Metabolic reprogramming has emerged as a key driver of therapy resistance in acute myeloid leukemia (AML). Here, we identify phosphoserine aminotransferase 1 (PSAT1) as a critical metabolic determinant of venetoclax (VEN) resistance through the suppression of ferroptosis. PSAT1 was consistently upregulated in VEN-resistant cell lines and relapsed patient samples. Mechanistically, the transcription factor ATF4 directly bound the PSAT1 promoter, enhancing its expression and subsequently promoting glutathione synthesis, depleting the labile iron pool, and attenuating lipid peroxidation. Concurrently, PSAT1 functioned to restrain JNK/c-Jun signaling. Knockdown of PSAT1 restored VEN sensitivity by triggering ferroptosis and modulating the expression of BCL-2 and GPX4. Clinically, elevated PSAT1 expression predicted poor patient survival. Our findings unveil the ATF4/PSAT1/JNK axis as a master regulator of ferroptosis in AML, revealing a druggable pathway to overcome VEN resistance.

Currently, chemotherapy remains the primary treatment for acute myeloid leukemia (AML). Drug resistance in AML cells is a critical factor contributing to the failure of chemotherapy remission and subsequent relapse. Iron overload frequently occurs in AML patients because of hematopoietic suppression or supportive blood transfusion therapy. Previous studies have indicated that iron overload may promote the progression of AML; however, the underlying mechanisms remain unclear. Our results demonstrate that, compared with TP53-wild-type AML cells, TP53-mutant AML cells exhibit increased resistance to cytarabine-induced cytotoxicity. Moreover, reducing TP53 expression in wild-type AML cells diminishes their sensitivity to cytarabine. The TP53 signaling pathway is essential for mediating cytarabine-induced apoptosis in AML cells. In this study, an iron overload model in AML cells via the use of ferric citrate is constructed. Our data indicate that iron overload can suppress the TP53/BCL2/BAX signaling pathway, counteracting cytarabine-induced apoptosis. In TP53 wild-type AML cells, TFR1 participates in iron-mediated resistance to cytarabine by regulating the entry of iron into the cells. These findings provide a foundation for further exploration of the molecular mechanisms involved in AML resistance to cytarabine.

BACKGROUND:Patients with relapsed or refractory T-cell acute lymphoblastic leukaemia have limited responses to conventional chemotherapy and poor prognoses. T-cell precursors exhibit high expression of BCL-2 and are sensitive to BCL-2 inhibitors. Retrospective case series have reported the successful use of venetoclax combined with chemotherapy or hypomethylating agents when treating relapsed or refractory T-cell acute lymphoblastic leukaemia. The study aimed to evaluate the activity and safety of the venetoclax plus azacitidine regimen in patients with relapsed or refractory T-cell acute lymphoblastic leukaemia. METHODS:In this single-arm, phase 2, multicentre trial, patients aged 15-70 years with relapsed or refractory T-cell acute lymphoblastic leukaemia and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. The venetoclax plus azacitidine regimen consisted of venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-21, orally) and azacitidine (75 mg/m2 per day on days 1-7, subcutaneously). The primary endpoint was overall response rate. Activity analyses were performed in the full analysis set that included all enrolled patients. This trial is registered with ClinicalTrials.gov (NCT05149378) and is complete. FINDINGS:Between Nov 28, 2021, and Dec 31, 2024, 25 patients were enrolled. The median age at enrolment was 39·0 years (IQR 27·5-56·5); 18 patients (72%) were male and seven (28%) were female; and all patients were Asian. The overall response rate was 76% (19 of 25; 36% [nine of 25] for complete remission, 16% [four of 25] for complete remission with partial haematological recovery, 16% [four of 25] for complete remission with incomplete haematological recovery, and 8% [two of 25] for morphological leukaemia-free state). As of the data cutoff (April 7, 2025), median follow-up was 31·8 months (IQR 16·2-39·3). The most common grade 3 or worse haematological adverse events were neutropenia (21 [84%] of 25), anaemia (11 [44%] of 25), febrile neutropenia (ten [40%] of 25), and thrombocytopenia (five [20%] of 25), followed by infections (three [12%] of 25). No treatment-related serious adverse events were observed and no treatment-related deaths occurred. INTERPRETATION:The venetoclax plus azacitidine regimen showed a manageable safety profile and promising activity as salvage therapy for relapsed or refractory T-cell acute lymphoblastic leukaemia. Given the limited sample size and single-arm design nature, further confirmatory trials are warranted to validate its efficacy as a potential salvage therapy for relapsed or refractory T-cell acute lymphoblastic leukaemia. FUNDING:National Natural Science Foundation of China. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood. We performed single-cell RNA sequencing of immune and tumor cells from 33 gliomas, identifying two distinct myeloid-derived suppressor cell (MDSC) populations in isocitrate dehydrogenase-wild-type (IDT-WT) glioblastoma: an early progenitor MDSC (E-MDSC) population with up-regulation of metabolic and hypoxia pathways and a monocytic MDSC (M-MDSC) population. Spatial transcriptomics demonstrated that E-MDSCs geographically colocalize with metabolic stem-like tumor cells in the pseudopalisading region. Ligand-receptor analysis revealed cross-talk between these cells, where glioma stem-like cells produce chemokines attracting E-MDSCs, which in turn produce growth factors for the tumor cells. This interaction is absent in IDH-mutant gliomas, associated with hypermethylation and repressed gene expression of MDSC-attracting chemokines. Our study elucidates specific MDSCs that may facilitate glioblastoma progression and mediate tumor immunosuppression.

