Br J Haematol
· 2026 Jun · PMID 41992976
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Mixed phenotype acute leukaemia (MPAL) is a rare subtype of acute leukaemia possessing significant therapeutic challenges, as no standardized, evidence-based treatment regimen has been defined. In this nationwide study,...Mixed phenotype acute leukaemia (MPAL) is a rare subtype of acute leukaemia possessing significant therapeutic challenges, as no standardized, evidence-based treatment regimen has been defined. In this nationwide study, we aimed to assess the effect of an acute lymphoid leukaemia (ALL)-like regimen; an acute myeloid leukaemia (AML)-like regimen; and a hybrid regimen on complete remission (CR), overall survival (OS) and event-free survival (EFS). Patients were identified through the Danish National Pathology Registry and validated according to the 2022 WHO classification. OS was estimated using the Kaplan-Meier estimator, and differences in OS were assessed with the log-rank test. Inverse probability weighting was used to balance compared groups with respect to age and calendar year. Among the 43 intensively treated WHO 2022 MPAL patients, 25 (58.1%) received ALL regimens, 10 (23.3%) received AML regimens and 8 (18.6%) received hybrid regimens. CR rates by treatment regimen were highest for hybrid regimen (87.5% (95% confidence interval (CI): 47.3%-99.7)), followed by ALL regimen (72% (95% CI: 50.6%-87.5%)) and AML regimen (40% (95% CI: 12.2%-73.8%)). Treatment with hybrid regimens consisting of a fludarabine-based approach (fludarabine, cytarabine, G-CSF and idarubicin [FLAG-IDA], fludarabine, cytarabine, G-CSF and mitoxantrone [Mito-FLAG] or fludarabine, etoposide, G-CSF, mitoxantrone and cytarabine [FLEGMA]) was associated with improved OS and EFS compared to a classic daunorubicin-cytarabine AML regimen (p = 0.02 and p = 0.002 respectively).
Arcanjo GS, Silva AP, Diniz MV
… +11 more, Domingos IF, Pereira-Martins DA, Araújo AB, França TSS, Anjos AC, Araujo AS, Belini-Junior E, Saad STO, Costa FF, Lucena-Araujo AR, Bezerra MAC
Br J Haematol
· 2026 Jun · PMID 41989145
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Individuals with sickle cell anaemia (SCA) exhibit significant clinical heterogeneity influenced by several factors, especially fetal haemoglobin (HbF) levels. Variations in adult HbF levels are partly explained by the c...Individuals with sickle cell anaemia (SCA) exhibit significant clinical heterogeneity influenced by several factors, especially fetal haemoglobin (HbF) levels. Variations in adult HbF levels are partly explained by the co-inheritance of genetic variants that regulate globin expression. In this study, we investigated the association of BCL11A rs4671393, rs1427407, rs11886868 and HBS1L-MYB rs9399137 polymorphisms with HbF levels and clinical complications in a cohort of 409 adult Brazilian SCA patients. Our findings reveal that variant alleles of all four single-nucleotide polymorphisms (SNPs) were significantly associated with higher HbF levels. Moreover, homozygosity for the major alleles was independently associated with higher risk and cumulative incidence of stroke, avascular necrosis, leg ulcers, priapism and acute chest syndrome. Haplotype analysis with BCL11A variants was also associated with HbF and the patient's phenotype. A genetic risk score (GRS) combining the risk genotypes was significantly associated with lower HbF levels (p < 0.0001) and increased complication risk (p < 0.0001). A model integrating the GRS with clinical variables demonstrated superior discriminatory performance (area under the curve (AUC): 0.72) compared to models based solely on clinical factors. In summary, this study underscores the clinical relevance of HbF-related genetic variants and supports their integration into risk stratification and personalized management strategies for SCA.
Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired platelet production. Both plasma/B cell-producing anti-platelet autoantibodies and autoreactive T cells lead to thromboc...Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired platelet production. Both plasma/B cell-producing anti-platelet autoantibodies and autoreactive T cells lead to thrombocytopenia and treatment refractoriness. Conventional treatments often fail to induce sustained remission off treatment (SROT). Chimeric antigen receptor (CAR) T cell therapy, developed for haematological malignancies, has recently been explored in autoimmunity to target plasma/B cells, reducing autoantibody production. Early studies suggest potential for benefit in refractory autoimmune disease, including ITP. This nutshell review summarizes CAR T cell therapy in autoimmunity, especially refractory ITP.
Although adult T-cell leukaemia/lymphoma (ATL) has a higher burden in certain world regions, outcomes have not been directly compared across regions. We conducted a multicentre cohort study comparing the distribution of...Although adult T-cell leukaemia/lymphoma (ATL) has a higher burden in certain world regions, outcomes have not been directly compared across regions. We conducted a multicentre cohort study comparing the distribution of ATL subtypes and overall survival (OS) across 1090 adults (≥18 years) diagnosed with ATL during 2000-2023 in Japan (n = 366), South America (n = 364), the United States (n = 275) and the United Kingdom (n = 85). Survival was estimated using Kaplan-Meier methods. Acute ATL was more frequent in Japan (59%) than in the United States (45%), South America (36%) and the United Kingdom (24%) (p < 0.0001). Conversely, lymphomatous ATL predominated in the United Kingdom (53%), South America (51%) and the United States (45%) relative to Japan (20%) (p < 0.0001). With a median follow-up of 38 months interquartile range (IQR 14-68), 3-year OS across regions ranged from 10% to 25% for acute, 16%-34% for lymphomatous, 49%-86% for chronic and 60%-83% for smouldering ATL. Evidence of regional differences in OS was observed for acute, lymphomatous and chronic ATL but not for smouldering ATL. In conclusion, the distribution of ATL subtypes varies globally, and OS for aggressive subtypes (i.e. acute and aggressive) remains poor across regions. Our findings could guide the design of clinical studies aimed at developing accessible therapies through international collaboration.
Arai Y, Jo T, Sato T
… +19 more, Sakurai M, Kaji D, Kitawaki T, Shimada K, Shimoyama T, Yoshihara S, Makita S, Fujii N, Yamamoto G, Kataoka K, Sakaida E, Goto H, Nakashima Y, Yoshida A, Umezawa Y, Kim H, Kato M, Atsuta Y, Kato K
Br J Haematol
· 2026 Jun · PMID 41986280
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Cytokine release syndrome (CRS) remains a major toxicity of chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL), and robust pre-infusion predictors are needed for risk-adapted management. We re...Cytokine release syndrome (CRS) remains a major toxicity of chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL), and robust pre-infusion predictors are needed for risk-adapted management. We retrospectively analysed LBCL patients in the Japanese nationwide registry who underwent CD19 CAR-T-cell therapy between 2019 and 2024. Among 900 patients (median age 62 years), cumulative incidences of CRS within 30 days after infusion were 75.0% for any grade, 20.8% for grade ≥ 2 and 14.0% for grade ≥ 3. In multivariable analysis, lower estimated glomerular filtration rate (eGFR) (adjusted hazard ratio [aHR] 1.108 per 10 mL/min per 1.73 m decrease; 95% confidence interval [CI] 1.015-1.209; p = 0.022), higher ferritin (aHR 1.006 per 100 ng/mL; 95% CI 1.001-1.010; p = 0.016), C-reactive protein (CRP) (aHR 1.142 per mg/dL; 95% CI 1.091-1.195; p < 0.001) and lactate dehydrogenase (LDH) (aHR 1.073 per 100 U/L; 95% CI 1.008-1.142; p = 0.028) independently predicted grade ≥ 2 CRS. We then built a four-factor CRS pre-infusion risk evaluation model, cytokine release syndrome-pre-infusion risk evaluation (CRS-PRE), that stratified grade ≥ 2 CRS risk into low, intermediate and high groups with incidences of 2.8%, 26.0% and 50.0% respectively. Decreased eGFR, a surrogate of host renal reserve, with elevated ferritin, CRP and LDH emerged as predictors of high-grade CRS. The CRS-PRE may facilitate risk-adapted monitoring and intervention in clinical practice.
