platelet counts were significantly lower in the complication group (73 g/L and 20 × 10/L vs. 85 g/L and 29 × 10/L, p < 0.05). Active disease (relapse or lack of remission) before delivery was strongly associated with adverse outcomes (78% vs. 37%, p = 0.002). No maternal deaths or neonatal haematological abnormalities were observed. Pregnancy with AA can achieve favourable outcomes with multidisciplinary management. Pre-delivery disease activity and haematological parameters (haemoglobin and platelet counts) are significant predictors of complications.
de Wilde JRA, Kuppens GZL, Boesveld ME
… +7 more, van Vuren AJ, van Solinge WW, Waanders E, van Beers EJ, Rab MAE, Bartels M, van Wijk R
Br J Haematol
· 2026 May · PMID 41914049
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Hereditary spherocytosis (HS) is a hereditary haemolytic anaemia, caused by pathogenic variants in genes encoding red blood cell membrane proteins. Osmotic gradient ektacytometry evaluates red cell deformability and hydr...Hereditary spherocytosis (HS) is a hereditary haemolytic anaemia, caused by pathogenic variants in genes encoding red blood cell membrane proteins. Osmotic gradient ektacytometry evaluates red cell deformability and hydration and is increasingly used in the diagnosis of HS. We retrospectively evaluated laboratory data from 233 HS patients focusing on osmotic gradient ektacytometry parameters, including two novel parameters, O-width and O-width. We found that the maximum elongation index (EI), representing the maximum deformability, was decreased in SPTB relative to SLC4A1 and SPTA1 (0.509 vs. 0.557 and 0.564, both p < 0.01). Hydration was most affected in SLC4A1, with the lowest median O (416 mOsm/kg). The novel parameters also showed differences: O-width was higher in SPTB and ANK1 compared to SLC4A1 and SPTA1 (p < 0.05). O-width was lowest in SLC4A1 (92 mOsm/kg). We found that non-missense variants, opposed to missense variants, were associated with decreased deformability in SPTB and ANK1 subgroups as well as with decreased hydration in the ANK1 subgroup specifically (O missense 472 mOsm/kg vs. non-missense 436 mOsm/kg). Lastly, when classifying disease severity based on reticulocyte production index, we found that O, EI, area under the curve (AUC), O-width and O-width differed between mild and moderate patients (all p < 0.05). Our findings suggest that osmotic gradient ektacytometry provides additional information on HS pathophysiology and clinical severity.
Allsup DJ, Cairns DA, Samy EF
… +21 more, Duley L, Bloor A, Varghese A, Meads D, Dawkins B, Girvan S, Howard DR, Hockaday A, Brown JM, Jackson S, Greatorex N, Templeton P, Tupper M, Phillips D, Yaqub S, Mortimer D, Stones D, Patten PEM, Rawstron A, Hillmen P, Munir T
Br J Haematol
· 2026 May · PMID 41912408
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Front-Line therapy in CLL: Assessment of Ibrutinib-containing Regimens (FLAIR) demonstrated improved progression-free survival for ibrutinib and rituximab (IR) compared with fludarabine, cyclophosphamide and rituximab (F...Front-Line therapy in CLL: Assessment of Ibrutinib-containing Regimens (FLAIR) demonstrated improved progression-free survival for ibrutinib and rituximab (IR) compared with fludarabine, cyclophosphamide and rituximab (FCR) in previously untreated chronic lymphocytic leukaemia (CLL). This report presents the secondary end-point of health-related quality of life (HR-QoL). FLAIR was a phase 3, open-label, randomised trial across 101 hospitals. Eligible patients were aged 18-75 years, World Health Organization performance status (PS) ≤2, requiring treatment; those with >20% 17p deletion were excluded. IR was administered for up to 6 years and FCR for six cycles. Participants completed European Organisation for Research and Treatment of Cancer Quality of Life C30 Questionnaire (EORTC-QLQ-C30), QLQ CLL Module (QLQ-CLL16), three-level EQ-5D (EQ-5D-3L) and EQ5D visual analogue (EQ-VAS) at baseline and follow-up. Function and symptom trajectories were analysed using repeated-measures multilevel regression. 84.4% of participants completed baseline questionnaires and subsequent compliance was 67.6%-83.5%. Median age was 63 years; most participants were white and male. HR-QoL trajectories were similar. FCR recipients had worse scores at end of treatment but recovered thereafter. By 48 months, more FCR-treated participants showed meaningful improvements in several scales. Statistically significant differences (p < 0.05) favoured IR for physical, role and social function; emotional function favoured FCR. Diarrhoea was more common with IR; fatigue and dyspnoea were more common with FCR, though differences did not exceed minimally important thresholds. Overall, scales were comparable between treatment groups, indicating that continuous IR does not compromise HR-QoL.
