In 82 patients with classic Hodgkin lymphoma, stable gonadal hormone levels were observed up to 24 months after nivolumab and AVD (N-AVD) first-line treatment in the NIVAHL trial. These findings suggest preserved gonadal function and fertility following 4×N-AVD. NCT03004833.

In the multinational, phase 3 RELEVANCE trial, 1,030 patients with previously untreated follicular lymphoma were randomized to receive rituximab plus lenalidomide (R2; n=513) or rituximab-based immunochemotherapy (R-Chemo; n=517). In the final analysis, at 120 months of follow-up, median PFS was comparable between the treatment groups: 110.6 months with R2 versus 102.8 months with R-Chemo, according to Independent Review Committee assessment. The 10-year PFS rates were 46.4% and 46.6%, respectively. Median overall survival (OS) and time-to-next lymphoma treatment (TTNLT) were not reached in either arm; 10-year OS rates were 82.4% and 81.1%, respectively, and 10-year TTNLT rates were 62.2% and 66.3%, respectively. Overall, patients with POD24 had a poorer prognosis compared to those without POD24 (HR, 6.215; P<0.0001); however, no difference was observed between the study groups. The incidence of second primary malignancies (SPMs) was 2.11 cases per 100 patient-years (95% CI, 1.80-2.46). Only 9 transformations occurred after 24 months (3 with R2 versus 6 with R-chemo). In each study group, 87 patients died, mainly due to lymphoma progression and SPMs. This long-term follow-up of RELEVANCE confirmed that R2 provides a chemo-free alternative to immunochemotherapy in this patient population. Trial registration: NCT01476787 and NCT01650701; EudraCT: 2011-002792-42.

Innate immunity is increasingly recognized as a driver of neurodegeneration, though pathogenic mechanisms are incompletely understood. Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplastic disorder caused by activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most commonly BRAFV600E, in myeloid precursors. A subset of LCH patients develop progressive neurodegeneration (LCH-ND). We generated a human induced pluripotent stem cell (iPSC) model from patients with somatic hematologic mosaicism for BRAFV600E. Brain macrophages/microglia from LCH iPSCs exhibit unique disease specific pathogenic features. Stepwise differentiation identified hematopoietic progenitors as hyperproliferative, whereas brain macrophages were apoptosis resistant. Through application of cerebral organoids and a humanized murine xenotransplantation model we identify marked heterogeneity of differentiation potential within clonal BRAFV600E lines in vivo. This model phenocopied human specific phenotypes including dense basal ganglia foci of abnormal macrophages, marked neurodegeneration with astrogliosis, and progressive ataxia. This approach will allow for preclinical testing of therapeutics for LCH-ND.

Malignant histiocytic neoplasms (MHNs) are rare tumors derived from the mononuclear phagocyte system (MPS), encompassing histiocytic sarcoma, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, and other high-grade MPS lineage tumors. Despite advances in understanding histiocytic neoplasms, MHNs remain diagnostically challenging and lack standardized treatment algorithms. Current classification systems differ in lineage framing and fail to address mixed or ambiguous phenotypes, contributing to diagnostic uncertainty and inconsistent care. To address these gaps, the Histiocyte Society convened an international working group of pathologists and oncologists, including World Health Organization (WHO) and International Consensus Classification (ICC) contributors, to harmonize nomenclature, define minimum diagnostic criteria, and develop pragmatic treatment recommendations. Using a modified Delphi process and case-based review, the group formulated over 40 consensus statements spanning classification, pathology, molecular testing, clinical evaluation, and therapeutic strategies. Key recommendations include adoption of a unified MHN designation, use of a minimum immunophenotypic panel, integration of broad molecular profiling, and documentation of prior hematopoietic malignancy. Treatment algorithms emphasize surgical resection for unifocal disease and targeted therapy or immune checkpoint inhibition for multifocal disease when actionable mutations or PD-L1 expression are present. These consensus recommendations aim to reduce diagnostic ambiguity, standardize reporting, and improve outcomes for both pediatric and adult patients. Future priorities include international registries to refine risk stratification and biomarker-driven trials exploring targeted therapy, immunotherapy, and combination approaches.

