Acute myeloid leukaemia (AML) patients with concurrent FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), nucleophosmin 1 (NPM1) and DNA methyltransferase 3 alpha (DNMT3A) mutations exhibit heterogeneous...Acute myeloid leukaemia (AML) patients with concurrent FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), nucleophosmin 1 (NPM1) and DNA methyltransferase 3 alpha (DNMT3A) mutations exhibit heterogeneous treatment outcomes. To identify optimal strategies for this subset, we retrospectively analysed 2541 AML patients with next-generation sequencing from 2016 to 2023. Among them, 113 harboured triple mutations and had treatment outcomes: 79 received allogeneic haematopoietic stem cell transplantation (allo-HSCT), and 34 underwent continuous chemotherapy (CMT). Compared with CMT, allo-HSCT was associated with superior 2-year overall survival (OS) (62.2% vs. 17.8%, p < 0.001). However, no clear additional benefit from allo-HSCT was observed in patients who achieved composite complete remission (CRc) with DNMT3A measurable residual disease (MRD) negativity or complete remission with negative multiparameter flow cytometry MRD after the first cycle of CMT (CMT). Among patients who underwent allo-HSCT, those in CRc after CMT had significantly improved post-transplant 2-year OS (71.9% vs. 44.1%, p = 0.028), leukaemia-free survival (65.4% vs. 40.2%, p = 0.029) and non-relapse mortality (17.4% vs. 40.4%, p = 0.037). CRc rates were higher with venetoclax-based intensive (88.2%) or non-intensive (63.6%) CMT than with CMT alone (p = 0.001). In conclusion, this study offers a potential treatment paradigm for AML patients with co-occurring FLT3-ITD, NPM1 and DNMT3A mutations.
Childhood autoimmune neutropenia (AIN) encompasses heterogeneous entities; phenotype-specific immunological profiles and their relationship to infection outcomes remain incompletely defined. To characterise clinical, imm...Childhood autoimmune neutropenia (AIN) encompasses heterogeneous entities; phenotype-specific immunological profiles and their relationship to infection outcomes remain incompletely defined. To characterise clinical, immunological and long-term outcomes across distinct phenotypes of childhood AIN. We conducted a retrospective cohort study of 112 children with antibody-confirmed AIN at a tertiary centre over 20 years. Patients were classified into three phenotypes: primary autoimmune neutropenia (pAIN), long-lasting neutropenia (LL-Np) and late-onset neutropenia (LO-Np). Outcomes included lymphocyte subsets, immunoglobulin levels, infection-related hospitalisation rates and time to resolution. The cohort comprised 90 pAIN (80.4%), 10 LL-Np (8.9%) and 12 LO-Np (10.7%) patients. LO-Np was characterised by higher neutrophil counts, marked leucopenia, multi-lineage lymphopenia (CD3+, CD4+, CD19+), frequent antinuclear antibodies (ANA) positivity (50%) and associated autoimmune disease (25%). No infection-related hospitalisations occurred in LO-Np (0.00/100 person-years [PY]; 95% confidence interval [CI] 0.00-2.30) versus 1.38/100 PY in pAIN and 5.58/100 PY in LL-Np. Immunoglobulin levels were normal across all patients. Median time to resolution was 19, 67 and 59 months in pAIN, LL-Np and LO-Np respectively (both p < 0.001 vs. pAIN). Late-onset AIN represents a distinct phenotype with systemic immune dysregulation and multi-lineage lymphopenia, yet paradoxically absence of infection-related hospitalisations, reflecting preserved humoral immunity. Phenotype-based stratification may guide clinical monitoring and therapeutic decisions.
