Recent studies have described acquired ring chromosomes (aRCs), marker chromosomes, and extrachromosomal DNA (ecDNA) in various tumors. However, the genomic copy number aberrations (CNAs) and gene rearrangements within these aRCs require further genomic analysis, and the knowledge base to interpret their clinical implications remains largely unformed. A working group was organized by the International Consortium of Human Ring Chromosomes (ICHRC) to conduct a systematic evidence review of the role of aRCs in hematologic malignancies. This retrospective review summarizes the current molecular cytogenetic and genomic technologies for aRC analysis, presents an overview of the types of aRCs in various hematological malignancies, and provides evidence to support cytogenomic analysis and diagnostic interpretation. The findings from this study recommend an integrated cytogenomic analysis for aRCs and prompt further functional analyses to elucidate the molecular mechanisms for disease causation and targeted treatment.

Fms-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30

IPSS-M has improved prognostication in MDS by integrating clinical, cytogenetic, and molecular data. Here, we investigate the potential added value of considering frailty and comorbidity for improving prognosis prediction. Using data from a training set of 412 subjects with newly diagnosed MDS, we develop “Integrated IPSS-M”, a risk-stratification model that recalibrates IPSS-M based on age, frailty, and comorbidity. We then confirm the model’s performance on a validation set of 275 subjects. The Integrated IPSS-M showed higher concordance scores for overall survival compared with the IPSS-M (training set, 0.77 [95-percent confidence interval [CI], 0.73, 0.80] vs. 0.68 [0.64, 0.72], P < 0.001; validation set, 0.73 [0.68, 0.78] vs. 0.69 [0.64, 0.74], P = 0.03). Our study indicates that integration of IPSS-M, age, frailty, and comorbidity enhances prognostic accuracy in MDS. These findings suggest that Integrated IPSS-M may inform treatment decision-making and trial enrollment for new therapies.

Background:Enterococcal bloodstream infection (EBSI) carries high mortality in hematologic patients, yet no prognostic model tailored to this population exists. Methods:We retrospectively analyzed 192 hematologic patients (≥14 years) with EBSI admitted between 2014 and 2024. Clinical features, microbiology, treatment, and outcomes were assessed. Candidate predictors for 30-day mortality were selected by LASSO and entered into multivariable logistic regression. A simplified risk score was derived from regression coefficients and internally validated by bootstrap resampling. Results:The median patient age was 43 years, and acute leukemia was the predominant underlying disease (72.4%). Enterococcus faecium was the leading pathogen (71.4%), with low vancomycin resistance (1.6%). Most cases (71.9%) occurred as breakthrough infections, mainly during carbapenem therapy, and 72.9% met mucosal barrier injury laboratory-confirmed bloodstream infection criteria. The 14- and 30-day all-cause mortality rates were 13.5% and 22.4%, respectively. Independent predictors of 30-day mortality included age ≥50 years (aOR=2.29, p=0.038), severe graft-versus-host disease (aOR=6.06, p=0.003), septic shock (aOR=30.01, p<0.001). The final predictive model, incorporating these three factors along with pneumonia and high-risk hematologic disease, demonstrated optimal discrimination (AUROC 0.79, 95% CI 0.705-0.867) and calibration. A derived risk score stratified patients into low- (<2 points) and high-risk (≥2 points) groups, with markedly different 30-day mortality (11.3% vs. 39.0%, P<0.001). Conclusions:In hematologic patients, EBSIs commonly arise as breakthrough infections despite broad-spectrum antibiotic coverage, most often associated with mucosal barrier injury. Our parsimonious risk score enables early identification of patients at high risk of 30-day mortality to guide timely interventions.