Complement activation has been reported in primary immune thrombocytopenia (ITP); however, its clinical relevance remains poorly understood. This study aimed to clarify the association between complement activation and various biomarkers and the clinical characteristics of patients with ITP. Forty patients with ITP were enrolled in this study. Platelet-bound C1q, C3d, and C4d were elevated in a substantial population of patients with ITP compared with healthy controls with highly variable titers, Hierarchical clustering analysis showed that patients with ITP could be classified into three groups according to their levels: all negative (Cluster 1), elevated C1q with negative to low C3d and C4d (Cluster 2), and high C3d and C4d (Cluster 3). Platelet-associated (PA) IgM was detected mostly in Cluster 3, and PA-IgG was detected in Clusters 2 and 3. The number of cases refractory to first-line therapy increased in Clusters 2 and 3. Complement deposition on the platelet surface correlated with an increased percentage of immature platelets. There was no significant association between complement activation and PA-GPIIb/IIIa or -GPIb/IX antibodies, C1s ratio in the plasma, and fatigue score. Our results suggest that PA-IgG and PA-IgM contribute differentially to the complement activation profile on the platelet surface, and are associated with increase in platelet turnover, characterizing a distinct subset of ITP patients with complement activation. Our findings also may provide a rationale for stratifying patients in future clinical trials of complement-targeted therapies.

Fixed-duration venetoclax combinations have become a standard first-line treatment in chronic lymphocytic leukemia (CLL). The phase 3 CLL13/GAIA trial assesses three time-limited combinations: venetoclax-rituximab (RV), venetoclax-obinutuzumab (GV), and venetoclax-obinutuzumab-ibrutinib (GIV) compared to chemoimmunotherapy (CIT). Fit patients with CLL without TP53 aberrations were randomized between six cycles of CIT (fludarabine-cyclophosphamide-rituximab [FCR], bendamustine-rituximab [BR]) or 12 cycles of RV, GV or GIV (GIV: ibrutinib continuation until cycle 36 if measurable residual disease [MRD] at months 12/15). In total, 926 patients were randomized (GIV: 231, GV: 229, RV: 237, CIT: 229 [FCR: 150, BR: 79]). With a median observation time of 63.8 months, 5-year progression-free survival (PFS) rates were 81.3% (GIV), 69.8% (GV), 57.4% (RV), and 50.7% (CIT). PFS was superior for GV and GIV compared to CIT and RV (p<0.001 in each case). In addition, GIV showed longer PFS than GV (p=0.0046). Venetoclax-based retreatment after venetoclax-based first-line regimens was efficacious with 2-year treatment-free survival >80% from second-line treatment. No differences in overall survival were observed between treatment arms (5-year rates, GIV 94.3%; GV 93.6%; RV 94.7%; CIT 90.7%). Incidence rates of severe infections were highest with CIT while cardiac events were most frequent with GIV. Patients treated with GV or RV reported rapid and significantly greater quality of life (QoL) improvements compared to patients treated with CIT. In the GIV arm, clinically relevant QoL improvements occurred later (month 15, after the end of treatment in most patients) than with GV/RV, likely due to a higher treatment-related symptom burden. The trial is registered at clinicltrial.gov with the identifier, NCT02950051.

The process of non-occlusive thrombus formation is well known, but the mechanism keeping the thrombus silent at the end stage remains unclear. The aim of this work was to evaluate the role of fibrin in limiting further growth of a thrombotic remnant. Intravital microscopy showed that attachment of platelets to a fibrin-rich thrombus stopped after partial thrombus disaggregation, indicating that the thrombus activation potential is lost, a stage we named the stillness phase. Histological analyses showed that 80% of internal cross-section area of thrombus remnant is bordered by fibrin while 20% of superficial thrombus area was covered only by few platelet layers, suggesting a role of fibrin in limiting platelet recruitment. This result was confirmed in a flow-based assay where fibrin-rich thrombi recruited circulating platelets inefficiently as compared to fibrin-poor thrombi. Moreover, we found that in vitro, lysis of fibrin with rtPA released active thrombin. This observation was confirmed in vivo as treating a thrombus with rtPA to promote fibrin breakdown during the stillness phase resulted in the release of thrombin, leading to an unexpected re-growth of the thrombus. This finding was further supported by the dynamics of thrombus formation in FgaEK mice, which displayed repeated cycles of thrombus growth and detachment after vessel injury, with an inability to reach the stillness phase, accompanied by the continuous release of active thrombin. Altogether, these findings identify a novel role of fibrin in maintaining an end-stage thrombotic remnant in an inactive state.