Although antiviral prophylaxis is standard for lymphoma patients with chronic hepatitis B virus (HBV) infection to prevent HBV reactivation (HBVr), the optimal timing for high-risk patients (baseline HBV deoxyribonucleic...Although antiviral prophylaxis is standard for lymphoma patients with chronic hepatitis B virus (HBV) infection to prevent HBV reactivation (HBVr), the optimal timing for high-risk patients (baseline HBV deoxyribonucleic acid (DNA) ≥4 log10 IU/mL) during immunochemotherapy remains unclear. A multicentre retrospective study analysed 112 chronic HBV patients among 1120 newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients, stratified by baseline viral load (low: <10 IU/mL, n = 82; high: ≥10 IU/mL, n = 30). We assessed antiviral timing, virological dynamics and clinical outcomes. Antivirals (mainly entecavir) suppressed HBV DNA to undetectable levels in high-load patients (median start 1.65 × 10 IU/mL; p = 0.001). The 3-year cumulative HBVr rates were low (4.2% overall; 4.5% high vs. 4.1% low load, p = 0.955), with one fatal HBVr after discontinuation. Liver toxicity was mild (grade 1-2 transaminase elevations: 33.3%-36.7%). High and low viral load groups achieved comparable 3-year progression-free survival (80.9% vs. 70.6%, p = 0.137), overall response rates (86.7% vs. 82.9%) and complete remission rates (70.0% vs. 64.6%). Propensity score-matched analysis confirmed no significant differences in progression-free survival or HBVr. Concurrent initiation of antiviral prophylaxis with immunochemotherapy is safe and effective, preventing HBVr and enabling timely immunochemotherapy in DLBCL patients with high HBV DNA levels.
Central nervous system (CNS) involvement and relapse remains a clinical challenge in the management of acute lymphoblastic leukaemia (ALL), and studies among adult ALL patients are scarce. We identified all adult ALL pat...Central nervous system (CNS) involvement and relapse remains a clinical challenge in the management of acute lymphoblastic leukaemia (ALL), and studies among adult ALL patients are scarce. We identified all adult ALL patients in Sweden between 2007 and 2022 (n = 838) from the population-based ALL register and evaluated factors associated with CNS involvement and relapse. CNS involvement at diagnosis was detected in 7.8% of patients, more often in patients with T-cell ALL (T-ALL) and with white blood cell (WBC) count >30 × 10/L, without affecting overall survival or risk of any relapse. The 5-year cumulative incidence of CNS relapse was 4.6% (95% confidence interval [CI] 3.1-6.6), with WBC count >100 × 10/L and male sex as independent risk factors. Furthermore, CNS involvement at diagnosis increased the rate of CNS relapse in B-cell ALL (B-ALL) (hazard ratio [HR] 4.52, 95% CI 1.35-15.2), but not T-ALL (HR 0.94, 95% CI 0.12-7.53). Neither Philadelphia chromosome status nor KMT2A::AFF1 was associated with CNS involvement at diagnosis or CNS relapse. Patients with CNS relapse had a 2-year overall survival of 34% (13% if relapse occurred <12 months from diagnosis). We conclude that contemporary treatment protocols can prevent CNS relapse for most patients but suggest that B-ALL patients with CNS involvement may have an unmet need for improved CNS-directed therapy.
