We evaluated the effectiveness of adding anti-PD-1 antibody to P-GEMOX regimen in previously untreated advanced-stage natural killer/T-cell lymphoma (NKTCL) compared to P-GEMOX alone or with autologous stem cell transplantation (ASCT). 418 patients (135 and 283 in the immunochemotherapy and chemotherapy groups, respectively) were analyzed from 15 Chinese centers (2014-2023). The median follow-up was 40.7 months. The immunochemotherapy group had a higher objective response rate (ORR) (89.6% versus 77.0%), complete response (CR) rate (77.0% versus 50.5%), 3-year progression-free survival (PFS) rate (64.1% versus 40.7%), and 3-year overall survival (OS) rate (79.5% versus 60.8%) compared to the chemotherapy group. Grade 3-4 neutropenia was more common in the immunochemotherapy group (40.0% versus 20.8% in the chemotherapy group, p < 0.001). Grade 3-4 hematologic toxicities were prevalent during ASCT, whereas anti-PD-1 maintenance was well tolerated. Grade ≥3 non-hematologic adverse events during anti-PD-1 maintenance were rare. In propensity score-matched (PSM) analysis of patients achieving CR after induction (n = 41 per group), the 3-year disease-free survival (DFS) rate was 72.6% for immunochemotherapy plus anti-PD-1 maintenance versus 50.9% for chemotherapy plus ASCT (p = 0.032), and the 3-year OS rate was 91.5% versus 72.9% (p = 0.029). First-line anti-PD-1 antibody plus P-GEMOX followed by anti-PD-1 maintenance shows better response and survival over P-GEMOX chemotherapy alone and P-GEMOX with ASCT, while maintaining acceptable toxicity.

Current staging systems for natural killer/T cell lymphoma (NKTCL) inadequately reflect its predominantly extranodal presentation and lack prognostic accuracy in the asparaginase era. This retrospective multicenter study analyzes 1,872 newly diagnosed NKTCL patients treated with asparaginase-based regimens or radiotherapy alone, from 15 institutions across China. For nasal-type NKTCL, skull base invasion (SBI) is identified as an independent adverse prognostic factor. We reclassify Ann Arbor stage I patients with SBI as stage II and stage II patients with SBI as stage III. For non-nasal-type NKTCL, we retain the Chinese Southwest Oncology Group and Asia Lymphoma Study Group (CA) system due to its superior prognostic discrimination. The revised system demonstrates improved outcome prediction, hazard discrimination, hazard consistency, and sample balance across training, internal, and external validation cohorts. Time-dependent receiver operating characteristic (ROC) analysis confirms superior predictive accuracy over existing systems. This proposal provides a refined prognostic framework to guide clinical decision-making and optimize patient selection for future trials.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, among which NK-cell malignancy-associated HLH represents a clinically rare entity that has not been systematically investigated. The multicenter retrospective cohort study analyzed data from 136 adult patients diagnosed with HLH related to NK-cell malignancies between 2010 and 2024. The results demonstrated that initial treatment with etoposide-containing HLH therapy improved 60-day survival rates (P = 0.009) but did not affect overall survival (OS) (P = 0.306), whereas asparaginase-containing lymphoma regimens significantly improved both OS (P = 0.025) and 60-day survival rates (P = 0.016) in treatment-naive patients. By multivariate analysis, significant independent predictors of 60-day poor outcomes included serum albumin level < 30 g/L (HR, 2.03; 95

