The increasing availability of genomic and transcriptomic sequencing has uncovered diverse genomic alterations and distinct gene expression profiles driving hematologic diseases, yet a data integration and sharing platform dedicated to hematology remains lacking. We developed the American Society of Hematology (ASH) HematOmics Program (ASHOP, ashop.hematology.org), a resource for exploring somatic alterations and gene fusions, transcriptomic results, and clinical data from 5,960 patients spanning B-cell precursor and T-cell acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndromes, and chronic lymphocytic leukemia. Users can explore genomic alteration landscapes and co-mutation patterns via lollipop and matrix plots, and analyze significantly altered genes in user-defined sub-cohorts. Transcriptomes can be explored through interactive UMAPs, clustering, differential expression, and pathway enrichment. Genomic, transcriptomic features, and clinical outcomes can be correlated in a user-driven manner, or combined to precisely define study cohorts. We illustrate four use cases of ASHOP: (1) stratification of DUX4-rearranged B-cell leukemias into Early/Multipotent and Committed subgroups with distinct outcomes, (2) characterization of HOXA/HOXB expression patterns in acute myeloid leukemias, (3) correlating mutational burden with mismatch repair deficiency and mutational signatures, (4) investigation of TP53 alteration landscape. ASHOP is an open-access resource to inform genomic and transcriptomic data interpretation for hematologic malignancies, and will expand to support additional diseases and data modalities from the ASH community.

Dynamin-related protein 1 (Drp1) is an abundant platelet protein best known for its function in mitochondrial fission. Yet little is known about how Drp1 is controlled during platelet activation. While evaluating signaling pathways leading to phosphorylation of Drp1 in platelets, we identified a phosphorylation network wherein activation of G protein-coupled receptors or ITAM/hemITAM receptors resulted in phosphorylation of Ser616-Drp1 via p38. These signaling mechanisms were reinforced by ADP- and TxA2-mediated amplification pathways. In contrast, exposure of platelets to pacifying agents such as PGE1 or nitric oxide resulted in Ser637-Drp1 phosphorylation by cyclic nucleotide-dependent protein kinases. This unique circuitry was leveraged to develop immune-based platelet function assays, enabling ELISA and lateral flow assay formats. Compared to standard platelet function assays, Drp1 phosphorylation remained robust in whole blood samples following agitation or extended incubation and samples could be frozen for batching. As proof-of-principle for antiplatelet testing, phospho-Drp1 measurements were obtained at baseline, during a week of aspirin or clopidogrel exposure, and during a week of washout. Arachidonic acid-induced Ser616-Drp1 phosphorylation following aspirin ingestion demonstrated an enhanced dynamic range with improved linearity relative to light transmission aggregometry and improved signal to noise relative to the VerifyNow™ aspirin test. Ser637-Drp1 phosphorylation enabled sensitive detection of clopidogrel ingestion. These studies elucidate the unique signaling circuit controlling Drp1 phosphorylation in platelets and validate the approach of using detailed knowledge of platelet signaling pathways to develop high-fidelity immune-based assays to monitor platelet function.

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.