Cao L, Wu J, An Z
… +22 more, Zhou F, Li D, Ji L, Gong Y, Yu Z, Cai K, Zhang G, Xie Y, Zhou Z, Cheng Y, Lu Y, Cheng P, Ma L, Yan Z, Fu H, Zhu X, Huang Q, He Y, Zhao X, Chang Y, Huang X, Zhang X
To investigate the risk factors, treatment strategies and prognosis in patients with acute ischaemic stroke (AIS) after immune thrombocytopenia (ITP), we conducted a multicentre case-control study. One hundred and thirte...To investigate the risk factors, treatment strategies and prognosis in patients with acute ischaemic stroke (AIS) after immune thrombocytopenia (ITP), we conducted a multicentre case-control study. One hundred and thirteen adult ITP patients with AIS were included, and each ITP-AIS was paired with three control subjects. The ITP-AIS cohort had a median age of 65 (24-97) years, was predominately female (61 vs. 52) and had a median platelet count of 44 × 10/L (range: 4-355 × 10/L) at the time of AIS. Post-infarction treatment included anti-platelet therapy (n = 36, 31.9%), anti-coagulation therapy (n = 4, 3.5%), combined anti-platelet-anti-coagulation therapy (n = 4, 3.5%) and endovascular thrombectomy (n = 1, 0.9%). Haemorrhagic transformation occurred in 5 (4.4%) patients. Three patients (2.7%) died due to intracranial haemorrhage, gastrointestinal haemorrhage or severe pulmonary infection. Multivariate analysis revealed that age greater than 60 years (p < 0.001; odds ratio [OR] 3.12; 95% confidence interval [CI] 1.82-5.37), diabetes mellitus (p = 0.018; OR 1.99; 95% CI 1.13-3.52), hypertension (p < 0.001; OR 2.75; 95% CI 1.62-4.66), renal failure (p = 0.036; OR 3.00; 95% CI 1.08-8.38), smoking (p < 0.001; OR 5.02; 95% CI 2.31-10.88) and hyper-low-density lipoprotein (LDL)-C (p = 0.02; OR 2.34; 95% CI, 1.14-4.78) were independent risk factors for AIS after ITP. This study revealed that ITP-related treatments might not increase the risk of ITP-AIS. The management of ITP-AIS patients requires close collaboration between haematologists and vascular neurologists to carefully balance therapeutic benefits against the risk of haemorrhagic complications.
Avatrombopag is a thrombopoietin receptor agonist (TPO-RA) suitable for patient-centred care. Avatrombopag achieved lasting platelet count (PC) increases in small series of immune thrombocytopenia (ITP) patients in whom...Avatrombopag is a thrombopoietin receptor agonist (TPO-RA) suitable for patient-centred care. Avatrombopag achieved lasting platelet count (PC) increases in small series of immune thrombocytopenia (ITP) patients in whom other TPO-RAs had failed. We recruited 208 patients with ITP who switched from eltrombopag or romiplostim to avatrombopag due to ineffectiveness (115 [55.3%]), convenience (66 [31.7%]) or treatment-emergent adverse events (TEAEs) (27 [13.0%]). Patients were followed up for 63.9 (31.1-100.4) weeks (median [interquartile range]). Ninety-two per cent of switchers due to ineffectiveness who had baseline PC <50 × 10/L responded to avatrombopag (PC ≥50 × 10/L with doubling of baseline values). Response was maintained in 81.2% of patients after 56.4 (24.6-90.2) weeks. Ninety-two per cent of switchers due to convenience or TEAEs maintained a long-term response. Fifty-one per cent of switchers due to TPO-RA failure who used concomitant medications discontinued these while on avatrombopag. In switchers due to convenience or TEAEs, the maintenance dose decreased from 140 (140-140) to 80 (60-140) mg/week. Fourteen patients (6.7%) discontinued avatrombopag due to TEAEs. The thromboembolism rate was 3.8%. No new safety concerns arose. In this large real-world cohort, switching from eltrombopag or romiplostim to avatrombopag safely induced durable PC recovery.
Sickle cell disease (SCD) is a complex thrombo-inflammatory disorder in which haemolysis, platelet activation, thrombocytosis, inflammation and endothelial activation operate as an intricate network creating a perpetual...Sickle cell disease (SCD) is a complex thrombo-inflammatory disorder in which haemolysis, platelet activation, thrombocytosis, inflammation and endothelial activation operate as an intricate network creating a perpetual cycle of cellular injury and vascular dysfunction that drives vaso-occlusive crises, tissue ischaemia and progressive end-organ damage. Thrombocytosis is common in SCD, especially in response to acute chest syndrome, vaso-occlusive crises and chronic haemolysis. Increased platelet activity contributes to the proinflammatory and prothrombotic environment. Activated platelets release platelet-derived microparticles (PMPs) containing phospholipids and inflammatory mediators, which enhance thrombin generation, entrap leucocytes and promote cellular adhesions leading to endothelial dysfunction and vaso-occlusion within the microvasculature. This review provides insights into the mechanisms underlying thrombocytosis and PMP formation in SCD and discusses therapeutic strategies targeting platelet activation to mitigate inflammation and vascular complications.