Arcaini L, Merli M, Rattotti S
… +23 more, Nizzoli ME, Tarantino V, Consoli C, Talami A, Murru R, Deodato M, Cencini E, Re F, Visco C, Duffles G, Spina M, Annibali O, Pulsoni A, Ferreri AJM, Stelitano C, Pennese E, Varettoni M, Cappello E, Favrin G, La Fauci M, Marcheselli L, Paulli M, Luminari S
Br J Haematol
· 2026 Jun · PMID 41905881
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Caserta S, Martino EA, Skafi M
… +11 more, Alvaro ME, Bruzzese A, Amodio N, Fiorillo M, Lucia E, Olivito V, Labanca C, Mendicino F, Vigna E, Morabito F, Gentile M
Br J Haematol
· 2026 May · PMID 41905770
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Mature T-cell lymphomas comprise a heterogeneous group of aggressive non-Hodgkin lymphomas with limited therapeutic options in the relapsed or refractory setting. Among them, anaplastic lymphoma kinase (ALK)-positive ana...Mature T-cell lymphomas comprise a heterogeneous group of aggressive non-Hodgkin lymphomas with limited therapeutic options in the relapsed or refractory setting. Among them, anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) represents a biologically distinct subtype driven by constitutive activation of ALK fusion proteins, which promote oncogenic signalling through signal transducer and activator of transcription 3, phosphatidylinositol 3-kinase (PI3K)/AKT Serine/Threonine Kinase 1 (AKT)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase pathways. This molecular dependency provides a strong mechanistic rationale for targeted ALK inhibition. Small-molecule ALK inhibitors, including crizotinib, have demonstrated high overall response rates (67%-88%) and complete remission rates (~60%-80%) in relapsed or refractory ALK-positive ALCL, often with rapid clinical responses. Next-generation ALK inhibitors have shown activity in patients who progress on crizotinib, supporting the concept of sequential ALK-targeted therapy to overcome acquired resistance. Resistance mechanisms include secondary ALK kinase domain mutations, such as L1196M and G1202R, as well as activation of compensatory signalling pathways, including PI3K/AKT/mTOR, underscoring the importance of molecular reassessment at relapse and the potential role of rational combination strategies. This review critically summarizes the molecular basis of ALK-driven lymphomagenesis, evaluates the clinical evidence supporting ALK-targeted therapy and discusses mechanisms of resistance. In addition, it explores emerging strategies for integrating ALK inhibitors into precision-based management of T-cell lymphomas, including combination approaches with chemotherapy, immunotherapy or antibody-drug conjugates. Collectively, these developments highlight a paradigm shift towards biology-driven, personalized therapy in ALK-positive ALCL.
Chronic active Epstein-Barr virus disease (CAEBV), an Epstein-Barr virus (EBV)+ T/Natural Killer (NK)-cell lymphoproliferative disorder, remains critically undefined in treatment and prognostic stratification due to its...Chronic active Epstein-Barr virus disease (CAEBV), an Epstein-Barr virus (EBV)+ T/Natural Killer (NK)-cell lymphoproliferative disorder, remains critically undefined in treatment and prognostic stratification due to its rarity. We analysed 149 paediatric systemic CAEBV patients, of whom 134 received LDEP (liposomal doxorubicin, etoposide, pegylated asparaginase and methylprednisolone) chemotherapy as a bridge to haematopoietic stem cell transplantation (HSCT). Diagnostic delay was common (median 6.0 months), with 41.6% presenting atypically with localized symptoms at onset. Haemophagocytic lymphohistiocytosis developed in 50.3%. EBV infection involved pan-lymphoid lineages in 85.2%, with NK-cell predominance (44.3%) enriched in the hydroa vacciniforme/severe mosquito bite allergy subtype. LDEP induced favourable response in 59.0%, significantly improving HSCT rates (98.7% vs. 69.1%). Overall, 127 patients (85.2%) underwent HSCT, with 3-year post-transplant survival of 84.5% ± 3.5%. Inferior post-HSCT survival was independently associated with active disease at transplantation (hazard ratio [HR] = 6.17, p < 0.001) and also linked to longer chemotherapy-to-HSCT interval (>3.5 months) and poor LDEP response. Non-transplanted patient had 90.9% mortality. The entire cohort had a 3-year overall survival of 72.6% from diagnosis, with poor LDEP response, hepatic dysfunction and leucopenia as independent risk factors. This large paediatric cohort defines the clinical spectrum of CAEBV, establishes LDEP as an effective bridging regimen to HSCT-particularly in early-stage disease-and highlights the need for early disease activity control and timely transplantation.