Graft failure (GF) is a barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myelofibrosis (MF). We investigated the incidence, risk factors, and prognosis for GF after allo-HSCT for MF. Two hundred and eleven patients with MF who underwent allo-HSCT across 32 hematology centers in China between December 2008 and December 2024 were retrospectively analyzed. Among them, 66 underwent matched sibling donor HSCT, 127 haploidentical HSCT, and 18 unrelated donor HSCT. The overall GF incidence was 12.5%. GF incidence was significantly associated with donor type (matched sibling, 4.8%; alternative, 13.3%; P = 0.024). Pretransplant massive splenomegaly increased GF incidence (non-massive splenomegaly, 8.5%; massive, 18.5%; P = 0.034). In multivariate analysis, massive splenomegaly (HR = 3.047; P = 0.007) and alternative donors (HR = 3.528; P = 0.041) increased GF risk. With median follow-up of 734 days, 3-year OS, DFS, relapse rate and NRM was 65.5%, 60.8%, 10.1% and 27.8%, respectively. Multivariate analysis showed pretransplant splenomegaly reduced 3-year DFS (HR = 1.671; P = 0.025), and alternative donors reduced 3-year OS (HR = 2.033; P = 0.015). In conclusion, Allo-HSCT provides curative outcomes for MF patients. However, GF remains a significant challenge, particularly in haploidentical HSCT and those with massive pretransplant splenomegaly.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially the only curative option for high-risk acute myeloid leukemia (AML) patients. However, disease relapse remains the principal cause of treatment failure of these patients, and outcomes of salvage treatments are poor. This research seeks to evaluate the efficacy and safety of a dual epigenetic targeting maintenance therapy with chidamide and azacitidine (AZA) in patients with high-risk AML post-allo-HSCT. This multicenter, open-label, phase 2 prospective clinical trial (ChiCTR2300067593) recruited and followed up 48 patients diagnosed with high-risk AML post-allo-HSCT from 3 hospitals in China from November 2021 to March 2024. Chidamide (5 mg) was administered orally once daily for 5 days, combined with AZA (75 mg/m2) subcutaneously daily for 5 days, respectively. Treatment started as early as 3 months after transplantation. All patients were in complete remission before each maintenance cycle. A total of 6 cycles was recommended. The 2-year cumulative incidence of relapse (CIR) was 8.4

Accumulating evidence indicates that enhanced adipogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) derived from aplastic anemia (AA) could contribute to the excessive fat accumulation in the bone marrow. However, the underlying molecular mechanism remains to be determined. Here in this study, we further characterized the contributing role of miR-199a-5p in adipogenesis of AA BM-MSCs through specific inhibition of miR-199a-5p expression. Subsequently, we performed a systematic screening of the downstream targets of miR-199a-5p through web tool prediction, profiling data analysis, and experimental validation, with FZD6 and CELSR1 identified as the most promising targets of miR-199a-5p in the adipogenesis of AA BM-MSCs. Finally, we mainly focused on FZD6, which presents prominently decreased expression in adipogenic differentiation and AA BM-MSC samples and negatively correlates with miR-199a-5p expression. Besides, FZD6 is demonstrated as a negative regulator of adipogenesis of BM-MSCs, and overexpression of FZD6 alleviates the facilitating role of miR-199a-5p in the adipogenic differentiation of BM-MSCs. Overall, our findings provide further mechanistic insights into miR-199a-5p-mediated enhanced adipogenesis of AA BM-MSCs, implicating miR-199a-5p and FZD6 as potential intervention targets for improving BM-MSC-mediated microenvironments.