Tanasi I, Tamellini E, Marchetti E
… +12 more, De Bellis E, Ancora C, Angotzi F, Facchinelli D, Capraro F, Battaglia G, Sperotto A, Gottardi M, Leoncin M, Krampera M, Tiribelli M, Gurrieri C
In B-cell acute lymphoblastic leukaemia (B-ALL), paired box 5 (PAX5) rearrangement (PAX5-r) represents a critical genetic driver. Here, we report the identification of an in-frame PAX5::GSE1 fusion gene in a patient with...In B-cell acute lymphoblastic leukaemia (B-ALL), paired box 5 (PAX5) rearrangement (PAX5-r) represents a critical genetic driver. Here, we report the identification of an in-frame PAX5::GSE1 fusion gene in a patient with B-ALL. Functional characterization revealed that the PAX5::GSE1 protein localizes to the nucleus, promotes cell proliferation and suppresses wild-type PAX5 transcriptional activity. Notably, its transcript levels correlated with treatment response, supporting its utility as a minimal residual disease biomarker. By analysing 330 patients with PAX5-r B-ALL, we identified 76 distinct in-frame partner genes and delineated their breakpoint characteristics. Integrated multi-cohort transcriptomic analysis further revealed that PAX5-r induces a convergent expression profile relative to healthy individuals, characterized by dysregulation of the retinoblastoma transcriptional corepressor 1 (RB1) and p53 pathways and overexpression of nucleophosmin 1 (NPM1). These findings help to clarify core molecular mechanisms underlying PAX5-r-driven leukaemogenesis and highlight potential therapeutic vulnerabilities.
The hypercoagulable state is a major contributor to thromboembolic events and mortality in β-thalassaemia. The mechanisms underlying platelet-induced neutrophil activation leading to immunothrombosis remain poorly unders...The hypercoagulable state is a major contributor to thromboembolic events and mortality in β-thalassaemia. The mechanisms underlying platelet-induced neutrophil activation leading to immunothrombosis remain poorly understood. Three-dimensional confocal microscopy demonstrated that platelets induced neutrophil extracellular trap (NET) formation through P-selectin- or high mobility group box 1 protein (HMGB1)-mediated binding to P-selectin glycoprotein ligand-1 (PSGL-1) or receptor for advanced glycation end products (RAGE), respectively, on neutrophils. Molecular signalling pathways involved in NETs-focusing on mitogen-activated protein kinase kinase (MAPKK) or mitogen-activated protein kinase kinase 1/2 (MAP2K) (MEK)/extracellular signal-regulated kinase (ERK), reactive oxygen species (ROS), ofnicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2), myeloperoxidase (MPO) and peptidylarginine deiminase 4 (PAD4)-were investigated in neutrophils from β-thalassaemia/haemoglobin E (HbE) patients (splenectomy and non-splenectomy) and from normal subjects by priming neutrophils with specific inhibitors before treatment with either platelets, recombinant P-selectin or disulphide HMGB1. In splenectomised patients, neutrophils primed with U0126, but not an ERK inhibitor, exhibited reduced web-like NETs and cell aggregation, associated with antioxidant effects. In non-splenectomised patients and normal subjects, P-selectin activated MEK/ERK, NOX2, MPO and PAD4 pathways, promoting web-like NETs and cell aggregation. HMGB1 activated neutrophils via MEK/ERK, NOX2, MPO and PAD4 pathways, in all groups, resulting in NETs without aggregation-associated NET morphology. These findings indicate that splenectomy alters P-selectin and HMGB1 expression on platelets, leading to altered signalling dynamics in neutrophils and promoting neutrophil-platelet aggregation. ROS pathway could be a key regulator of NET-driven thrombosis in splenectomised β-thalassaemia/HbE disease and highlight its potential as a therapeutic target.