Purpose:Diffuse large B-cell lymphoma (DLBCL) is genetically heterogeneous. We aimed to define a compartment-aware driver mutation landscape of DLBCL by integrating tumor tissue and circulating cell-free DNA (cfDNA) sequencing, and to assess its biological and prognostic relevance. Materials and Methods:Somatic mutations were analyzed from targeted sequencing of tumor tissue or bone marrow and cfDNA from peripheral blood or cerebrospinal fluid, including paired tissue-liquid samples, together with whole-genome sequencing data from TCGA. Driver genes were identified using four complementary algorithms. Functional enrichment and protein-protein interaction analyses were performed. Prognostic relevance was evaluated using multigene expression-based modeling with Cox and LASSO regression in independent cohorts. Results:Recurrent driver alterations converged on core pathogenic pathways, including B-cell receptor signaling, NF-κB activation, epigenetic regulation, and immune escape. Twenty-two high-confidence driver genes, including PIM1, KMT2D, CD79B, B2M, TP53, MYC, and EZH2, were consistently identified across clinical cohorts and supported by TCGA data. cfDNA profiling showed substantial concordance with tissue-derived drivers while revealing gene-specific differences in mutation burden and co-mutation patterns, indicating complementary capture of clinically relevant heterogeneity. Network analysis highlighted TP53, MYC, EP300, and CREBBP as central hubs. A four-gene expression-based model (MYC, PLCL1, IRF8, LNPEP) stratified patients by overall survival and modestly improved prognostic discrimination beyond the International Prognostic Index. Conclusion:Integrated analysis of tumor tissue and cfDNA sequencing defines a clinically relevant driver framework for DLBCL. cfDNA preserves core oncogenic signals while complementing tissue profiling, supporting refined genomic risk stratification.

Background:Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder characterized by uncontrolled inflammation. In adults, lymphoma is the most common underlying cause. The lipid profile is frequently dysregulated in lymphoma-associated HLH (LA-HLH), and the clinical significance remains to be determined. Objectives:This study aimed to evaluate the prognostic value of baseline lipid profiles and the dynamic changes in high-density lipoprotein cholesterol (HDL-c) in adult patients with LA-HLH. Design:A multicenter, retrospective cohort study. Methods:We analyzed 277 adult patients with LA-HLH from 27 medical centers (2015-2023). Baseline lipid levels and post-treatment HDL-c levels were measured. The optimal prognostic cutoff was determined using X-tile software. Survival analysis was performed using Kaplan-Meier and Cox regression methods. Results:Low HDL-c (<1.03 mmol/L) was observed in 93.9% (260/277) patients at diagnosis. A baseline HDL-c <0.48 mmol/L was independently associated with reduced overall survival (OS; hazard ratio, HR = 1.51, 95% confidence interval, CI: 1.10-2.09, p = 0.012) and 60-day survival (HR = 1.66, 95% CI: 1.10-2.49, p = 0.015). The post-treatment/baseline HDL-c ratio was significantly lower in patients with T/NK-cell malignancies than in those with B-cell non-Hodgkin lymphoma. A lower ratio (<1.71) was significantly associated with reduced survival. Patients with both low baseline HDL-c (<0.48 mmol/L) and low ratio (<1.71) constituted a high-risk group with the worst outcomes (60-day survival: 46.7% vs 81.8%, p = 0.004; median OS: 52 days vs not reached, p < 0.001). Conclusion:HDL-c and its dynamic changes are clinically feasible markers for predicting outcomes in patients with LA-HLH.

The FDA granted accelerated approval to KPT-330 (selinexor) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, 80% of patients experienced gastrointestinal toxicity. Milk exosomes (mExos) possess high stability in the gastrointestinal environment and the ability to traverse the gastrointestinal barrier, making them an excellent choice for oral drug delivery. Here, we isolated and identified mExos, which demonstrated good stability in simulated fed-state gastrointestinal fluids. These exosomes effectively encapsulated KPT-330, enhancing drug accessibility within DLBCL and sustaining intracellular accumulation over an extended period. mExo-KPT-330 showed a slight increase in size, with no apparent changes in shape or biological characteristics. mExo-KPT-330 outperformed free KPT-330 in vitro, exhibiting a more potent DLBCL-suppressive effect. Furthermore, in DLBCL mouse models, mExo-KPT-330 exhibited a significantly reduced disease burden compared to free KPT-330. Notably, mExo-KPT-330 alleviated the disorganization of the intestinal epithelium, edema in the villous stroma of the small intestine, lymphocyte infiltration, and elevated serum levels of LPS and IL-12 caused by free KPT-330 treatment. Additionally, mExo-KPT-330 exhibited no organ toxicity. Encapsulating KPT-330 in mExos significantly increased its permeability across the intestinal epithelial barrier. Moreover, mExo-KPT-330 maintained its intact exosomal form after being transported across the intestinal epithelial barrier. Collectively, our results suggest that mExo loaded with KPT-330 has promising anti-DLBCL effects and that oral administration is beneficial for alleviating gastrointestinal adverse reactions induced by KPT-330.

