Lymphomas are biologically and clinically heterogeneous malignancies. While liquid biopsies using circulating cell-free DNA (cfDNA) offer a non-invasive alternative, current methods typically require expensive deep sequencing. We developed Fragmentia-AI™ Lymphoma, a transformer-based genomic language model that enables lymphoma detection using ultra-low-pass whole-genome sequencing (ULP-WGS). The model integrates a genomic language model backbone with attention-based multiple instance learning to identify mutation-independent, malignancy-associated signals directly from raw cfDNA sequences. The model was trained on 389 samples (189 lymphoma, 200 healthy) and evaluated in an independent validation cohort of 190 lymphoma patients and 200 healthy controls. The model demonstrated robust diagnostic performance in the validation cohort, achieving an AUC of 0.944, with a sensitivity of 0.842 at 98

7019 Background: Despite the potential of cfDNA liquid biopsy for non-invasive cancer monitoring, its clinical utility is often limited by high sequencing costs and a reliance on detectable driver mutations. To address these barriers, we introduce Fragmentia AI – Lymphoma, a novel transformer-based cfDNA language model designed for lymphoma detection using cost-effective ultra-low-pass whole genome sequencing (ULP-WGS). Methods: Trained on a cohort of 389 samples (189 lymphoma and 200 healthy), the architecture integrates genomic language model backbone with gated attention-based multiple instance learning. Fragmentia AI – lymphoma learned to identify malignancy-associated, mutation-independent signals directly from raw cfDNA sequences. We validated performance on an independent test cohort of 190 lymphoma patients and 200 healthy controls. Additionally, to evaluate clinical scalability, we conducted a read-depth titration analysis to test the minimum input requirements for sustained model performance. Results: Fragmentia AI – lymphoma achieved an AUC of 0.943 in the training cohort and 0.944 in the testing cohort. At 95% specificity, the model demonstrated a sensitivity of 0.889 (F1 score: 0.913). Notably, diagnostic performance remained robust even with a threefold reduction in sequencing reads (AUC > 0.94), significantly lowering the required depth compared to standard somatic mutation calling. Feature attribution analysis revealed that model’s decision-making was predominantly anchored in pathognomonic fragmentomic signatures, specifically GC-content biases and aberrant fragment-size distributions characteristic of malignant cfDNA. Conclusions: Our model effectively identified mutation-independent diagnostic signals from low coverage sequencing data, providing a scalable and cost-effective approach for lymphoma screening and monitoring.

Mucosa-associated lymphoid tissue (MALT) lymphoma, a common primary extranodal B cell lymphoma that arises in diverse mucosal tissues, has a pathogenesis closely linked to the supportive lymphoma microenvironment (LME). However, its microenvironmental heterogeneity and therapeutic implications remain unclear. Here, we report a cohort of 89 MALT lymphoma samples from multiple anatomical sites, profiled by bulk (n = 89), single-nucleus (n = 16), and spatial (n = 9) RNA sequencing. Integrative analysis of 120 bulk transcriptomes from our cohort and two independent cohorts, guided by cell-type-resolved signatures derived from single-nucleus data, identifies three LME subtypes: mesenchymal, inflammatory, and depleted. Single-cell and spatial mapping further reveal distinct cellular compositions and interaction networks across these subtypes, particularly in relation to B cell activation and angiogenesis, suggesting distinct biological states and subtype-specific therapeutic vulnerabilities. This study establishes an LME-based classification framework for MALT lymphoma with biological and clinical relevance.