Hao Z, Song M, Wang H
… +17 more, Yan C, Cao S, Xia J, Zhang M, Zhang X, Feng J, Li S, Li C, Liu S, Wei Y, Ren F, Yang W, Ren H, Huang L, Bian S, Chen X, Wang H
Progression to moderate-to-severe myelofibrosis (MF) in JAK2 V617F-positive myeloproliferative neoplasms (MPNs) is often clinically silent, and bone marrow biopsy is invasive and unsuitable for regular monitoring. In thi...Progression to moderate-to-severe myelofibrosis (MF) in JAK2 V617F-positive myeloproliferative neoplasms (MPNs) is often clinically silent, and bone marrow biopsy is invasive and unsuitable for regular monitoring. In this multicentre pilot proof-of-concept study, we aimed to develop an interpretable, non-invasive model using peripheral blood parameters to detect significant fibrosis and to explore the inflammatory mechanisms involved. A total of 336 JAK2 V617F-positive MPN patients were enrolled for model training and 92 for external validation. Candidate features (blood counts, cytokines, clinical data) were screened using least absolute shrinkage and selection operator (LASSO) and Boruta algorithms. Ten machine learning methods were compared; model discrimination, calibration and clinical benefit were evaluated. Molecular validation focused on interleukin-1β (IL-1β) in Jak2V617F knock-in mice and co-culture assays. The support vector machine model yielded the best discrimination (area under the curve [AUC] = 0.916, 95% CI 0.83-0.99), good calibration and highest clinical utility. SHapley Additive exPlanations (SHAP) interpretation identified haemoglobin, IL-1β and age as the most influential features. Preclinical experiments confirmed IL-1β upregulation with fibrosis progression, reversed by ruxolitinib or pegylated interferon-α but not hydroxyurea (hydroxycarbamide). This multicentre pilot proof-of-concept study demonstrates that an interpretable blood-based tool shows preliminary accuracy for identifying moderate-to-severe MF and underscores IL-1β as a mechanistic biomarker. The data support potential utility as a complementary approach; bone marrow biopsy remains the reference standard.
To assess the cost-effectiveness of blinatumomab plus chemotherapy for paediatric patients from Hong Kong public healthcare provider's perspective, a 10-year Markov model was designed to simulate outcomes in paediatric p...To assess the cost-effectiveness of blinatumomab plus chemotherapy for paediatric patients from Hong Kong public healthcare provider's perspective, a 10-year Markov model was designed to simulate outcomes in paediatric patients with newly diagnosed standard-risk B-cell ALL at: (1) average risk and (2) high risk of relapse. Three treatment strategies were evaluated: (1) blinatumomab plus chemotherapy as first-line therapy; (2) blinatumomab plus chemotherapy as second-line therapy for patients who failed first-line chemotherapy; (3) chemotherapy alone. Model outcomes included direct medical cost, life-year gained (LYG), quality-adjusted life-year (QALY) gained and incremental cost-effectiveness ratio (ICER). Comparing to the next less costly strategy, the ICERs of blinatumomab second-line therapy (10 534 and 12 375 USD/QALY) and blinatumomab first-line therapy (50 312 and 54 799 USD/QALY) were below the willingness-to-pay threshold (162 721 USD/QALY) for high and average risk of relapse groups respectively. One-way sensitivity analysis found that exponential rates of survival with blinatumomab as first-line and blinatumomab drug cost were influential factors. In probabilistic sensitivity analysis, blinatumomab first-line group was the preferred option in 71.4% and 90.3% of simulations in the high and average risk of relapse groups, correspondingly. In conclusion, adding blinatumomab to first-line therapy appears to be cost-effective for paediatric patients with newly diagnosed standard-risk B-cell ALL.