BACKGROUND:Standard initial therapy with intensive glucocorticoids requires further optimization due to high relapse rates and unsatisfying long-term outcomes in patients with primary immune thrombocytopenia (ITP). Caffeic acid (CA) has been reported to increase platelet counts in thrombocytopenia. This study investigated the efficacy and safety of CA tablets plus high-dose dexamethasone (HD-DXM) as a novel initial treatment for adults with newly diagnosed ITP. METHODS:This multicenter, double-blind, randomized, placebo-controlled trial was conducted from July 1, 2015 to February 28, 2022 in fourteen tertiary medical hospitals in China. Eligible patients aged ≥18 years with newly diagnosed, treatment-naïve primary ITP who had a baseline platelet count of <30 × 109/L were enrolled during routine outpatient visits. Participants were randomly assigned in a 1:1 ratio to receive either CA tablets (0.3 g three times daily for 12 weeks) plus HD-DXM (40 mg/day for four days, repeated with a 10-day interval) or placebo plus HD-DXM. The primary endpoint was a 24-week sustained response (SR), defined as the maintenance of a platelet count higher than 30 × 109/L, at least doubling of the baseline platelet count, and an absence of bleeding. The Chi-squared test and Kaplan-Meier method were used to compare the 24-week SR and duration of response (DOR) between groups. RESULTS:The intention to treat analysis included 214 patients who received at least one-dose of allocated treatments (median [Q1-Q3] age, 45 [32-55] years; 154 females [72.0%]). At week 24, 56.5% (61/108) of participants in the CA plus HD-DXM group achieved SR, which was significantly higher than 29.2% (31/106) of those in the placebo plus HD-DXM group (odds ratio [OR] 3.14; 95% confidence interval [CI] 1.78-5.53; P <0.0001). Adding CA to HD-DXM resulted in a longer DOR than the placebo (hazard ratio 0.50; 95% CI 0.34-0.74; P = 0.00028). The most commonly observed adverse events (AEs) in both groups were gastrointestinal symptoms, anxiety or mood disorders, and fatigue, without statistically significant differences. No grade 4 or worse AEs or death occurred. CONCLUSION:This study confirms CA tablets plus HD-DXM as a well-tolerated, cost-effective, and optimized initial therapy for patient with newly-diagnosed ITP to conveniently maintain platelet counts and avoid early relapse. TRIAL REGISTRATION:ClinicalTrials.gov. NCT02556814.

Background Early-onset multiple myeloma (MM), defined as being diagnosed before the age of 50, has become an increasing global concern. However, a systematic examination of the global epidemiological landscape of early-onset MM is still lacking.Methods We analyzed the epidemiological characteristics of early-onset MM using data from the Global Burden of Disease Study, including incidence, prevalence, disability-adjusted life years (DALYs), and trends from 1990 to 2021. We also conducted cross-country inequality and decomposition analyses and projected the disease burden through 2045.Results Between 1990 and 2021, the global incidence, prevalence, and DALYs of early-onset MM increased by 142%, 182%, and 115%, respectively. In 2021, the age-standardized incidence, prevalence and DALYs rate of early-onset MM were 0.28, 1.00, and 8.59 per 100 000. The average annual percent changes from 1990 to 2021 were 0.91, 1.41, and 0.61, respectively, indicating significant upward trends. In comparison, this upward trend was faster than that of older patients. Notably, the disease burden of early-onset MM was higher in males and in countries/territories with high socio-demographic index (SDI), though disparities are narrowing. Decomposition analysis showed that, unlike most regions, epidemiological change was a negative contributor in high-SDI regions. Projections to 2045 suggest continued increases in early-onset MM incidence and prevalence.Conclusion The disease burden of early-onset MM has steadily risen and is projected to continue, with significant socioeconomic and geographical heterogeneity, highlighting the need for targeted healthcare policies and resources.

Dendritic cells (DCs) derived extracellular vesicles represent a promising vehicle for the activation of adaptive immunity, demonstrating significant potential in the development of cancer nanovaccines. The aim of this study was to evaluate the antitumor efficacy of a functional DCs-derived extracellular vesicles in castration-resistant prostate cancer. A pre-modification strategy was employed to overexpress XCL1 in dendritic cells, enabling their extracellular vesicles to highly express XCL1 protein. In vitro experiments, prostate cancer-bearing mouse models, and OVA-expressing prostate cancer mouse models demonstrated that dendritic cells efficiently internalize extracellular vesicles derived from XCL1-overexpressing mature dendritic cells (DEXXCL1), thereby enhancing the chemotaxis, activation, and antigen-presenting capacity of cDC1 cells. When combined with the immunogenic cell death effect induced by cisplatin, this approach significantly increased the number and cytotoxic activity of CD8+ T cells, improved the tumor microenvironment, and effectively suppressed prostate cancer tumor growth. The coding sequence of XCL1 successfully inserted upstream of the PDGFR transmembrane domain and transfected into dendritic cells, enabling their extracellular vesicles to highly express XCL1 protein. Extracellular vesicles derived from XCL1-overexpressing mature dendritic cells not only exhibited high XCL1 expression, but were also enriched with chemokine receptor CCR7 and MHC I molecules on their surface. This nanovaccines enhanced the uptake of extracellular vesicles by dendritic cells, recruited cDC1 cells within the tumor tissue, and significantly improved their antigen-presenting capacity. When combined with the immunogenic cell death effect induced by cisplatin, which generates a large amount of tumor-associated antigen STEAP1, this strategy effectively enhanced the proliferation and cytotoxic activity of CD8+T cells. Moreover, it reduced the proportion of regulatory T cells and immunosuppressive factors, thereby reshaping the tumor immune microenvironment. This approach effectively inhibited tumor growth in mice and prolonged their survival. These findings demonstrate the strong synergistic effects of the nanovaccines and cisplatin in promoting antitumor immunity. A novel nanovaccines induces potent antitumor immune responses and, in combination with the chemotherapeutic agent cisplatin, effectively remodels the tumor immune microenvironment. This approach offers a new strategy and preclinical evidence for the immunotherapy of “cold tumors” prostate cancer.