6576 Background: Patients with essential thrombocythemia (ET) have limited disease-modifying options. This integrated analysis of 182 ET patients from 2 trials evaluated consistency the efficacy of ropeginterferon alfa-2b (ropeg, BESREMi) across treatment lines and examined the impact of ethnicity and molecular subtype on outcomes. Methods: Data were pooled from the phase 3 randomized SURPASS-ET study (ropeg vs anagrelide [ANA] in HU-resistant/intolerant high-risk ET) and the phase 2b single-arm EXCEED-ET study enrolling both treatment-naïve and previously treated patients in North America. Endpoints included durable modified ELN response, hematologic and molecular responses, thrombotic events, and safety. Results: In SURPASS-ET, ropeg achieved a significantly higher durable modified ELN response at months 9 and 12 than ANA (42.9% vs 6.0%; p<0.0001), with superior platelet and WBC control, greater JAK2 V617F allelic burden reduction, and fewer major thrombotic events. In EXCEED-ET, durable objective modified ELN responses reached 60.2%, with ELN2009 molecular response rates of 35.0% for JAK2 V617F, 16.0% for CALR , and 25.0% for MPL, demonstrating consistent efficacy across treatment lines and mutation subtypes (Table 1). Safety profiles were comparable between studies, with mostly low-grade, manageable AEs. In the integrated analysis across studies, grade ≥3 TEAEs occurred in 28.6% of ropeg recipients and 33.8% of ANA. TEAEs leading to discontinuation (8.8% vs 20.0%) and serious AEs (12.6% vs 30.0%) were less frequent in the ropeg group. Fatal AEs occurred only in the ANA group (3.8%). Conclusions: Across the two studies, consistent molecular and hematologic efficacy with a favorable and manageable safety profile was demonstrated in treatment-naïve and pretreated ET populations, across ethnicities and disease drivers. These findings support ropeg as a disease-modifying treatment option with a favorable benefit–risk profile for all ET patients regardless of ethnicity, treatment line, driver mutation status, and mutational complexity. Clinical trial information: NCT04285086 , NCT05482971 . Key efficacy outcomes from both trials. Outcome SURPASS-ET EXCEED-ET RopegN=91 ANAN=83 RopegN=91 Durable modified ELN response, % Subgroup analysis by race, % (n)CaucasianAsianAfrican AmericanHispanicOther 42.920 (1/5)44.2 (38/86)--- 6.00 (0/2)6.2 (5/81)--- 60.257.2 (41/71)53.0 (4/7)100.0 (5/5)66.7 (2/3)100.0 (5/5) Platelet control ≤400×10⁹/L, % 56.0 21.7 48.4 WBC normalization, % 73.6 13.3 48.4 Molecular response*, % (n) JAK2 V617F 30.6 (19/62) 0 (0/42) 35.0 (7/20) CALR 30.0 (3/10) 0 (0/4) 16.0 (4/25) MPL 0 (0/1) 0 (0/1) 25.0 (2/8) Major thrombotic events, % 1.1 10.0 1.1 *The molecular response per the 2009 ELN criteria includes complete and partial responses.

Congenital factor XII (FXII) deficiency is a rare disorder resulting from F12 gene mutations and its precise contribution to thrombotic or haemorrhagic risk has yet to be established. We identified the same mutation of the F12 gene across five pedigrees, yet the clinical manifestations varied markedly, ranging from asymptomatic to thrombotic and haemorrhagic phenotypes. Haematological assessments and deoxyribonucleic acid sequencing were conducted in five pedigrees. All five probands displayed prolonged activated partial thromboplastin time, markedly reduced FXII activity and an identical frameshift mutation in F12 (c.303_304delCA, p.H101Qfs*36), leading to the loss of functional domains. In Pedigree A, characterized by thrombotic clustering, thrombotic events were documented in 4 of 6 mutation carriers and 4 of 13 non-carriers. In Pedigree B, the proband experienced bleeding events, and her father died of intracerebral haemorrhage. Probands C and D remained asymptomatic. Proband E was diagnosed with essential thrombocythaemia and thrombosis. Across all pedigrees, haemorrhagic or thrombotic events could be attributed to additional contributing factors. The identified apolipoprotein E and butyrophilin subfamily 2 member A1 variants were consistently associated with thrombotic events in Pedigree A. This F12 variant does not appear to independently drive pathological coagulation phenotypes but may potentiate susceptibility to thrombosis in the presence of additional genetic or acquired risk factors.

We report a case of a 25-year-old male with recurrent oral ulcers, upper respiratory tract infections, and an 8-year history of chronic neutropenia. Previously diagnosed with Behçet's disease, the patient had undergone comprehensive hematological evaluations at multiple tertiary institutions, yet the etiology of his persistent neutropenia remained undetermined. Whole-exome sequencing revealed a TLR8-G572D mutation, leading to a diagnosis of autoimmune myelofibrosis (AIMF) secondary to TLR8 gain-of-function (GOF). While concurrent Behçet's disease and neutropenia may occur clinically, the underlying pathogenesis is often neglected. TLR8-GOF screening should be emphasized in young patients with such presentations. To our knowledge, this is the first reported association between TLR8-GOF mutation and AIMF, expanding the phenotypic spectrum of TLR8-related disorders.

