Tesakov IP, Korobkin JD, Fedorova DV
… +13 more, Galkina SV, Golomysova MM, Obydennyi SI, Ignatova AA, Adamanskaya EA, Yushkova EV, Pavlova AV, Zharkov PA, Kireev II, Novichkova GA, Zgoda VG, Panteleev MA, Sveshnikova AN
Br J Haematol
· 2026 Jun · PMID 42049211
·
Full text
ETV6-related thrombocytopenia (ETV6-RT) is an inherited platelet disorder caused by germline ETV6 variants. Despite recent progress, the mechanisms underlying platelet dysfunction in ETV6-RT remain unclear. We investigat...ETV6-related thrombocytopenia (ETV6-RT) is an inherited platelet disorder caused by germline ETV6 variants. Despite recent progress, the mechanisms underlying platelet dysfunction in ETV6-RT remain unclear. We investigated 12 patients from six families using functional assays, electron microscopy, quantitative proteomics and cytoskeletal imaging. Most patients exhibited mild-to-moderate thrombocytopenia with variable paediatric bleeding symptoms (median International Society on Thrombosis and Haemostasis Bleeding Assessment Tool 3, range 1-9) but consistently mild bleeding in adulthood (median 0, range 0-1). Ex vivo thrombus formation was reduced independent of platelet count. Electron microscopy revealed defective platelet shape maintenance, characterized by spheroid morphology, reduced D/D ratios and diminished alpha-granule pools. Flow cytometry and single-platelet total internal reflection fluorescence imaging demonstrated largely preserved calcium signalling but impaired activation-dependent shape change, dense-granule release and integrin activation. Proteomics showed reduced alpha-granule and lysosomal proteins alongside imbalanced regulators of actin remodelling and β-tubulin. Phalloidin staining confirmed impaired actin cytoskeletal remodelling with reduced lamellipodia formation, while immunofluorescence revealed abnormal β1-tubulin localization with disrupted marginal bands and reduced lysosome-associated membrane protein 1 (LAMP1) expression. Additionally, granulocyte recruitment and migration within thrombi were impaired, suggesting broader thromboinflammatory defects. These findings suggest that combined disruption of cytoskeletal integrity and granule biogenesis underlies impaired thrombus formation in ETV6-RT, providing mechanistic insight into the haemostatic defects associated with this disorder.
Wang T, Ferreira AC, Hossain NM
… +6 more, Fu D, Hill EG, Jimenez Jimenez AM, Benjamin C, Komanduri KV, Paczesny S
Br J Haematol
· 2026 Apr · PMID 42047487
·
Full text
While plasma-derived proteins have emerged as potential biomarkers for prognosis after haematopoietic stem cell transplantation (HSCT), there are insufficient data assessing if established proteins interleukin 1 receptor...While plasma-derived proteins have emerged as potential biomarkers for prognosis after haematopoietic stem cell transplantation (HSCT), there are insufficient data assessing if established proteins interleukin 1 receptor-like 1 (IL1RL1), chemokine ligand 9 (CXCL9) and regenerating islet-derived 3-α (REG3α) retain their utility in the mismatched unrelated donor (MMUD) setting. We assessed their prognostic ability in 53 subjects who received MMUD HSCT from 2016 to 2023 with Day 14 or Day-30 post-HSCT samples in batch using sequential enzyme-linked immunosorbent assay. Elevated Day-30 biomarker concentrations held more prognostic value than Day 14 concentrations. Day-30 CXCL9 value showed association for overall survival (OS) with a hazard ratio of 5.86 (95% confidence interval [CI] 1.21, 28.3, p = 0.03). When stratified by high or lower threshold concentrations, Day-30 concentration revealed differences in 2-year OS for IL1RL1 (p = 0.027), CXCL9 (p = 0.011) and REG3α (p = 0.044). Day-30 area under the curve (AUCt) performance for risk of death by 2 years was 0.86 (95% CI 0.71, 1) for the combination of CXCL9 and IL1RL1, which was superior to any individual biomarker value. In this pilot analysis, Day-30 biomarkers are discriminative for OS at 2 years post-HSCT and may be able to guide future pre-emptive intervention and monitoring.