OBJECTIVE:Pulmonary microvascular endothelial cell (PMEC) injury is a hallmark of septic acute lung injury (ALI). Elevation of chemokine C-X-C motif ligand 2 (CXCL2) is associated with inflammatory response in various diseases. Recent studies have demonstrated the involvement of CXCL2 in septic ALI. Herein, the role and mechanism of CXCL2 in regulating PMEC inflammation and apoptosis in septic ALI were explored. MATERIALS AND METHODS:Human PMECs (HPMECs) were treated with lipopolysaccharide (LPS) for the establishment of in vitro septic ALI models. HPMEC viability was validated using CCK-8 assay. HPMEC apoptosis was evaluated by flow cytometry analysis. Measurement of proinflammatory cytokine concentration was conducted using enzyme-linked immunosorbent assay kits. RT-qPCR were required for determining gene levels. Western blotting was prepared for testing friend leukemia integration 1 (Fli1) and CXCL2 protein levels. The binding of Fli-1 to CXCL2 promoter was confirmed by chromatin immunoprecipitation and luciferase reporter assays. RESULTS:LPS upregulated CXCL2 expression in HPMECs. Moreover, LPS administration suppressed HPMEC viability and accelerated HPMEC inflammation and apoptosis, which was antagonized by CXCL2 depletion. Mechanistically, Fli1 served as a transcription factor and bound to CXCL2 promoter. In rescue assays, CXCL2 overexpression counteracted the restrictive impact of Fli1 deficiency on LPS-induced HPMEC apoptotic behaviors and inflammatory response. CONCLUSIONS:The Fli1 transcription factor aggravates LPS-induced HPMEC dysfunction via binding to CXCL2 promoter in septic ALI.

Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematological malignancy with a low survival probability and limited therapeutic options. Although galectin-1 (LGALS1) has been implicated in tumor cell survival and immune evasion in solid tumor, its role in AML is still unclear. In this study, we found that LGALS1 presents prominent upregulation in AML patients at both mRNA and protein levels compared with the control samples. Bioinformatics analysis indicated that high expression of LGALS1 is a significant unfavorable prognostic factor for overall survival in AML, correlating with adverse clinical and genetic features as well as immune cell infiltration. Depletion of LGALS1 in AML cells impeded cell proliferation, induced apoptosis and promoted myeloid differentiation. Treatment with OTX008, an LGALS1 inhibitor, markedly diminished the viability of primary malignant bone marrow cells from AML patients. Notably, LGALS1 expression was significantly reduced exclusively in AML-M5 patients after treatment, which may be due to its higher expression in AML-M5 subtype compared to other FAB subtypes. In summary, our findings indicate that LGALS1 could serve as an independent prognostic risk factor and a promising therapeutic target in AML, providing novel insights into AML pathogenesis and laying the foundation for the development of new therapeutic strategies.