RUNX1 is one of the most commonly mutated genes in myelodysplastic neoplasms (MDS) and essential for hematopoiesis. However, clinical phenotype features of RUNX1 mutated patients and the interaction between RUNX1 and other genes mutations remains incompletely explored. We enrolled 1473 consecutive adult patients with primary MDS to investigate the laboratory, genomic characteristics, and survival of RUNX1-mutated MDS subjects. We found that RUNX1 mutations are associated with older age (median, 59 vs. 56 years, p = 0.007), lower platelet counts (median, 50 × 109/L vs. 66 × 109/L; p < 0.001), higher bone marrow blasts (median, 6.0% vs. 2.5%, p < 0.001) and a higher proportion of micro-megakaryocytes (median, 26.0% vs. 18.7%, p < 0.001). Additionally, our data showed a correlation between the variant allele frequency (VAF) of RUNX1 mutations and proportion of micro-megakaryocytes (r = 0.242, p = 0.006), suggesting RUNX1 mutations burden was associated with dysmegakaryopoiesis. Mutations in ASXL1, SRSF2, EZH2 and NRAS were significantly more frequent in RUNX1-mutated patients compared with those without RUNX1 mutations (adjusted p < 0.05). RUNX1-mutated patients exhibited poorer overall survival (median OS 18 months vs. 51 month, p < 0.001), while U2AF1 co-mutations were associated with a relatively better prognosis (median OS 34 months vs. 17 months, p = 0.003), indicating a potential modifying effect of U2AF1 on the outcome of RUNX1-mutated patients.

Germline variants of DDX41 were broadly investigated in myeloid neoplasms (MNs), while there is a lack of a larger cohort of Chinese patients report, and impact of donor-derived DDX41 variants on transplant outcomes has not been fully explored. We retrospectively analyzed 460 patients carrying DDX41 variants among 41 290 individuals. Although most of patients (65%) were diagnosed with MNs (mostly MDS/AML), other rarer diseases, such as AA, ALL, and lymphoma, can occur. A total of 417 germline and 262 somatic DDX41 variants were identified. The predominant pathogenic/likely pathogenic (P/LP) germline variants were P258L (26%) and Y259C (20%), followed by loss-of-function variants (25%) and c.935+4A>T (5%), which can cause aberrant intron retention. The most common somatic variants were R525H (53%), then G530D (7%) and T227M (4%). Germline variants in MNs were more often P/LP than in AA or ALL. GO (germline only) and GS (germline+somatic) mutations were distinctly distributed among diseases. Among thirteen donors included in this cohort, nine underwent transplantation. Four out of five recipients with donor-derived DDX41-VUS variants continued to be in complete remission at 18 or 19 months after transplantation, compared to two out of four patients with donor-derived DDX41-P/LP variants. For the first time, this study identified P258L/Y259C as predominant Chinese-specific germline DDX41 variants, expanding disease spectrum to include non-myeloid disorders, and established GS genotype as a key biomarker for myeloid malignancies. In addition, our results suggested that pre-transplant DDX41 germline screening in related donors may be beneficial for mitigating donor-derived leukemia and achieving better clinical outcomes.

IntroductionMyelofibrosis (MF) is driven by JAK/STAT dysregulation. Gecacitinib, a novel JAK/ACVR1 inhibitor, is newly approved in China.Patients and MethodsThis study used matching-adjusted indirect comparison (MAIC) to compare gecacitinib vs ruxolitinib and pelabresib-ruxolitinib in JAK-naive MF. Individual patient data (IPD) from ZGJAK002/016 (gecacitinib, n=137) were weighted to match aggregated data from COMFORTI/II, SIMPLIFY1, A2202, MANIFEST2 (ruxolitinib), and MANIFEST-2 (pelabresib-ruxolitinib). Outcomes included SVR35, TSS50, HGB improvement, and safety.ResultsAfter matching baseline characteristics, gecacitinib showed better efficacy in 24-week SVR35 and TSS50 than most ruxolitinib groups, with lower risks of anemia, neutropenia, and treatment discontinuation due to adverse events (AEs). Versus pelabresib-ruxolitinib, gecacitinib had similar SVR35 (59.0% vs 65.9%, OR 0.74, P = 0.27), numerically higher TSS50 (59.9% vs 52.3%, OR 1.36, P = 0.24), but better hemoglobin improvement (HGB ≥ 1.5g/dl, 26.4% vs 10.7%, OR 2.98, P = 0.0012), lower AEs and AE-related discontinuation (RD -0.06, P = 0.033).Conclusion Gecacitinib may offers advantages over ruxolitinib and comparable efficacy but better tolerability than pelabresibru-xolitinib in JAK-naive MF.