Multiple myeloma (MM) progression involves extensive immunosuppressive remodeling of the bone marrow microenvironment. In this study, we performed a comprehensive mass spectrometry-based proteomic analysis of exosomes derived from MM cells (MM-Exos), revealing that these exosomal proteins are predominantly enriched in pathways associated with immune regulation. We demonstrated that MM-Exos effectively drive macrophage polarization toward the M2 phenotype, thereby facilitating the establishment and maintenance of an immunosuppressive tumor microenvironment. Mechanistically, we identified the ERK1/2 signaling pathway as a critical mediator of MM-Exo-induced macrophage polarization. Importantly, we found that simvastatin, a widely used inhibitor of cholesterol biosynthesis, effectively impaired exosome secretion from MM cells and subsequently reduced M2 macrophage polarization. Collectively, our study reveals a novel mechanism of immune evasion in MM, in which MM-Exos promote the polarization of macrophages toward the M2 phenotype via ERK1/2 pathway activation. These findings underscore the therapeutic potential of targeting exosome-mediated intercellular communication within the MM bone marrow microenvironment to improve clinical outcomes.

Resistance to proteasome inhibitors (PIs) and inadequate engagement of anti-tumor immunity remain major barriers to effective treatment of multiple myeloma (MM). Here, we identified anwulignan, a bioactive natural product, as a translationally promising agent that retains activity in PI-resistant MM cells and promotes anti-myeloma immune responses. Anwulignan demonstrated potent cytotoxic activity against MM cells and exhibited strong synergy with proteasome inhibitors both in vitro and in vivo. In mouse MM models, anwulignan significantly suppressed tumor growth while maintaining favorable tolerability and safety profiles. Mechanistically, nucleophosmin 1 (NPM1) has been identified as a direct molecular target of anwulignan. Elevated NPM1 expression correlates with poor clinical outcomes in MM, and its inhibition by anwulignan induces cell cycle arrest and apoptosis. In addition to its tumor-intrinsic cytotoxic effects, anwulignan activated the caspase-1–dependent gasdermin D (GSDMD) pyroptosis pathway, thereby inducing immunogenic cell death. Genetic silencing of GSDMD markedly impaired anwulignan-mediated tumor suppression in vitro and in vivo, highlighting pyroptosis as a critical effector mechanism. In immunocompetent syngeneic MM models, anwulignan treatment increased bone marrow and splenic T-cell proportions and achieved superior tumor control compared with GSDMD-deficient tumors. Collectively, these findings establish anwulignan as a dual-function therapeutic that directly targets MM cell survival while simultaneously promoting anti-tumor immunity through pyroptosis-driven immunogenic cell death. This study provides a strong translational rationale for leveraging natural products as immune-engaging strategies to target drug-resistant multiple myeloma and improve therapeutic outcomes.

Light-chain (AL) amyloidosis is a rare disease and its early diagnosis remains challenging. This study aimed to develop an artificial intelligence (AI)-based diagnostic assistance system to improve the early diagnosis of AL amyloidosis and facilitate earlier and more precise disease management. Through cooperation with 18 hospitals in the Chinese Registration Network for Light-chain Amyloidosis (CRNLA), 1,355 patients with AL amyloidosis were registered and followed up from January 2010 to January 2022. Ten variables that are easily monitored in clinics, including age, cardiac troponin I (cTnl), N-terminal prohormone B-type natriuretic peptide (NT-ProBNP), creatinine (Crea), albumin (ALB), total bilirubin (Tbil), alkaline phosphatase (ALP), interventricular septum (IVS), left ventricular posterior wall (LVPW), and ejection fraction (EF), were selected. An early assistant diagnostic model of AL amyloidosis was established using gradient boosting decision tree (GBDT), support vector machine (SVM), random forest (RF), and ensemble learning models. A validation subset of challenging cases from the external validation set was used to compare the performance of the AI-based early diagnostic assistance system to that of physicians. All of the typical machine learning algorithms, namely the GBDT, SVM, RF, and ensemble learning models, performed well. The ensemble learning model was considered to have the best performance in the external validation set based on its highest F1 value (0.94) and an area under the receiver operating characteristic (ROC) curve of 0.9784 (95% confidence interval [CI]:0.963-0.987). Performance comparisons between the AI-based early diagnostic assistance model and physicians suggested that the diagnostic accuracy of the AI model (0.95,95%CI:0.92-0.98;P < 0.05) substantially exceeded that of the hematologists (0.73,95%CI:0.7-0.82) and other physicians (0.65,95%CI: 0.61-0.71). The model established by AI, which uses routine laboratory and echocardiography results, can predict the possibility of AL amyloidosis in various scenarios, which may support the early diagnosis of this rare disease.