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by monoclonal IgM autoantibodies that bind to red blood cells and trigger hemolysis through activation of the classical complement pathway. Cold agglutinins are produced by a clonal population of lymphocytes recognized by the WHO as a low grade lymphoproliferative disorder. Traditional therapy relied on B-cell-targeted immunosuppression with rituximab which mainly yielded partial responses in about half of the patients. The combination of rituximab with fludarabine or bendamustine significantly increased and prolonged response rates, though with a substantial infectious risk. Sutimlimab, the first C1s complement inhibitor, has shown efficacy in rapidly and sustainably increasing hemoglobin levels, reducing hemolysis, and significantly improving quality of life. However, the drug does not act on the B-cell clone and does not decrease the cold agglutinins. Therefore, several unmet needs remain, including identifying patients who can discontinue sutimlimab while maintaining remission, developing combination strategies effective against cold-induced symptoms, and improving infection prevention and control of hemolytic flares. This perspective article briefly recapitulates the pathophysiology of CAD, outlines the evolution of its treatment landscape, and focuses on the role of sutimlimab-its clinical positioning, therapeutic benefits, and management considerations-offering insights into optimizing care for patients with this challenging condition.

Large scale sequencing efforts have defined up to 27 diagnostic entities in B-ALL, leaving few samples without subtype assignment. Extended genomic and transcriptomic profiling in routine diagnostics broadens the sample collection and holds the potential to identify novel B-ALL subtypes. By analyzing an aggregated set of 4,857 B-ALL patients from three cohorts, we identified a novel group of twenty cases (age 18-66 years, median: 34 years) characterized by a previously undescribed IGH::FENDRR rearrangement exclusive to this subtype (n=17/20), KRAS p.A146T/V/P mutations (n=17/20 vs. n=86/4,857; p<0.001) and distinct DNA-methylation/gene expression profiles, including overexpression of the lncRNA FENDRR and the transcription factor FOXF1 ('FOXF1/FENDRR') as well as JAK/STAT and RAS signaling signatures. A gene expression machine learning classifier identified FOXF1/FENDRR cases in two independent cohorts with high accuracy. Patients treated according to GMALL/GRAALL protocols showed very poor chemotherapy response with n=8/13 having induction failure or MRD ≥10-3 and n=8/12 remaining MRD positive after 1st consolidation / salvage. MRD-stratified intensification including blinatumomab (n=10) and/or allogenic stem cell transplantation (n=12) resulted in ongoing molecular remission in 13/16 cases. FOXF1/FENDRR patients represent a novel B-ALL subtype which might benefit from early immunotherapeutic treatment or targeted interventions.

Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.