Bacterial and fungal pulmonary infections (BFPI) are common in hematological patients and pose significant diagnostic challenges. Metagenomic next-generation sequencing (mNGS) is valuable for diagnosing BFPI. However, for hematological patients with limited access to lower respiratory tract samples (LRTS), the clinical value of blood-mNGS compared to LRTS-mNGS requires further investigation. A retrospective analysis was conducted on 160 cases with suspected pneumonia who underwent both blood-mNGS and LRTS-mNGS within one week. Diagnostic performance and impacts on antimicrobial adjustments were evaluated using clinical composite diagnosis (CCD) as the reference. Compared to CCD, LRTS-mNGS showed significantly higher positive percent agreement (PPA) than blood-mNGS [93.7

Ruxolitinib is first-line therapy for intermediate/high-risk myelofibrosis (MF), but ∼50% of patients discontinue within 1 year due to loss of efficacy or intolerance. Four JAK inhibitors (gecacitinib, fedratinib, pacritinib, momelotinib) are approved for ruxolitinib-pretreated MF, with no head-to-head trials comparing their efficacy and safety. This study used matching-adjusted indirect comparison (MAIC) to compare these four agents, aiming to provide evidence-based insights for treatment decision-making in ruxolitinib-resistant or intolerant MF. Individual patient data (IPD) of gecacitinib (100 mg BID; ZGJAK006/ZGJAK017, n = 78) and published data of comparators (fedratinib: JAKARTA-2/FREEDOM2; pacritinib: PAC203; momelotinib: SIMPLIFY-2/MOMENTUM) were analyzed. Eight baseline characteristics were matched. Efficacy outcomes (week-24 SVR35, TSS50, transfusion independence [TI]) were reported as odds ratios (ORs); safety as risk differences (RDs). Gecacitinib showed superior SVR35 versus fedratinib (JAKARTA-2: OR = 3.96, 95% CI = 1.37-11.39, P = 0.0108), pacritinib (PAC203: OR = 6.10, 95% CI = 1.54-24.23, P = 0.0101), and momelotinib (SIMPLIFY-2: OR = 8.65, 95% CI = 1.86-40.31, P = 0.0060), and superior TSS50 versus pacritinib (OR = 7.62 95% CI = 1.84-31.51, P = 0.0050) and momelotinib (MOMENTUM: OR = 7.52, 95% CI = 1.63-34.61, P = 0.0096). Numerically, gecacitinib had better TI. It also had significantly lower incidences of diarrhea, nausea, and AE-related treatment discontinuation. Hematologic AE profiles of gecacitinib varied by comparator cohort. Gecacitinib showed favorable efficacy and tolerability signals versus several comparators, suggesting it may be a valuable second-line option.

Proinflammatory signaling is a hallmark of myeloproliferative neoplasms. Several studies have shown that monocytes are a major source of proinflammatory cytokines and that monocyte-derived fibrocytes play a pivotal role in the pathogenesis of myelofibrosis (MF). To further explore the role of monocytes in MF, we generated inducible NrasG12D/+- Jak2V617F/+ (NJ) mice. Recipients transplanted with NJ bone marrow (BM) cells developed MF with an early onset of anemia and monocytosis. In vitro, NJ recipients' BM nucleated cells exhibited an increased quantity of CD45 +CollagenI+ fibrocytes, which were mainly derived from the Ly6chigh monocytes. RNA sequencing identified a significant elevated expression of CD38 (a NAD+ hydrolase) in Ly6chigh monocytes from NJ mice, which results in a pronounced lower level of NAD +. In humans, CD14+ monocytes from patients with MF showed a significantly higher expression of CD38 than controls and monocytes from patients with polycythemia vera with grade 1 fibrosis had higher CD38 expression than those without fibrosis. Finally, boosting NAD+ via pharmacological CD38 targeting or NAD+ precursor supplementation inhibited the differentiation of fibrocytes in vitro and targeting CD38 can effectively prevent the onset of fibrosis in vivo. Collectively, our findings shed light on the role of CD38 in monocytes and suggest potential clinical applications such as the use of CD38 as a biomarker of fibrotic progression and the clinical utility of CD38 inhibition in patients with MF.