Immune thrombocytopenia (ITP) is a complex autoimmune disorder characterized by accelerated destruction of peripheral platelets and impaired megakaryopoiesis. While the cellular effectors, dysregulated T cells, hyperacti...Immune thrombocytopenia (ITP) is a complex autoimmune disorder characterized by accelerated destruction of peripheral platelets and impaired megakaryopoiesis. While the cellular effectors, dysregulated T cells, hyperactive B cells and phagocytic macrophages are well characterized, the upstream epigenetic mechanisms orchestrating this multicellular immune network remain largely elusive. This review explores the hypothesis that microRNAs (miRNAs) may serve as critical architects of immune dysregulation and bone marrow failure in ITP. We evaluate the clinical utility of circulating miRNAs as non-invasive biomarkers for diagnosis, risk stratification and predicting response to steroid and thrombopoietin receptor agonists therapies. Finally, we address current translational difficulties, such as data fragmentation and pre-analytical variables. We propose a roadmap for integrating functional validation with multi-omics, utilizing miRNA-based approaches to facilitate and advance precision medicine in ITP.
Delimpasi S, Špička I, Butler JP
… +6 more, Stevens DA, Mesa MG, Bygrave C, Merlo GM, la Porte C, Dimopoulos MA
Br J Haematol
· 2026 Jun · PMID 41978554
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A subgroup analysis of efficacy, safety and QOL in patients who received selinexor in combination with bortezomib and dexamethasone (SVd) with and without selinexor dose reduction and who had lenalidomide-refractory dise...A subgroup analysis of efficacy, safety and QOL in patients who received selinexor in combination with bortezomib and dexamethasone (SVd) with and without selinexor dose reduction and who had lenalidomide-refractory disease in the phase 3 BOSTON trial showed improvements in efficacy, quality of life (QOL) and safety outcomes with selinexor dose reduction in this difficult-to-treat population. These findings demonstrate the benefit of selinexor dose reductions in optimizing the treatment of patients with lenalidomide-refractory multiple myeloma (MM) receiving SVd.
Oksenhendler E, Malphettes M, Meignin V
… +2 more, Boutboul D, Galicier L
Br J Haematol
· 2026 Jun · PMID 41968947
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Under the Castleman disease (CD) eponym, three distinct diseases sharing common pathological features have been described over time. Using the French national registry for CDs, we revisited the full spectrum of these dis...Under the Castleman disease (CD) eponym, three distinct diseases sharing common pathological features have been described over time. Using the French national registry for CDs, we revisited the full spectrum of these diseases to update our current knowledge on the optimal management of these patients. The unicentric type (UCD) has usually an indolent course and can be cured by surgical resection. However, a small percentage of the UCD patients develop severe autoimmune or malignant complications. The human herpesvirus 8 (HHV8)-associated multicentric type (HHV8+ MCD) has been mainly described in human immunodeficiency virus (HIV)-infected patients but is an emerging condition outside this setting in other populations. The third type, idiopathic multicentric Castleman disease (iMCD) remains a challenging diagnosis as the pathological features observed in these patients are shared with many other conditions such as lymphoid neoplasia and systemic diseases. Other syndromes such as POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes), TAFRO (thrombocytopenia, anasarca, myelofibrosis, renal dysfunction and organomegaly), IgG4-RD (IgG4-related disease) and IPL (idiopathic plasmacytic lymphadenopathy) may also overlap with iMCD and could be considered either associated conditions or differential diagnosis. In addition, the clinical phenotype of iMCD exhibits several striking differences among populations with a much more heterogeneous pattern in Western populations than in patients of Asian ancestry.