Background: The rising incidence of AML in elderly patients poses significant challenges due to adverse biology and comorbidities. Venetoclax (Ven) combined with hypomethylating agents (AZA) or reduced-intensity chemotherapy improves response and survival in unfit/fit elderly AML. Direct comparisons between Ven-based regimens and intensive chemotherapy (IC) in fit elderly AML are lacking. This multicenter, randomized phase II study (NCT06066242) compared efficacy and safety of different induction therapies. Methods: Patients aged 60–75 years with newly diagnosed, non-M3/CBF AML fit for IC were randomized 1:1:1 (Oct 2023–Jan 2025) to: Arm A (IC): Standard “3+7” (D/IA: daunorubicin 60mg/m² or idarubicin 10 mg/m² d1-3, cyctarabine 100mg/m² d1-7)；Arm B (VA): Ven (100mg d1, 200mg d2, 400mg d3-21/28; on day 21, a bone marrow aspiration will be performed. If the bone marrow morphology indicates that the blast count is <5% or shows severely hypoplastic marrow, venetoclax will be discontinued.) + AZA (75mg/m² d1-7)；Arm C (D/IAV): Ven (100mg d3, 200mg d4, 400mg d5-11) + modified “2+5” (daunorubicin 60mg/m² or idarubicin 10mg/m² d1-2, cyctarabine 100mg/m² d1-5). Patients achieving complete remission/complete remission with incomplete hematologic recovery (CR/CRi) received same consolidation and maintenance therapy. Two cycles of intermediate-dose cytarabine consolidation (cyctarabine 1g/m² q12h d1,3,5), followed by maintenance: 2 cycles of DA/IA (daunorubicin 30mg/m² or idarubicin 8mg/m² d1-2, cyctarabine 100mg/m² d1-5) and 4 cycles of VA (Ven 400mg d1-7, AZA 75mg/m² d1-5). Primary endpoint was event-free survival (EFS). Secondary endpoints included CR/CRh/CRi rates; measurable residual disease (MRD) clearance rate after achieving CR/CRh/CRi; relapse-free survival (RFS); OS and mortality within 30 days after induction therapy. Results: 102 patients enrolled (median age 65; 55.9% male). ELN 2022 risk: favorable 26%, intermediate 30%, adverse 44%. Arms: A (n=32), B (n=36), C (n=34). Baseline characteristics were balanced across arms. After excluding 2 inevaluable and 9 induction deaths (8.8%), 91 were response-evaluable. The CRc rate for the entire cohort was 55.9% (57/102, CR rate: 50%). With a median follow-up of 12.5 months, the median EFS was 6.4 months, RFS was 9.4 months, and OS was not reached (NR). The 1-year EFS, RFS, OS rate was 36.3±5.2%, 44.6±5.4%, and 55.0±5.4%, respectively. Complete remission (CR) rates following cycle 1 of Arm C was numerically higher than Arm A (A:37.5%,B: 47.2%, C: 61.8%, A vs.C: P= .07), but composite complete remission (CRc) rates had no difference among three arms (A:40.6% , B:60.9%, C:61.8% ; P= .313). Mortality within 30 days after induction therapy was higher in Arm A (12.5%) and Arm C (11.7%) compared to Arm B (2.8%) (P= .281).No significant differences in event-free survival (EFS), relapse-free survival (RFS), or overall survival (OS) were observed across arms overall: median EFS: Arm A: 7.1 months; Arm B: 5.7 months; Arm C: 4.5 months; (P= .602); median RFS: Arm A: 8.6 months ; Arm B: NR; Arm C: 8.1 months; (P= .792); median OS: Arm A (IC): 10.4 months; Arm B (VA): not reached (NR); Arm C (D/IAV): 14.1 months; (P= .407). While subgroup survival analyses across different risk group revealed efficacy variations among treatment regimens.Within the ELN 2022 adverse-risk subgroup (n=44 evaluable), EFS, RFS, and OS were improved in Arm B (VA) compared to Arm A (IC): 1-year EFS: Arm A: 17.9±11.0% vs. Arm B: 59.3±12.1% (P= .005); 1-year RFS: Arm A: 17.3±11.1% vs. Arm B: 65.0±11.7% (P= .043); 1-year OS: Arm A (IC, n=14): 25.7±12.3% vs. Arm B (VA, n=18): 71.3±10.9% (P= .012). No survival differences were observed within the favorable- or intermediate-risk subgroups. Common treatment-emergent non-hematologic adverse events included elevated liver enzymes, creatinine, bilirubin, and hypoalbuminemia; hematologic events included cytopenias and febrile neutropenia. Incidence and severity did not differ significantly between treatment arms. Conclusion: No significant differences in survival were observed across three regimens. CRc rates were similar between VA and D/IAV regimen, which shows trend better than D/IA. VA improved survival compared to D/IA in patients with ELN 2022 adverse-risk disease. According to our data, Venetoclax-based regimens, particularly Ven+AZA, demonstrate efficacy, especially in high-risk fit older AML patients.