Polycythemia vera (PV), a BCR::ABL1-negative myeloproliferative neoplasm characterized by erythrocytosis and commonly associated with the JAK2V617F mutation, remains incurable. Leukocytosis and JAK2V617F variant allele frequency (VAF) in peripheral blood cells correlate with thrombotic risk and disease progression. Durable complete molecular response (CMR), defined by undetectable JAK2V617FVAF, indicates clearance of disease-driving neoplastic cells and improved clinical outcomes. Ropeginterferon alfa-2b (ropeg), a mono-pegylated interferon, selectively inhibits neoplastic cell proliferation, reducing tumorigenicity and clonal expansion. One study to date has shown that a Higher Initial Dose (250 µg) and Accelerated Titration (HIDAT) regimen can lead to rapid complete hematologic and deep molecular remission. Here, we present 36-month follow-up data from this phase 2, multicenter, single-arm trial (N=49) evaluating the HIDAT regimen in hydroxyurea-intolerant PV patients. Forty-four patients entered the extension phase post-first-year treatment, with 43 completing 36 months of treatment. Despite dose reductions and extended intervals from biweekly to monthly dosing during stabilization, patients maintained high complete hematologic remission (CHR) rates: 75.0% (33/44) at Month 24; 84.1% (37/44) at Month 30, and 75.0% (33/44) at Month 36. Median JAK2V617F VAF significantly reduced from 61.2% (baseline) to 4.9% (at 36 months), with molecular responses observed in 86.0% (37/43) of patients, including 34.9% (15/43) achieving CMR. Event-free survival (EFS) was significantly higher in patients achieving CMR (3-year EFS 100%) compared to those without molecular response (3-year EFS 70%, p=0.035). There was no significant difference in EFS between patients achieving partial molecular response compared to those without molecular response. Furthermore, ropeg demonstrated a favorable safety profile, with no Grade 4 or higher adverse events (AEs) observed and grade 3 AEs occurring in only 9.1% of patients (4/44). The most common AEs included leukopenia and elevated transaminases. None of which resulted in significant clinical consequences. No patients developed disease progression to secondary myelofibrosis or acute myeloid leukemia on the study, and only one major thrombosis and two bleeding events occurred. In conclusion, long-term ropeg administration under an optimized HIDAT regimen effectively sustains CHRs, induces profound molecular responses, and exhibits favorable safety in hydroxyurea-intolerant PV patients. Achieving CMR correlated with improved EFS, highlighting its prognostic significance.

Inappropriate empirical antimicrobial therapy (IEAT) significantly increases mortality in patients with resistant Gram-negative bacteremia. We developed a multitask machine learning framework to predict carbapenem resistance (CR), β-lactam/β-lactamase inhibitor combinations resistance (BL/BLI-R), and third-/fourth-generation cephalosporins resistance (3GC/4GC-R) in HM patients with monomicrobial BSIs caused specifically by Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae. Using retrospective data from 1,353 HM patients with three specific Enterobacterales BSIs (2017–2023), we trained support vector machines, eXtreme Gradient Boosting, and logistic regression models through 5-fold cross-validation with hyperparameter tuning and conducting internal validation via bootstrap. Model thresholds were optimized via Pareto front analysis to minimized IEAT and carbapenem use while maximizing sensitivity. The models achieved AUCs of 0.81 (95

Hypoplastic myelodysplastic neoplasms (MDS-h) and MDS with low blasts (MDS-LB) are characterized by low blasts and absence of defining cytogenetic abnormalities, generally conferring better outcomes than other MDS subtypes. We retrospectively analyzed 146 patients with MDS-h and 490 with MDS-LB. Median follow-up was 1168 days and median age was 52 years. MDS-h patients had more severe cytopenias, while MDS-LB showed greater disease burden. U2AF1 (27.29%) and ASXL1 (24.13%) were common mutations. At diagnosis, 42.41% were transfusion-dependent (TD), and 52.08% were Molecular International Prognostic Scoring System (IPSS-M) higher-risk, with comparable rates between subgroups. Among initially transfusion-independent patients (n=368), the cumulative incidence of TD during follow-up was 45.56%, independently predicted by IPSS-M higher-risk (HR=2.065). The estimated 5-year OS was 60.5%, higher in MDS-h (75.6%) than MDS-LB (55.6%, P=0.001). The 5-year cumulative incidence of progression was 14.7%, without subtype difference (P=0.141). TD at diagnosis (HR=3.271), U2AF1 mutations (HR=1.473), age>65 (HR=2.282), and bone marrow blasts≥2% (HR=1.433) were independent adverse predictors for OS. U2AF1 mutations (HR=2.096), bone marrow blasts≥2% (HR=2.105) and IPSS-M higher-risk (HR=2.027) were also associated with progression. In TD patients≤65 years, allogeneic hematopoietic stem cell transplantation (allo-HSCT) improved OS (HR=0.513, P=0.017) and reduced transfusion burden. In this large cohort, we observed a strong association between TD and IPSS-M risk classification. Both MDS-h and MDS-LB patients demonstrated generally favorable survival with low rates of disease progression. Allo-HSCT should be considered for TD patients to improve long-term outcomes.