Chen Y, Zhang X, Shen N
… +16 more, Zhang J, Guo R, Xing H, Han L, Liu Y, Tian W, Wang M, Xie X, Jiang Z, Wan D, Zhou X, Xu H, Qin L, Shi W, Cao W, Bian Z
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for patients with high-risk myelodysplastic syndrome (MDS). However, the optimal timing and value of pretransplant cytored...Allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for patients with high-risk myelodysplastic syndrome (MDS). However, the optimal timing and value of pretransplant cytoreduction and post-transplant maintenance remain unclear, and transplant-modifiable variables are not well defined in real-world settings. We retrospectively analysed 215 consecutive MDS patients who underwent allo-HSCT. Clinical, molecular and transplant-related factors were evaluated for their impact on relapse, relapse-free survival (RFS) and overall survival (OS). TP53 mutation, complex karyotype, and positive measurable residual disease (MRD) after cytoreductive treatment were associated with increased relapse risk. Among transplant-related variables, younger donor age (<42 years) and higher CD34 cell dose (≥3.1 × 10/kg) significantly reduced relapse risk. Notably, pretransplant cytoreduction did not confer measurable benefit on outcomes. In contrast, post-transplant maintenance therapy significantly reduced relapse incidence and prolonged RFS. Pretransplant cytoreduction offers limited clinical value, whereas post-transplant maintenance and modifiable transplant variables (CD34 cell dose and donor age) substantially improve outcomes after allo-HSCT for MDS. These findings highlight actionable strategies that may refine transplant decision-making and optimize outcomes in clinical practice.
Lum SH, Greener S, Memon IL
… +13 more, Amrolia P, Nademi Z, Chiesa R, Silva J, Young H, Owens S, Williams E, Ng KF, Flood T, Gennery AR, Hambleton S, Rao K, Slatter M
Br J Haematol
· 2026 May · PMID 41958357
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Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative therapy for severe combined immunodeficiency (SCID). Conditioning improves donor engraftment and freedom from immunoglobulin replacement (IgR) but...Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative therapy for severe combined immunodeficiency (SCID). Conditioning improves donor engraftment and freedom from immunoglobulin replacement (IgR) but increases the risks of acute and late toxicity. Treosulfan, a reduced toxicity alkylating agent, has emerged as an alternative to busulfan. In this UK multicentre study, we evaluated outcomes of 104 infants with SCID who underwent first HSCT following treosulfan-fludarabine conditioning between 2006 and 2022. After a median follow-up of 5.4 years, 5-year overall survival (OS) and event-free survivals (EFS) were 81% and 77% respectively. On multivariate analysis, molecularly undefined SCID (OS hazard ratio [HR] 5.61; EFS HR 5.55) and pre-HSCT cytomegalovirus (CMV) infection (OS HR 3.94; EFS 3.68) were independently associated with inferior OS and EFS; RAG-DCLRE1C genotypes also predicted worse EFS (HR 4.35). Cumulative incidence of endothelial cell dysfunction (ECD) was 11%. Treosulfan dose was not associated with OS, EFS, ECD or donor myeloid chimerism. Low mixed donor myeloid chimerism was observed across all treosulfan doses, but IgR freedom was achieved in 92% of survivors after first HSCT. Treosulfan-fludarabine provides excellent survival with low endothelial toxicity for SCID HSCT, with potential for optimisation via pharmacokinetic guided dosing.