NUP98 rearrangements define a high-risk, genetically heterogeneous subtype of paediatric acute myeloid leukaemia (AML), yet comprehensive clinicogenetic and survival data remain limited. This retrospective, single-centre...NUP98 rearrangements define a high-risk, genetically heterogeneous subtype of paediatric acute myeloid leukaemia (AML), yet comprehensive clinicogenetic and survival data remain limited. This retrospective, single-centre study of 32 paediatric patients (2017-2025) found a median age of 8.7 years and predominance of the NUP98::NSD1 fusion (68.8%), frequently co-mutated with FLT3-ITD (50%) and WT1 (43.8%). Complete remission (CR) rates increased from 53.1% to 87.5% after first and second induction. With a median follow-up of 41.7 months, the estimated 3-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 81.2% (95% confidence interval [CI], 65.9%-96.5%), 62.8% (95% CI, 43.8%-81.8%) and 28.1% (95% CI, 12.9%-45.6%), respectively; corresponding rates among the 29 transplanted patients were 79.8% (95% CI, 63.5%-96.1%), 68.7% (95% CI, 50.3%-87.1%) and 26.0% (95% CI, 11.1%-43.9%) respectively. Exploratory multivariate analysis identified failure to achieve CR after induction 2 as a risk factor for OS, WT1 mutation for relapse in the entire cohort and pretransplant minimal residual disease (MRD) positivity for relapse in the transplant subgroup. This confirms that NUP98-rearranged AML necessitates intensive therapy including transplant and highlights WT1 and pretransplant MRD as key prognostic markers for risk-adapted strategies.
Toda Y, Jo T, Arai Y
… +19 more, Harada K, Yanada M, Fukuda T, Yoshihara S, Doki N, Uchida N, Mori Y, Hasegawa Y, Kondo Y, Kawakita T, Eto T, Nishida T, Tanaka M, Onizuka M, Shono K, Hino M, Ichinohe T, Atsuta Y, Konuma T
CD34 cell dose is believed to impact the outcomes of allogeneic peripheral blood stem cell transplantation (PBSCT), yet the optimal dose remains unclear. We retrospectively reviewed 2407 adult patients with acute myeloid...CD34 cell dose is believed to impact the outcomes of allogeneic peripheral blood stem cell transplantation (PBSCT), yet the optimal dose remains unclear. We retrospectively reviewed 2407 adult patients with acute myeloid leukaemia who underwent their first related PBSCT between 2000 and 2019. The median infused CD34 cell dose was 3.67 × 10/kg. Patients were divided into three groups based on infused CD34 cell dose: low (1.0-2.0 × 10/kg), intermediate (2.0-4.0 × 10/kg) and high (4.0-10.0 × 10/kg) groups. The 5-year overall survival rates were 37.2%, 40.2% and 37.4% in the low, intermediate and high groups respectively (p = 0.176). Although the high-group patients experienced faster neutrophil engraftment, cumulative incidences of infection and primary engraftment failure were comparable across groups. Platelet engraftment was significantly delayed in the low group, with 21.7% failing to engraft at day 100, compared to 14.6% and 13.4% in the intermediate and high groups (p < 0.001). Furthermore, the incidence of secondary graft failure was significantly higher in the low group. In conclusion, a CD34 cell dose >2.0 × 10/kg improves platelet engraftment and reduces the risk of secondary graft failure but does not confer additional long-term benefits.
Isolated thrombocytopenia is commonly diagnosed as immune thrombocytopenia (ITP). Recent publications have stimulated discussions regarding the diagnosis of ITP, including the potential for misclassification, the interac...Isolated thrombocytopenia is commonly diagnosed as immune thrombocytopenia (ITP). Recent publications have stimulated discussions regarding the diagnosis of ITP, including the potential for misclassification, the interaction between autoimmunity and clonality, and downstream complications of malignancy. This review focuses on these considerations in the workup and management of patients with thrombocytopenia.
Vazquez et al. High frequency of CD95/CD45RA regulatory T cells defines an immunosuppressive profile associated with MDS progression. Br J Haematol 2026; 208:1993-2003.Vazquez et al. High frequency of CD95/CD45RA regulatory T cells defines an immunosuppressive profile associated with MDS progression. Br J Haematol 2026; 208:1993-2003.