FLT3-ITD mutation is associated with poor prognosis in acute myeloid leukemia (AML), yet its kinase-independent mechanisms remain unclear. To investigate kinase-independent immunosuppressive mechanisms in FLT3-ITD AML, we integrated single-cell RNA sequencing from two public datasets and multiparameter flow cytometry data from 104 primary patient samples, identifying profound CD8+ T cell exhaustion as a hallmark of the FLT3-ITD immune microenvironment. Mechanistically, FLT3-ITD acts as a mutation-specific scaffold that assembles a ternary complex with PKCι and STAT1, as demonstrated by co-immunoprecipitation and intracellular colocalization. This complex enables PKCι-mediated phosphorylation of STAT1 specifically at serine 727 (S727), driving CD276 transcription independent of the canonical tyrosine 701 (Y701) site. Chromatin immunoprecipitation, electrophoretic mobility shift, promoter-reporter assays, and phosphosite-mutant constructs confirmed that S727 phosphorylation is necessary and sufficient for CD276 transactivation. Multiplex immunohistochemistry of patient bone marrow validated co-elevation of pS727-STAT1 and CD276 in FLT3-ITD blasts, accompanied by CD8+ T cell depletion. Functionally, CD276 upregulation induced profound CD8+ T cell exhaustion, characterized by reduced cytotoxicity, impaired proliferation, diminished IFN-γ production and elevated inhibitory checkpoints expression. Targeting CD276 restored CD8+ T cell function by 1.2-1.7-fold (cytotoxicity), 1.4-1.7-fold (proliferation), 1.5-1.8-fold (IFN-γ secretion) and 25.4%-67.6% (checkpoints expression) in ex vivo co-culture. In patient-derived xenograft models, co-treatment with FLT3i (quizartinib) and CD276-targeting agents led to 72.9%-80.4% tumor burden reduction and enhanced CD8+ T cell function, outperforming quizartinib monotherapy. These findings define a scaffolded PKCι-pS727-STAT1 signaling axis that promotes immune evasion in FLT3-ITD AML, supporting combined FLT3 and CD276 targeting as a promising translational strategy in this aggressive leukemia subtype.

The therapeutic landscape for relapsed or refractory large B-cell lymphoma (R/R LBCL) has undergone rapid and profound change, driven by cellular therapies, bispecific antibodies, and next-generation antibody-drug conjugates (ADCs). These advances have redefined historical standards while exposing persistent gaps in trial design, biological insight, and therapeutic sequencing. Recent randomized studies show that ADC- and bispecific-anchored regimens can outperform legacy chemotherapy comparators, yet interpretation is hindered by geographic heterogeneity, selective enrollment, and a proliferation of trials lacking contemporary control arms.Next-generation approaches including bispecific-ADC combinations, dual-target CAR-T constructs, and strategies explicitly designed to circumvent antigen escape are poised to challenge long-standing therapeutic hierarchies and may broaden curative potential to patients who are ineligible for, or relapse after, CAR-T. The field now stands at an inflection point where therapeutic innovation is advancing faster than the evidence infrastructure required to guide practice. Delivering durable, equitable benefit will require control arms aligned with current CAR-T standards, harmonized eligibility criteria, prospective molecular profiling, and adaptive trial platforms capable of evolving with the standard of care.As ADCs and bispecifics move earlier in treatment and diffuse into community practice, the central challenge is no longer the development of active therapies alone, but the creation of biologically rational, accessible, and interpretable pathways that make chemotherapy-free cure a realistic and universal goal for patients with R/R LBCL.

Modern intravenous (IV) iron formulations allow treatment of iron deficiency anemia (IDA) with one or two infusions. Ferric carboxymaltose (FCM) is a widely used IV iron, which causes hypophosphatemia in the majority of patients. Osteomalacia and fractures are increasingly recognized after repeated infusions of FCM. It is unknown why ferric derisomaltose (FDI) rarely causes hypophosphatemia. In this study, we compare the effects of FCM and FDI on fracture risk and investigate potential underlying mechanisms explaining different effects on bone- and mineral-metabolism. For this aim, fracture rate and osteomalacia were assessed in a cohort of 357 patients treated with either drug, which reported a significantly higher rate of incident osteomalacia or fracture after FCM. These findings were validated in over 20,000 patients from the TriNetX database, where FCM-treatment was independently associated with a higher fracture risk compared with FDI. The underlying mechanisms were investigated in a mouse model of IDA treated with FCM or FDI, an osteocyte model and biochemically. FCM caused lower expression of collagen and ossification genes, associated with significantly higher bone iron concentrations than FDI. Electron microscopy showed iron-loaded vesicles in osteoblasts and early osteocytes. FCM but not FDI inhibited binding of dentin matrix protein 1 to [alpha]V[beta]3-integrin on osteocytes. This is a potential mechanism for reduced bone formation and higher levels of intact fibroblast-growth factor-23 after FCM. Our data report that IDA and FCM treatment can directly impair bone formation and increase fracture risk.