Tauveron-Jalenques U, Inchiappa L, Paillassa J
… +12 more, Maitre E, Willems L, Stocker N, Merabet F, Lok A, Lara D, Bijou F, Herbaux C, Ramos I, Guièze R, Tomowiak C, Troussard X
Theocharaki K, Delicou S, Ntzoura-Kani A
… +6 more, Simantiris N, Politou M, Komninaka V, Samiotaki M, Zoidakis J, Antonelou MH
Br J Haematol
· 2026 Jun · PMID 41958006
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Omics technologies have transformed research in haemoglobinopathies, yet the proteome of RBCs remains largely unexplored in transfusion-dependent thalassaemia (TDT). In this proteomic analysis, Red blood cell (RBC) membr...Omics technologies have transformed research in haemoglobinopathies, yet the proteome of RBCs remains largely unexplored in transfusion-dependent thalassaemia (TDT). In this proteomic analysis, Red blood cell (RBC) membranes from 48 adults with TDT were compared with healthy controls. The resulting profile, corresponding to patient and donor RBCs, captured disease-linked features and exposure to donor blood. Certain differentially expressed proteins were plasma-absorbed or remnants of erythroid precursors, recapitulating findings in non-transfusion-dependent thalassaemia. Structural proteins were overexpressed en bloc, especially in severe haemoglobin subunit beta (HBB) mutations, though higher transfusion doses attenuate these abnormalities. Other changes suggested impaired volume regulation, increased RBC adhesion and features not included in storage lesions, like downregulation of galectin-3 and septins (identified in TDT for the first time), which were modulated by genetic- and transfusion-related variables. JAM-A, an endothelium inflammation marker, was significantly related to heart T2*. Splenectomy correlated with oxidative, coagulative and inflammatory patterns. The moderate and severe genotype groups had similar proteomic and cell morphology profiles compared to the mildest cases. Upregulation of ferroportin, ICAM4, eryptosis and circadian rhythm-related proteins further characterized severe HBB genotypes. Transfusion dose effects varied across clinical groups. Overall, the RBC membrane emerges as both a target and a sensitive reporter of the complex pathophysiology underlying TDT.
Patients with immune thrombocytopenia (ITP) have a higher thrombotic rate than the general population, and certain ITP treatments may further increase this risk. This narrative 'In a Nutshell' review provides an overview...Patients with immune thrombocytopenia (ITP) have a higher thrombotic rate than the general population, and certain ITP treatments may further increase this risk. This narrative 'In a Nutshell' review provides an overview on thrombosis in adults with primary ITP and the haemostatic changes contributing to the hypercoagulability and thrombosis associated with ITP and its treatments.
Martynchyk A, Chong G, Khor R
… +13 more, Lee D, Lee ST, Scott AM, Grobler AC, Campbell BA, Thachil T, Manos K, Douglas G, Romano A, Palmer JB, Burgess M, Keane C, Hawkes EA
Br J Haematol
· 2026 Jun · PMID 41949430
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Follicular lymphoma (FL) first-line chemoimmunotherapy yields high efficacy but serious toxicity in 65% of patients. In high tumour burden treatment-naïve FL, we aimed to exploit known immunostimulatory and cytotoxic pro...Follicular lymphoma (FL) first-line chemoimmunotherapy yields high efficacy but serious toxicity in 65% of patients. In high tumour burden treatment-naïve FL, we aimed to exploit known immunostimulatory and cytotoxic properties of combination checkpoint inhibition (atezolizumab) and obinutuzumab (6 cycles) with positron emission tomography (PET)-adapted ultra-low dose radiotherapy (RT; 4Gy) to all PET-avid sites after cycle 2, followed by 2 years of obinutuzumab maintenance. Sixteen eligible patients were enrolled (15 evaluable for response) to our Phase II trial (NCT04962126). Median age was 53 years with 94% intermediate/high Follicular Lymphoma International Prognostic Index (FLIPI) score. The primary end-point of complete response (CR) was achieved in 93% (95% confidence interval [CI]: 70%-99%) with objective response rate (ORR) of 100% (95% CI: 75%-100%). With 41-month median follow-up, 3-year progression-free survival (PFS) was 80% (95% CI: 55-93) and OS was 100% (95% CI: 79.6-100). Grade 3-4 adverse events occurred in 31% of patients (2 immune-related). Baseline PET radiomics and immune transcriptomics demonstrated profiles suggesting promise as predictive markers of immunotherapy response, consistent with our prior findings. The novel multimodality combination of obinutuzumab, atezolizumab and ultra-low dose nodal RT in treatment-naïve FL has promising efficacy and safety, offering a potential novel chemo-free option. Further studies using low-cost RT to augment immunotherapy are warranted. This trial was registered in clinicaltrials.gov, registration number: NCT04962126.