Goel U, Dragomirescu C, Zanwar S
… +7 more, Cassano RC, Cicero KI, Cowan AJ, Banerjee R, Anwer F, Khouri J, Dima D
Br J Haematol
· 2026 Jun · PMID 42023513
·
Full text
Functional high-risk (FHR) multiple myeloma (FHRMM) is often defined as progression within 12-24 months of front-line autologous hematopoietic stem cell transplantation (AHSCT). For patients with early progression after...Functional high-risk (FHR) multiple myeloma (FHRMM) is often defined as progression within 12-24 months of front-line autologous hematopoietic stem cell transplantation (AHSCT). For patients with early progression after suboptimal front-line therapies, it is challenging to assign the disease progression to a true FHR phenotype versus less effective front-line therapy. In this study, we combined data from three Center for International Blood and Marrow Transplant Research studies (MM18-02, MM19-01 and MM20-03). We included patients who received front-line AHSCT between 2008 and 2018 and had progression <12 (FHR12, n = 465), <18 (FHR18, n = 672) or <24 months (FHR24, n = 853) after AHSCT. We classified induction therapy as standard lenalidomide-containing triplets (bortezomib, lenalidomide, dexamethasone [VRD]/carfilzomib, lenalidomide, dexamethasone [KRD]) versus other (bortezomib, thalidomide, dexamethasone [VTD]/bortezomib, cyclophosphamide, dexamethasone [VCD]/bortezomib, dexamethasone [VD]/lenalidomide, dexamethasone [RD]) and studied the impact of front-line therapy on post-FHR overall survival (OS). In the FHR12 cohort (follow-up 48 months), the OS after VRD/KRD (n = 238) was 21 versus 17 months with other regimens (n = 227, hazard ratio [HR] = 1.2, 95% confidence interval [CI]: 0.6-1.06). In a multivariable model, the HR for OS was 0.94 (95% CI: 0.7-1.3, p = 0.69) for VRD/KRD versus other regimens. There was no significant interaction between type of first-line (1L) therapy and time from 1L AHSCT to first relapse in predicting OS. Similar results were seen for FHR18 and FHR24. FHRMM remains a negative prognostic factor irrespective of front-line therapy and warrants consideration of T-cell engagers' second-line therapy.
Anti-CD38 monoclonal antibodies have demonstrated rapid responses in immune thrombocytopenia, with response rates across several agents ranging from moderate to high. However, the durability of these responses after trea...Anti-CD38 monoclonal antibodies have demonstrated rapid responses in immune thrombocytopenia, with response rates across several agents ranging from moderate to high. However, the durability of these responses after treatment discontinuation appears to vary. The therapeutic effects of anti-CD38 antibodies likely extend beyond depletion of CD38 plasma cells and may involve broader modulation of the immune system.
Dingli S, Rothweiler P, Corraes AMS
… +12 more, Atallah-Yunes A, Ansell SM, Bennani NN, Durani U, Johnston PB, Khurana A, Paludo J, Bisneto JCV, Wang Y, Lin Y, Erdman AG, Dingli D
Chimeric antigen receptor T cells directed against CD-19 are highly effective therapies for various subtypes of B-cell non-Hodgkin lymphoma (NHL). We have studied the impact of patient-specific lymphocyte growth kinetics...Chimeric antigen receptor T cells directed against CD-19 are highly effective therapies for various subtypes of B-cell non-Hodgkin lymphoma (NHL). We have studied the impact of patient-specific lymphocyte growth kinetics after lymphoid depletion chemotherapy on both long-term outcomes and toxicity in patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL). The growth of the lymphocyte populations early after chimeric antigen receptor T-cell (CAR-T) therapy is well described by an exponential function and the growth rate of the cells appears to be one of the most critical determinants of overall survival in these patients. The maximum lymphocyte peak and the area under curve for lymphocytes within the first 4 weeks after CAR-T therapy had no impact on survival. Receiver operator characteristic analysis determined that a replication rate ≥0.3876/day is associated with superior rates of complete response and durable responses. This threshold is associated with higher grades of cytokine release syndrome and the need for tocilizumab. However, patients with this threshold have a median overall survival of 3.04 years compared to 1.035 years for patients with slower lymphocyte replication (p = 0.0206). The major determinant of depth of response and durability of response to CAR-T in NHL is the speed of lymphocyte expansion.