Acquired thiopurine resistance and mismatch repair (MMR) deficiency are increasingly recognised drivers of relapse in paediatric B-cell acute lymphoblastic leukaemia (B-ALL); however, their real-world genomic prevalence...Acquired thiopurine resistance and mismatch repair (MMR) deficiency are increasingly recognised drivers of relapse in paediatric B-cell acute lymphoblastic leukaemia (B-ALL); however, their real-world genomic prevalence and link to maintenance dosing patterns remain poorly characterised. Paediatric B-ALL relapse cases (2018-2024) were subjected to whole exome sequencing (WES; 200-250× depth; n = 70) and deep targeted sequencing (700-900×; n = 5). Per-sample frequencies of resistance gene mutations, single-base mutational signatures, tumour mutational burden-high (≥10 mutations/Mb), microsatellite instability-high (MSI-H) and thiopurine S-methyltransferase (TPMT)/nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) status were determined. Clinical variables included the median weekly 6-mercaptopurine (6-MP) dose (mg/m, time-weighted) and duration of 6-MP dose interruptions. A total of 18/75 (24%) relapse cases showed SBS87 (thiopurine-related), SBS6/15 (MMR-related) or Thio-deficient mismatch repair (Thio-dMMR) mutational signature. Thiopurine resistance clones in cytosolic 5'-nucleotidase II (NT5C2) (13), phosphoribosyl pyrophosphate synthetase 1 (PRPS1) (2) or tumor protein p53 (TP53) (7) were noted in 19/75 (25%) cases; germline or somatic clones in MMR genes were noted in 19/75 (25%). Correlation analysis revealed that both low median weekly 6-MP dose (<45 mg/m) and ≥4 weeks of dose interruptions were significantly associated with higher hazard for SBS87 or Thio-dMMR signature (hazard ratio [HR] 7.09 [95% confidence interval (CI): 1.77-28.34], p = 0.006, and HR 6.21 [95% CI: 1.66-23.32], p = 0.007 respectively). This real-world study demonstrates that suboptimal median 6-MP dosing and prolonged dose interruptions during maintenance are significantly associated with thiopurine resistance and MMR deficiency-related mutational signatures at relapse. These findings underscore the importance of optimised dose intensity and minimal interruptions during maintenance therapy in paediatric B-ALL.
Gloude NJ, Brundige K, Loveless S
… +14 more, Atkinson I, Chandra S, Cooper R, Coyne K, Dusa C, Galvin A, Geddis A, Joos M, Malsch M, Michniacki T, Millecker J, Walkovich K, Shimamura A, Myers KC
Br J Haematol
· 2026 May · PMID 42185746
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Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome characterized by neutropenia and pancreatic insufficiency. The current understanding of immune function in SDS is limited. We performed a retr...Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome characterized by neutropenia and pancreatic insufficiency. The current understanding of immune function in SDS is limited. We performed a retrospective study of the US-based Shwachman-Diamond Syndrome Registry (SDSR) to characterize the immunological profile of patients with SDS. Data were obtained from chart review of patients with biallelic mutations in SBDS enrolled on the SDSR (n = 223) or followed clinically at participating institutions with local IRB approval (n = 6). Immunological data were available from 409 time points on 98 individuals with SDS at healthy time points. We identified limited immune deficits, largely quantitative changes in the B-cell compartment in a subset of patients with SDS including low absolute B cells in 31% of patients and low IgM in 30% of patients. Patients with SDS with low B cells may be at increased risk for sinopulmonary, skin or soft tissue infections particularly if they also have low IgG levels. These data support a baseline immunological evaluation, including a full blood count, lymphocyte subpopulations and immunoglobulin levels, for patients with SDS. However, it is reasonable to reserve more detailed assessments for patients with recurrent or severe infections.