High-dose methotrexate (HD-MTX) serves as the cornerstone of central nervous system lymphoma (CNSL) treatment, but its efficacy is limited due to low blood–brain barrier (BBB) penetration and adverse effects. This study is focused on an exosome-based drug delivery approach aimed at enhancing BBB permeability, thereby reducing the required dosage of methotrexate (MTX) while ensuring specific targeting of CNSL. Human adipose-derived mesenchymal stem cells (hAMSCs) were modified with a lentiviral vector encoding anti-CD19, incorporated into exosomes characterized by colloidal gold immunoelectron microscopy and Nano flow cytometry. MTX loaded into anti-CD19-Exos via co-incubation, assessed for loading and encapsulation efficiencies using HPLC. In vitro BBB model constructed using hCMEC/D3 and astrocytes to investigate BBB permeability. In vivo efficacy of anti-CD19-Exo-MTX evaluated in intracranial CNSL models using MRI. Biodistribution tracked with DiR-labeled exosomes, drug concentration in CSF measured by HPLC. LC-MS/MS identified and characterized exosomal proteins analyzed using GO Analysis. Neuroprotective effects of exosomal proteins assessed with TUNEL and Nissl staining on hippocampal neurons in CNSL models. Liver and kidney pathology, blood biochemical markers, and complete blood count evaluated exosomal protein effects on organ protection and MTX-induced myelosuppression. We generated anti-CD19-Exo derived from hAMSCs. These adapted exosomes effectively encapsulated MTX, enhancing drug accessibility within lymphoma cells and sustained intracellular accumulation over an extended period. Notably, anti-CD19-Exo-MTX interacted with cerebrovascular endothelial cells and astrocytes of the BBB, leading to endocytosis and facilitating the transportation of MTX across the barrier. Anti-CD19-Exo-MTX outperformed free MTX in vitro, exhibiting a more potent lymphoma-suppressive effect (P < 0.05). In intracranial orthotopic CNSL models, anti-CD19-Exo-MTX exhibited a significantly reduced disease burden compared to both the MTX and Exo-MTX groups, along with prolonged overall survival (P < 0.05). CSF drug concentration analysis demonstrated enhanced stability and longer-lasting drug levels for anti-CD19-Exo-MTX. Anti-CD19-Exo-MTX exhibited precise CNSL targeting with no organ toxicity. Notably, our study highlighted the functional potential of reversal effect of hAMSCs-exosomes on MTX-induced neurotoxicity, hepatic and renal impairment, and myelosuppression. We present anti-CD19-Exo-MTX as a promising exosome-based drug delivery platform that enhances BBB permeability and offers specific targeting for effective CNSL treatment with reduced adverse effects.

Diffuse large B-cell lymphoma (DLBCL) is a common subtype of Richter transformation (RT) in chronic lymphocytic leukaemia (CLL), accounting for 90-95% of all transformation cases. However, RT with isolated cerebral involvement is rare. Herein, we report the case of a 67-year-old man with DLBCL that transformed from CLL during obinutuzumab treatment. This patient developed RT with only central nervous system (CNS) involvement and no systemic features. After undergoing single-agent treatment with the CD20×CD3 bispecific antibody glofitamab, the patient regained consciousness and improved clinically. Although only one successful case has been presented, glofitamab may be considered a promising therapeutic option for patients with RT and isolated CNS involvement.