Acute myeloid leukemia (AML) is a clinically aggressive hematologic malignancy characterized by high relapse rates and treatment resistance, highlighting the need for novel biomarkers to improve clinical outcomes. In this study, we explore the roles of nuclear receptor-interacting protein 1 (NRIP1) in AML, focusing on its associations with tumor progression and immune infiltration. Analysis of public AML gene expression datasets reveals that NRIP1 expression is significantly increased in AML patients. Those with high NRIP1 expression have markedly shorter overall survival than those with low expression. Furthermore, NRIP1 expression is significantly associated with the infiltration of diverse immune cells, including B cells, dendritic cells, T cells, mast cells, eosinophils, and T helper cells, suggesting that NRIP1 may be a regulator of immune cell infiltration. Functional enrichment analysis indicates that NRIP1 and its interacting partners are involved in tumorigenesis, immune microenvironment remodeling, and metabolic reprogramming. Survival analysis confirms the prognostic value of NRIP1. Importantly, functional validation in AML cell lines confirms that NRIP1 knockdown suppresses proliferation and induces apoptosis. Our study identifies NRIP1 as a multifaceted regulator that promotes AML by driving tumor progression, regulating immune cell infiltration, and modulating ferroptosis, highlighting its role as a novel prognostic biomarker.

The multi-center randomized phase III NHL-004 study compared etoposide, dexamethasone and pegaspargase (ESA) versus the methotrexate, etoposide, dexamethasone and pegaspargase (MESA) regimen, combined with sandwiched radiotherapy, in newly diagnosed early-stage nasal natural killer / T-cell lymphoma (NKTCL). Here we report the long-term outcomes (median follow-up, 64 months) and biomarker analysis. A total of 256 eligible patients aged 14-70 years were randomly assigned (1:1) to the ESA or the MESA arm. The 5-year progression-free survival (PFS) rates were 80.3% and 74.9% in the ESA and MESA arms (hazard ratio [HR]=0.78 [95% CI: 0.46-1.33], P=0.371), and the 5-year overall survival (OS) rates were 85.1% and 80.9% (HR=0.74 [95% CI: 0.40-1.37], P=0.332), respectively. No new safety signals related to treatments were observed. Interim plasma Epstein-Barr virus (EBV) DNA positivity and stable disease / progressive disease response were independent predictors of inferior PFS and OS. No prognostic significance was observed according to molecular subtypes. Interim EBV DNA positivity correlated with up-regulated chromatin remodeling alterations, immune escape-related genes, and decreased infiltrating monocytes / M1 macrophages. With low toxicity, non-intravenous administration, and an outpatient design, ESA with sandwiched radiotherapy achieved long-term durable response in patients with newly diagnosed early-stage NKTCL. Dynamic monitoring of plasma EBV DNA provided a clinical rationale for future mechanism-based therapy in NKTCL.