The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.

The protein-protein interaction between menin and KMT2A (histone lysine methyltransferase 2A) plays a critical role in acute leukemia with KMT2A rearrangements, nucleophosmin 1 (NPM1) mutations and nucleoporin 98 rearrangements, and represents an emerging opportunity for therapeutic intervention. Here, we report development and comprehensive evaluation of the activity of ziftomenib as an orally bioavailable, highly potent and selective small molecule inhibitor of the menin-KMT2A interaction. In leukemia cells and primary patient samples with the menin-KMT2A dependency, ziftomenib profoundly inhibited proliferation, reduced clonogenic potential and induced differentiation, which was associated with strong downregulation of the menin-KMT2A target genes, including MEIS1, HOXA9 and HOXB2. In xenografts and patient-derived xenograft models of KMT2A-rearranged leukemia, ziftomenib induced leukemia regression or reduced leukemia burden, accompanied by a pronounced reduction of the menin-KMT2A target genes. We next assessed ziftomenib against four MEN1 (gene encoding menin) mutants (T349M, M327I, G331R, G331D) associated with clinical resistance to another menin inhibitor revumenib. Ziftomenib retained anti-leukemic activity against T349M mutant cells and demonstrated low-nanomolar potency (GI50≤25 nM) against G331R cells, despite several-fold reduced potency relative to MEN1 wild-type cells, whereas M327I and G331D mutants were resistant. The crystal structures of ziftomenib in complex with menin wild-type, T349M or G331R mutants revealed a similar binding mode of ziftomenib to these menin variants, rationalizing potent inhibitory activity towards these mutants. Ziftomenib has recently received FDA approval for adult patients with NPM1-mutated acute myeloid leukemia and continues to be evaluated clinically in leukemias with NPM1 or KMT2A alterations, both as monotherapy and in combinations.

The optimal graft-versus-host disease (GvHD) prophylaxis strategy in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) remains controversial. In this open-label, phase Ⅲ study, patients aged 14-70 years with acute myeloid leukemia or myelodysplastic syndromes with excess blasts Ⅰ or Ⅱ were randomized (2:1:1) to receive low-dose ATG (5 mg/kg)/PTCy (50 mg/kg), standard-dose ATG (total dose 10 mg/kg), or a PTCy (total dose 100 mg/kg)-based regimen for GvHD prophylaxis. The co-primary endpoints were the cumulative incidence (CI) of grade Ⅱ-Ⅳ acute GvHD (aGvHD) by day 100 and GvHD/relapse-free survival (GRFS) at 1 year post-transplant. A total of 407 patients were randomized to receive ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GvHD prophylaxis. By day +100, the CI of grade Ⅱ-Ⅳ aGvHD did not differ significantly among the three groups (P=0.210). Although the overall incidence of chronic GvHD (cGvHD) was comparable across all groups (P=0.110), the 2-year CI of moderate-to-severe cGvHD was numerically lower in the ATG/PTCy (17.4%) and ATG (17.3%) groups compared to the PTCy group (28.3%), without reaching statistical significance (P=0.095). No significant differences were observed in survival outcomes among the three groups. Notably, the cumulative incidence of neutrophil and platelet recovery was significantly higher in the ATG/PTCy group compared to the other groups (P<0.001). This trial suggested that the three GvHD prophylaxis strategies presented similar efficacy in preventing grade II-IV aGvHD and yielded comparable survival. This trial was registered at www.clinicaltrials.gov as NCT03608059.

Immunodeficiency-associated primary CNS lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted an international retrospective multi-center study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL, diagnosed at 23 participating sites in 7 countries. Pre-existing immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%), and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab-methotrexate-(RM)-based chemotherapy was associated with highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment HR: 1.05 (95%-CI:1.02-1.07); p < 0.001), Karnofsky Performance status (KPS) < 70 (HR: 3.10 (95%-CI:1.67-5.87); p < 0.001), EBV positivity (HR: 3.26 (95%-CI:1.47-7.33); p = 0.004) as prognostic factors for OS. A prognostic score was developed based on the sum of these adverse variables (age > 60 years, KPS < 70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to one, two and three unfavorable markers (p < 0.0001). It allowed improved prognostic stratification of ID-PCNSL as compared to the well-established MSKCC and IELSG models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiologic features of ID-PCNSL and introduces an easily applicable prognostic system with potential to guide future management.

Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy afflicting 1 in 5000 individuals, is the second-most-common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the U.S. Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS; NCT06259292), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median (range) age of 53 (0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of post-menarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring intravenous iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). This data from CHORUS, the first national registry of its kind, provides reliable, real-world estimates of the incidence, prevalence and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of over two decades, during which substantial serious, preventable HHT morbidity, including early intracranial hemorrhage, may occur.

Traumatic Brain Injury (TBI) is the leading cause of death in children and adults aged 18-44. Despite its high prevalence and devastating consequences, there are currently few effective therapies that target the acute, life-threatening complications of TBI - particularly cerebral edema and intracranial hemorrhage (ICH). The blood-brain barrier (BBB) and regulation of vascular stability following injury are emerging as critical therapeutic targets. In this study, we evaluate the therapeutic potential of a first-in-class, freeze-dried platelet-derived biologic (FDPlts) in a murine model of TBI. FDPlt transfusion significantly reduces post-TBI ICH and restores cerebral vascular perfusion. Additionally, FDPlts attenuate BBB permeability, suppress intravascular leukocytosis, and mitigate neuroinflammation evidenced by decreased microglial activation, astrocyte reactivity, and macrophage infiltration. Transcriptomic profiling of cortical and hippocampal tissues reveals that FDPlts downregulate gene networks associated with inflammation and fibrosis, suggesting a role for FDPlts in the modulation of post-injury repair. Mechanistically, FDPlts are enriched in Angiopoietin-1, a key bioactive protein that signals through the Tie2 receptor pathway, a central regulator of endothelial stability. Inhibition of Tie2 exacerbates BBB permeability after TBI, an effect attenuated by FDPlt administration; implicating Ang-1 as a key mediator of FDPlts mediated BBB protection in TBI. The BBB plays a vital role in maintaining cerebral homeostasis, and its breakdown after TBI initiates harmful cascades of edema, inflammation, and neuronal injury. Our findings demonstrate, for the first time, that a dried, platelet-derived biologic can promote vascular repair and neuroprotection in TBI.

Lenalidomide, a maintenance treatment in multiple myeloma first-line therapy, increases the risk of secondary malignancies, including B-cell precursor acute lymphoblastic leukemia (B‑ALL). We present a comprehensive molecular characterization of 57 patients with lenalidomide-associated B-ALL (LenB-ALL), revealing three mutational subgroups: (1) TP53mt (30%), (2) IDH2mt (p.R140Q) (23%) and (3) other, including NRAS/KRASmt. Remarkably, IDH2 R140Q mutations were highly enriched in LenB-ALL compared to primary B-ALL (p<0.001). Furthermore, IKZF1 intragenic deletions - often subclonal and likely RAG-mediated - were observed in 54% (7/13) of IDH2mt LenB-ALL cases. IDH2 mutations were not restricted to the leukemic clone: they persisted during MRD-negative remission and were identified in lymphoid as well as myeloid cell populations using fluorescence-activated cell sorting and single-cell RNA sequencing. This indicates a preleukemic origin of the IDH2 mutation within the context of clonal hematopoiesis. Transcriptomic and DNA methylation analyses revealed a distinct gene expression profile and a DNA hypermethylation phenotype in IDH2mt LenB-ALL, including IDH2mt-specific as well as lenalidomide-associated features. We propose that lenalidomide promotes expansion of IDH2-mutated clonal hematopoiesis and, via IKAROS downregulation, induces a maturation arrest at the B-cell precursor stage. Subsequent genetic or epigenetic alterations render leukemogenesis independent of ongoing lenalidomide exposure. Altogether, these data define IDH2mt B-ALL as a distinct molecular subtype that is markedly overrepresented after lenalidomide treatment and highlight clonal hematopoiesis as a key contributing factor in the development of LenB-ALL.