Introduction: Despite significant therapeutic advances, patients with triple-class-exposed and triple-class-refractory multiple myeloma continue to face poor clinical outcomes. TQB2934 is an innovative 2+1 BCMA × CD3 bispecific antibody featuring bivalent BCMA binding domains and a monovalent CD3 domain. This unique design enables simultaneous targeting of BCMA-expressing myeloma cells and CD3-expressing T cells, resulting in T cell activation and subsequent myeloma cell death. We present updated results from an ongoing phase I study (NCT05646758) evaluating TQB2934 monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). Methods: This study is an open-label, phase I trial comprising dose escalation and expansion phases. Eligible patients were aged 18-75 years with RRMM who had received ≥1 prior lines of therapy, including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. Patients with prior BCMA-targeted therapies were excluded from the dose escalation cohort. Dose escalation followed a Bayesian Optimal Interval design. TQB2934 was administered intravenously with weekly (QW) dosing in cycles 1-3, biweekly (Q2W) in cycles 4-6, and monthly (Q4W) from cycle 7 onward for patients achieving partial response or better (28-day cycles). The regimen included two step-up doses administered one week before target doses of 3mg, 10mg, 20mg, and 40mg. Primary objectives included safety assessment, determination of maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) based on dose-limiting toxicities (DLTs). Secondary objectives encompassed evaluation of preliminary anti-myeloma activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Results: As of July 20, 2025, 60 RRMM patients have been treated with TQB2934. The median age was 67 years (range 39-75), with 56.7% female patients. IgG and IgA myeloma subtypes accounted for 53.3% and 21.7% of cases, respectively. According to the Revised International Staging System (R-ISS), 63.3% of patients had stage II/III disease, while 45% harbored high-risk cytogenetic abnormalities and 13.3% presented with extramedullary disease. Patients had received a median of 3 prior lines of therapy (range 1-6), with all patients being refractory to their last line of treatment.TQB2934 was tested across dose levels ranging from 0.09 to 40mg, with the MTD not yet reached. A single DLT event (grade 4 ICANS) occurred at the 3mg dose level without step-up dose. 40mg was determined as the RP2D, which includes two step-up doses of 1mg and 6mg. Treatment-emergent adverse events (TEAEs) were observed in 93.3% (56/60) of patients. The most frequent TEAEs (occurring in ≥30% of patients) included lymphopenia (63.3%), CRS (58.3%), neutropenia (56.7%), leukopenia (55%), anemia (55%), thrombocytopenia (51.7%), hypokalemia (46.7%), hypocalcemia (40%), diarrhea (40%), and fever (31.7%). Grade ≥3 TEAEs were reported in 75% (45/60) of patients, with the most common being lymphopenia (40%), neutropenia (33.3%), anemia (25%), pneumonia (25%), thrombocytopenia (21.7%), and leukopenia (20%). CRS events were predominantly grade 1-2, with only two grade 3 cases reported. CRS typically occurred following the first target dose and resolved within 3 days. One patient experienced fatal grade 4 ICANS. Among 52 efficacy-evaluable patients across all dose levels, 32 patients achieved partial response or better, the overall response rate (ORR) was 61.54%. No responses were observed at doses below 3mg. At doses ≥20mg, the ORR was 70%, with ≥very good partial response (VGPR) and ≥complete response (CR) rates of 52.5% and 22.5%, respectively. Specifically, at the 20mg dose level, these rates were 61.5%, 53.8%, and 30.8%, while at 40mg they were 74.1%, 51.9%, and 18.5%, respectively. Pharmacokinetic analysis demonstrated dose-proportional increases in plasma peak concentrations and AUC, with no evidence of drug accumulation. Notably, changes in serum soluble BCMA levels at cycle 2 day 1 showed significant correlation with clinical response. Conclusions: TQB2934, a novel 2+1 BCMA bispecific antibody, has demonstrated a manageable safety profile and encouraging clinical activity at doses ≥20mg in heavily pretreated RRMM patients. These results position TQB2934 as a promising new therapeutic option for this challenging patient population.