Br J Haematol
· 2026 May · PMID 41889201
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Clinical decision-making based on myeloma-defining event criteria using thresholds for involved serum free light chain level of 10 mg/dL and ratio of involved to uninvolved light chain of >100 is a poor indicator for the...Clinical decision-making based on myeloma-defining event criteria using thresholds for involved serum free light chain level of 10 mg/dL and ratio of involved to uninvolved light chain of >100 is a poor indicator for the risk of progression to multiple myeloma. Poor performance of this criterion can be attributed to (a) methodological flaws in the publication on which the light chain level and ratio figures are based, (b) failure to apply light chain type-specific criteria for kappa and lambda chain-associated lesions, (c) 'drift' in the antibody reactivity for free kappa light chains resulting in higher values in more recent testing, (d) lack of high-sensitivity imaging in earlier studies resulting in inclusion of patients with occult multiple myeloma, and (e) evidence from newer studies showing much lower risk of progression to myeloma than presented initially. The light chain level and ratio-based criterion for myeloma-defining event, in its current form, ought to be removed from the International Myeloma Working Group guidelines. The criterion should be revised by collection of prospective data from multiple institutions using standardized patient selection criteria with emphasis on high-sensitivity imaging studies to exclude occult multiple myeloma patients, subgrouping patients by intact immunoglobulin smouldering multiple myeloma (SMM); light chain SMM; heavy chain and light chain type of lesion; and application of light chain type-specific levels per gram of monoclonal immunoglobulin, measuring monoclonal light chains. Both static and dynamic measures should be collected, followed by rigorous statistical analysis to identify parameters predicting risk of progression to multiple myeloma in 2 years.
Gozzetti A, Pacelli P, Caroni F
… +22 more, Raspadori D, Bestoso E, Antonioli E, Buda G, Ciofini S, Santoni A, Puccetti L, Bacchiarri F, Pengue L, Tocci D, Attucci I, Del Giudice ML, Ruggieri M, Lombardo A, Liberati AM, Candi V, Sammartano V, Cartocci A, Sicuranza A, Galimberti S, Vannucchi AM, Bocchia M
Br J Haematol
· 2026 Jun · PMID 41888038
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Daratumumab is approved for front-line and relapsed myeloma therapy. Here, we evaluated daratumumab in multiple myeloma patients already in ≥very good partial response but minimal residual disease (MRD) positive by next-...Daratumumab is approved for front-line and relapsed myeloma therapy. Here, we evaluated daratumumab in multiple myeloma patients already in ≥very good partial response but minimal residual disease (MRD) positive by next-generation flow after first-line therapy and daratumumab naïve with the potential to eradicate the disease. In this prospective, single-arm phase 2 trial, we consecutively evaluated 110 eligible patients with newly diagnosed multiple myeloma for positivity at 10 in the bone marrow. Fifty patients were positive and were treated with 6 months of daratumumab. The primary end-point was at 6 months: MRD-negative patients stopped treatment, while positive patients continued for a total of 24 months. At the primary end-point, 15/50 (30%) patients became MRD negative. At 24 months, 11/50 (22%) patients were still MRD negative. At a median follow-up of 50 months, 29 (58%) patients relapsed. Median progression-free survival is reached at 45 months, and overall survival is not reached. Achieving at least one-time MRD negativity was significant (median progression-free survival of 61 vs. 26 months, p = 0.0009). Of 50 patients, 21 did not progress at a median time of 44 months (range 31-73) and four of the relapsed patients are still in duration of response, not treated yet.