Background: Peripheral T-cell lymphoma (PTCL) represents a heterogeneous group of aggressive lymphomas, accounting for 25%–30% of non-Hodgkin lymphomas (NHL) in China. The CHOP regimen remains the standard first-line treatment for PTCL, yet its long-term efficacy requires improvement. Relapsed or refractory (R/R) PTCL is highly aggressive with extremely poor survival outcomes, exhibiting a 3-year overall survival (OS) rate of less than 30%. This MOMENT study demonstrated promising efficacy and safety of the mitoxantrone hydrochloride liposome (Lipo-MIT)-based regimen in PTCL (J Leuk Lymphoma, 2023, 32(8): 457-464). Nevertheless, additional data are warranted to establish further validation. We previously reported updated real-world evidence for Lipo-MIT in treatment-naïve (TN) PTCL (2025 EHA, #PF949), showing a complete response (CR) rate of 48.2% and objective response rate (ORR) of 83.6%. Herein, we present updated survival outcomes for Lipo-MIT in TN-PTCL and provide the most recent real-world evidence regarding Lipo-MIT in R/R PTCL. Methods: This multicenter, non-interventional, ambispective cohort real-world study was registered at www.chictr.org.cn (ChiCTR2200062067). It enrolled adult patients diagnosed with TN or R/R PTCL. The primary endpoint was ORR. Secondary endpoints included CR rate, progression-free survival (PFS), OS, and safety. Results: As of February 8, 2025, 609 patients were enrolled, comprising 494 with relapsed/refractory PTCL (R/R PTCL) and 115 with treatment-naïve PTCL (TN-PTCL). The R/R cohort had a median age of 56 years (range: 19–86) with 62.1% males; subtypes included angioimmunoblastic T-cell lymphoma (AITL, 30.0%), extranodal NK/T-cell lymphoma (NKTCL, 25.9%), PTCL not otherwise specified (PTCL-NOS, 24.9%), ALK-negative anaplastic large cell lymphoma (ALCL, ALK-, 5.9%), ALK-positive ALCL (ALCL, ALK+, 2.8%), and other subtypes (10.5%). Advanced-stage (III–IV) disease was present in 67.0% pts, 27.9% had International prognostic index (IPI) scores 3–5, and 21.1% exhibited B symptoms. Prior therapy exposure included: ≥1 lines in all patients (50.4% first-line, 21.3% second-line, 28.3% ≥third-line), with 74.9% previously receiving anthracyclines. Patients received Lipo-MIT-containing regimens for a median of 3 cycles (range: 1–11), with median Lipo-MIT doses of 17.7 mg/m² (monotherapy: range 11.2–20.3 mg/m²; combination: range 5.4–23.3 mg/m²). Among 456 efficacy-evaluable R/R patients, the overall response rate (ORR) was 62.1% (283/456) and complete response (CR) rate was 29.2% (133/456), with ORR varying by subtype: AITL 68.6% (96/140), NKTCL 60.8% (73/120), PTCL-NOS 57.5% (65/113), ALCL ALK- 51.9% (14/27), and ALCL ALK+ 61.5% (8/13). Response rates decreased with prior lines: 68.1% (160/235) after first-line, 61.6% (61/99) after second-line, and 50.8% (62/122) after ≥third-line therapy. With a median follow-up of 6.5 months, median progression-free survival (PFS) was 9.9 months (95% CI: 7.1–12.7) and median overall survival (OS) was not reached. In the TN cohort (n=115), median follow-up was 11.6 months with median PFS of 14.6 months (95% CI: 10.8–18.3); 1-year PFS rates was 58.6%. Median OS was not reached, with 1-year OS rates of 88.0%. Safety analysis of the full cohort (n=609) revealed treatment-related adverse events (TRAEs) in 89.0% (542/609), with grade ≥3 TRAEs in 66.0%. Predominant hematologic toxicities included neutropenia (46.6%), leukopenia (42.2%), lymphopenia (34.5%), anemia (22.5%), and thrombocytopenia (23.0%). Non-hematologic TRAEs were primarily grade 1–2; no unexpected or serious adverse events were observed. Conclusion: Lipo-MIT-based regimens demonstrated favorable clinical efficacy and tolerability in both TN-PTCL and R/R PTCL, representing a promising therapeutic option. Continued follow-up for survival outcomes is ongoing, with additional results forthcoming.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potentially curative treatment for peripheral T-cell lymphoma (PTCL), but the optimal conditioning regimen, particularly the use of total body irradiation (TBI), remains debated. To address this, we investigated outcomes from a cohort of 408 PTCL patients who underwent HSCT across five qualified medical centers in China. Focusing on a subset of 50 patients who received myeloablative conditioning prior to allo-HSCT, we compared outcomes between TBI-based (n = 28) and busulfan-based non-TBI (n = 22) regimens. Our analysis revealed comparable engraftment kinetics, incidence of acute and chronic graft-versus-host disease (GVHD), and overall survival (OS) between the TBI and non-TBI groups. These findings persisted even after propensity score matching (PSM) adjustment. Notably, at a median follow-up of 32.5 months, TBI conditioning was not identified as an independent risk factor for OS, progression-free survival (PFS), cumulative incidence of relapse, or non-relapse mortality. Importantly, non-TBI regimens demonstrated non-inferior OS and PFS compared to TBI, even in high-risk subgroups, including those with multiple prior treatments, elevated prognostic scores, or aggressive histology. Our findings suggest that non-TBI conditioning regimens represent a viable alternative for PTCL patients undergoing allo-HSCT, potentially offering comparable efficacy with reduced toxicity. Larger-scale studies are warranted to validate these findings.

Background: Haematopoietic stem cell transplantation (HSCT) is a crucial treatment for severe aplastic anemia (SAA). However, there is no standardized preconditioning regimen for patients without matched sibling or unrelated donors. Achieving successful engraftment remains a significant challenge in haploidentical HSCT, controlling transplantation-related complications and reducing transplantation-related mortality are urgent issues that need to be addressed. New conditioning regimens are still worth exploring. Objective: We conducted a prospective, multi-center clinical study to explore the efficacy and safety of a novel preconditioning regimen consisting of fludarabine, cyclophosphamide, and melphalan (FCM) in haploidentical HSCT for the treatment of SAA. Methods: Patients who were diagnosed with SAA according to NCCN guidelines and required haplo-identical HSCT were recruited. Patients with active infections or bleeding, severe liver or kidney dysfunction, ECOG > 2, <3 or >65 years old, psychiatric disorders, or pregnancy were excluded. The preconditioning regimen included: 30mg/m² fludarabine for 6 days, 50mg/kg cyclophosphamide on day -7 and day -5, 100mg/m² melphalan on day -2, and 2mg/kg ATG on day -1. The prevention of acute graft-versus-host disease (aGVHD) consisted of post-transplantation cyclophosphamide (PTCy) and short-term methotrexate ± other drugs, detailed aGVHD prophylaxis was determined according to each center’s decision. Chimerism was assessed on days +28, +60, +90 post-transplantation and then once half year. The primary endpoints was graft failure rate, the second endpoint were the incidence of transplantation-related complications, 2-year overall survival (OS) and disease-free survival (DFS). This study was approved by the Ethic Committee of 920th Hospital of Joint Logistics Support Force and was registered at www.clinicaltrial.gov as NCT06378060. Results: From April 2024 to May 2025, 25 SAA patients from 7 transplantation centers who underwent haploidentical HSCT were enrolled. The male-to-female ratio was 11:14, with a median age of 26 years (IQR 15-38). All patients achieved successful engraftment, with median times to neutrophil and platelet engraftment of 13 days (IQR 11-14) and 12days (IQR 11-14), respectively. One patient experienced poor graft function and developed aGVHD after donor stem cell transfusion, resulting in death on day +110. No seizures, severe mucositis, cardiac events, or bleeding events occurred during transplantation. The incidences of grade II-IV and grade III-IV aGVHD were 20% and 4%, respectively. Hemorrhagic cystitis occurred in 8% of patients. Epstein-Barr Virus (EBV) and cytomegalovirus (CMV) reactivation rates were 16% and 20%, respectively. Three patients developed pulmonary fungal infections post-transplantation, they were resolved after antifungal treatment. One patient developed post-transplant lymphoproliferative disorder (PTLD), she was cured by the treatment of rituximab. Till August 2025, the median follow-up time was 13.1 months, with 24 patients surviving. The transplantation-related mortality (TRM) rate was 4%. Conclusion: The FCM conditioning regimen in haplo-identical HSCT for severe aplastic anemia achieves a high engraftment rate with good safety and low infection rates.

Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy characterized by the rapid proliferation of abnormal myeloid cells in the bone marrow. Despite advances in chemotherapy and targeted therapies, drug resistance and high relapse rates remain the major challenges in AML treatment. Accumulating evidence indicates that bone marrow mesenchymal stem cells (MSCs)-mediated microenvironment changes play a crucial role in the pathogenesis of AML and may contribute to the therapeutic challenges of current treatment strategies. In this study, we further characterized the role and revealed the molecular mechanism of AML-derived MSCs (AML-MSCs) in AML pathogenesis. We found that AML-MSCs significantly promoted AML cell proliferation and inhibited apoptosis, primarily through direct cell-to-cell contact. Bioinformatics analysis of multiple sequencing datasets revealed that decorin (DCN), encoding a core extracellular matrix protein, is significantly upregulated in AML-MSCs. DCN could enhance AML cell viability through functional interplay with matrix metalloproteinase-2 (MMP2) in AML cells. Both inhibition of DCN in AML-MSCs and MMP2 in AML cells significantly attenuated the supportive effect of AML-MSCs on AML cells. These findings provide novel insights into the role of MSC-mediated bone marrow microenvironment remodeling in AML pathogenesis and highlight DCN and MMP2 as potential therapeutic targets for AML treatment.

Acute lung injury, a diffuse inflammatory injury caused by various factors, is characterized by respiratory distress and progressive hypoxemia. Shionone is a natural triterpenoid with anti-inflammatory activity. Here, we aimed to investigate the effects and action mechanisms of shionone on lipopolysaccharide-induced A549 cells. Lipopolysaccharide-stimulated A549 cells were used as an in vitro acute lung injury model. Lactate dehydrogenase, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and flow cytometry assays were used to assess lactate dehydrogenase activity, viability, and apoptosis in A549 cells, respectively. Reactive oxygen species accumulation and superoxide dismutase and catalase activities were analyzed using kits. Levels of the inflammatory cytokines, interleukin-6, interleukin-1β, and tumor necrosis factor-α were assessed via enzyme-linked immunosorbent assay. Apoptosis-related (cleaved caspase-3) and TNFAIP3-interacting protein 2 (TNIP2)/nuclear factor (NF)-κB pathway protein levels were measured via quantitative reverse transcription-polymerase chain reaction and western blotting. Shionone did not exhibit cytotoxicity in A549 cells. It markedly increased the viability, reduced the apoptosis, and inhibited cleaved caspase-3 levels in A549 cells compared to those in lipopolysaccharide-stimulated cells. Shionone also inhibited lipopolysaccharide-stimulated inflammation and oxidative stress, as indicated by the reduced reactive oxygen species release, increased superoxide dismutase and catalase activities, and decreased interleukin-6, interleukin-1β, and tumor necrosis factor-α levels. It significantly attenuated lipopolysaccharide-induced activation of the TNFAIP3-interacting protein 2/nuclear factor-κB pathway, thereby increasing TNFAIP3-interacting protein 2 mRNA and protein levels and decreasing p-65 levels and p-p65/p65 ratio. However, these effects were partially reversed by TNIP2-siRNA. Overall, this study revealed that shionone exerted protective effects against lipopolysaccharide-induced acute lung injury by regulating the TNFAIP3-interacting protein 2/nuclear factor-κB pathway, highlighting its potential for acute lung injury treatment.