Although the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been well recognized as the sensor of cytosolic DNA and plays a critical role in regulating anti-tumor immunity and cell death, whether and how cGAS plays a role in tumorigenesis and tumor progression is not well understood. Here we show that high level of cGAS was associated with poor prognosis in DLBCL patients. Using CRISPR-cas9 cGAS knockout DLBCL cell lines, we find that cGAS inhibition leads to a significant decrease of cell viability, cell growth and proliferation rate, and a significant increase of ferroptosis with mitochondrial and lipid ROS accumulation. These phenotypes can be largely rescued with ferroptosis inhibitors ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1). Pharmaceutically inhibition of cGAS with a cGAS inhibitor G140 exhibited the same phenotype. Furthermore, we find that this cGAS induced ferroptosis resistance is not STING dependent. In vivo mouse xenograft models also showed a decrease of tumor growth with cGAS knockout. Mechanically, cGAS inhibits tumor suppressor TP53 protein expression and prevents DLBCL cell lines from undergoing ferroptosis. cGAS knockout leads to a rescue of TP53 and a decrease of MDM2, which sensitizes cells to ferroptosis. Our findings uncover a new mode of tumor promotion based on cGAS regulation of p53-MDM2, ROS responses and ferroptosis. Collectively, this previously unrecognized role for cGAS in cancer progression suggests that cGAS can serve as potential targets for new cancer interventions. Citation Format: Rui Wang, Bingzong Li. cGAS inhibits TP53 and prevents DLBCL cell lines from ferroptosis death [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B003.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma characterized by high rates of relapse and limited responsiveness to standard chemotherapy. Selinxor, a selective inhibitor of XPO1, exhibited antitumor activity in various cancers. However, clinical trial results revealed that selinexor monotherapy exhibited unsatisfactory efficacy in DLBCL. Our study indicated that XPO1 expression was increased in DLBCL and was correlated with poor outcomes of DLBCL patients. Comprehensive proteomic and transcriptomics analysis showed that selinexor has significant impacts on various biological processes in DLBCL. Furthermore, we explored combination strategies involving selinexor to enhance DLBCL treatment. We examined the combined effects of selinexor with decitabine (DAC) and lenalidomide (LEN), and found that selinexor exhibited a synergistic effect with DAC against DLBCL. Further analysis revealed that DAC exerted a synergistic antitumor effect with selinexor by reversing the DNMT1 expression and DNA methylation alterations induced by selinexor. Overall, these findings provided valuable insights into the global impact of selinexor on DLBCL. The combination therapy of selinexor and DAC emerges as a highly promising strategy for effectively treating DLBCL, holding great potential for clinical application.

Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) is a life-threatening hyperinflammatory syndrome, and hierarchical management based on a prognostic model is important. The endothelial activation and stress index (EASIX) score has demonstrated prognostic utility in recipients of allogeneic stem cell transplantation and chimeric antigen receptor (CAR) T-cell therapy. However, its role in LA-HLH remains unestablished. We conducted a multicenter retrospective analysis of patients with LA-HLH from 28 medical centers to explore the prognostic impacts of EASIX in LA-HLH. EASIX was calculated using baseline lactate dehydrogenase, serum creatinine, and platelet counts. A total of 490 patients with LA-HLH were included and stratified by EASIX quartiles (Q1-Q4). Patients with a higher EASIX score had significantly inferior 2-month survival and overall survival, according to the Kaplan-Meier analysis (log-rank p < 0.001). In multivariable analyses, after adjustment for age, gender, lymphoma type, splenomegaly, bone marrow infiltration, lymphoma status (treatment-naïve versus relapsed/refractory), hemoglobin, absolute neutrophil count, serum ferritin levels, and aspartate aminotransferase, the highest EASIX quartile (Q4) exhibited a 7.01-fold risk of death compared to the lowest quartile (Q1) (Hazard ratio [HR] = 7.01, 95% confidence interval [CI]: 3.98-12.36; p < 0.001). Additionally, the restricted cubic splines (RCS) analysis illustrated an increase in the risk of mortality with an increasing EASIX score. Our findings support EASIX being a robust, universally accessible prognostic marker for LA-HLH, strongly associated with early mortality risk. This index can be used to stratify the risk levels of patients with LA-HLH and predict their survival outcomes.