Introduction: Chronic lymphocytic leukaemia (CLL), a hematologic malignancy of B cells, is one of the most frequent types of leukemia (Lancet 2024:404:694-706). Recently, Bruton's tyrosine kinase inhibitors (BTKis) have become a standard first-line treatment for patients (pts) with CLL, showing remarkable clinical efficacy compared to traditional chemoimmunotherapy (J Hematol Oncol 2021:14:69). However, first-generation BTKis are associated with limited target selectivity, which may result in off-target effects and serious adverse events (Haematologica 2018:103:874-879). Given the safety concerns, there is an urgent need for next-generation BTKis with enhanced selectivity and improved safety profiles. Orelabrutinib is a novel, orally administered, and highly selective irreversible BTKi (Blood 2024:144:4399). Its improved target selectivity contributes to a more favorable safety profile. Orelabrutinib has been approved in China for the treatment of pts with relapsed or refractory CLL (Blood 2021:138:2638). This retrospective study was conducted to assess the clinical efficacy and safety of orelabrutinib in pts with CLL. Methods: Between November 1, 2021, and May 28, 2024, we retrospectively reviewed CLL pts who received orelabrutinib monotherapy (150 mg orally once daily). Patient baseline characteristics, response data (overall response rate [ORR]), survival outcomes (progression-free survival [PFS] and overall survival [OS]), and safety data (incidence and severity of adverse events [AEs]) were descriptively analyzed. Results: As of the cut-off date (July 30, 2025), 30 pts were included; 28 were still receiving treatment, and 2 had discontinued. The median age was 66.5 years (IQR 54.0-71.0), with 18 (60.0%) males. Of these pts, all had an ECOG performance status of ≤1; 12 (40.0%) Binet stage C; 18 (60.0%) Rai stage I-IV. Based on CLL-IPI, 16.7% (5/30) of pts were classified as low-risk, 3.3% (1/30) intermediate-risk, and 23.3% (7/30) high-risk. Comorbidities were present in 11 pts, including 7 with hypertension, 2 with diabetes mellitus, 2 with hyperlipidemia, and 1 with heart disease. IGHV mutation was detected in 71.4% (10/14) of tested pts, while TP53 mutation was identified in 33.3% (4/12) of tested pts. Five pts had a history of BTKi treatment (ibrutinib, n=3; Zanubrutinib, n=2), all of whom switched due to inadequate efficacy or AEs. Orelabrutinib was administered to 4 pts in first-line and 26 pts in second- or later-line settings. Among all pts, 28 (93.3%) achieved an objective response, including 4 (13.3%) complete responses (CR) and 24 (80.0%) partial responses (PR). One patient (3.3%) had stable disease (SD), and 1 (3.3%) experienced progressive disease (PD), resulting in a disease control rate (DCR) of 96.7% (29/30). At a median follow-up of 28.0 months (IQR, 24.6-33.7), median PFS and OS were not reached. The 36-month PFS and OS rates were both 96.7% (95% CI, 90.5%-100.0%). Patients receiving first-line orelabrutinib achieved both an ORR and DCR of 100% (4/4). Among those treated in the second- or later-line setting, ORR and DCR were 92.3% (24/26) and 96.2% (25/26), respectively, with the 36-month PFS and OS rates of 96.2%. In the TP53-mutated subgroup, ORR was 50.0% (2/4) in mutated pts versus 100.0% in wild-type (8/8). When analyzed by IGHV-mutated subtype, ORR was observed in 10 (100.0%) pts with IGHV mutation and 2 (50.0%) pts without IGHV mutation. In the subgroup by prior BTKi exposure, the ORR was 100.0% (5/5) in pts with prior BTKi exposure and 92.0% (23/25) in those without. Notably, among 3 pts who switched from ibrutinib to orelabrutinib, 2 achieved an improved response, upgrading from SD to PR, and 1 patient maintained a PR. Additionally, 1 patient who switched from zanubrutinib to orelabrutinib also exhibited an improved response from SD to PR. Among these 5 pts, one experienced improvement in bleeding severity (grade 2 to 1), and another recovered from grade 2 thrombocytopenia to normal platelet counts following orelabrutinib treatment. In the total of 30 pts, any-grade AEs were reported in 20 (66.7%), with grade ≥3 anemia occurring in 1 (3.3%). AEs related to BTKi off-target activity were not observed. Conclusion: This real-world study suggested that orelabrutinib monotherapy showed promising efficacy and a favorable safety profile in pts with CLL, both as first-line and subsequent therapy. Further prospective investigations are needed to validate the observations.

Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas associated with poor survival outcomes. Relapsed or refractory (R/R) PTCLs have an even worse prognosis, with historically reported median overall survival (mOS) of less than 6 months. Current monotherapies yield only modest overall response rates (ORR) ranging from 22% to 38%, except for brentuximab vedotin in CD30-positive anaplastic large cell lymphoma (ALCL). Purinostat Mesylate (PM) is a highly selective HDAC I/IIb inhibitor. In a phase I dose-escalation study, PM achieved an encouraging ORR of 61.1% in R/R lymphomas with manageable toxicities. A phase IIa was conducted to further evaluate the efficacy and safety of PM in R/R PTCL (NCT06485219). Methods Eligible patients were adults with pathologically confirmed R/R PTCL who had received 1 to 5 prior lines of therapy, including anthracycline-based chemotherapy for PTCL and asparaginase-based therapy for NK/T-cell lymphoma (NKTCL), ECOG≤2. Patients were randomized 1:1 to receive PM at doses of 11.2 or 15.0 mg/m² on Days 1, 4, 8, and 11 of a 21-day cycle. 10-15 patients were planned to be enrolled at each group. Patients continued treatment until disease progression or unacceptable toxicity. The primary endpoint was ORR; secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results As of July 23, 2025, 24 patients with R/R PTCL were enrolled. Baseline characteristics included a median age of 58.0 years (range: 36–76), 19 males (79.2%), and a median of 2 prior lines of therapy. Twenty patients had at least one response evaluation. After a median follow-up of 5.39 months, the ORR was 55.0% (11/20), comprising 4 complete responses (CR) and 7 partial responses (PR). Four patients at 11.2 mg/m2 (4/8) achieved an ORR of 50.0% with 1 CR and 3 PR. Seven patients at 15.0 mg/m2 (7/12) achieved ORR of 58.3% with 3 CR and 4 PR. ORRs by histology were 20% (1/5) for PTCL-NOS (CR), 100% (1/1) for NKTCL, 50.0% (5/10) for AITL, and 100% (4/4) for ALCL. Most patients can benefit from the treatment at an earlier time with a median time to response (TTR) of 2.76 months (1.28, NR), and the median duration of response (mDOR) was 6.01 months (0.66, NR). Among responders, 5 patients remain on treatment, with the longest ongoing treatment lasting 16 cycles. Median PFS was 4.24 months (2.56, 7.29) and median OS was 7.59 months (6.18, NR). The most common grade ≥3 treatment-related adverse events included neutropenia (83.3%), thrombocytopenia (75.0%), leukocytopenia (50.0%), lymphocytopenia (41.7%), anemia (20.8%), infectious pneumonia (16.7%), bacterial pneumonia (12.5%), and hypokalemia (12.5%). There was one treatment-related death due to infection. Conclusion Preliminary results from this phase IIa study indicate that PM administered in 21-day cycles demonstrates promising efficacy compared with currently available single agents, with a manageable safety profile in patients with R/R PTCL.

Introduction: Zanubrutinib as a second generation bruton tyrosin kinase inhibitor (BTKi) has become the standard of care for both frontline and relapsed/refractory chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) in China regardless of TP53 mutation or fitness status. As it has a better safety profile in clinical trials over first-generation ibrutinib in CLL/SLL, patients on zanubrutinib may enjoy fewer adverse events (AE) and longer event-free survival. The objective of this study was to assess the real-world efficacy and treatment persistence of single agent zanubrutinib in CLL/SLL patients. Methods: This was a retrospective observational study of adult patients with CLL/SLL who initiated single agent zanubrutinib treatment between December 2020 and April 2024 in West China Hospital, Sichuan University, which was from the comparably underdeveloped Western China region. The end of follow-up was March 1, 2025. Duration of treatment, reasons for discontinuation, dose reduction, real-world event free survival (rwEFS) and outcomes of patients switched from ibrutinib were reported. Results: A total of 91 patients were enrolled with 49 male patients (53.8%). 39.6% (36/91) patients received zanubrutinib as first line (1L) treatment while 60.4% (55/91) were second line (2L) users. The median age of diagnosis was 59 years (range, 26 - 85). 25% (17/68) patients had a smoking history. Hypertension was documented in 5.4% (3/74) patients. 78 (84.8%) patients were diagnosed as CLL while 14 (15.2%) patients were SLL. At baseline, among 55 patients with intact staging data, 20% (11/55) were staged as Binet A, with 36% (19/55) as Binet B and 45% (25/55) as Binet C. The cytogenetic and molecular characteristics were as follows: mutated IGHV at 34.1% (14/41), unmutated IGHV at 65.9% (27/41), del17p at 21.1% (7/33) and TP53 mutation at 37.5% (9/24). Dose reductions were documented in 24.2% (22/91) patients. Only 31.8% (7/22) dose reductions were caused by intolerable AEs. The others were attributed to personal preferences. Treatment discontinuation was documented in 18.7% (17/91) patients. 64.7% (11/17) treatment discontinuations were caused by economic or personal reasons, with 17.6% (3/17) by intolerable AEs 11.2% (2/17) by progression of disease (PD) and only 1 death from COVID19 infection. 94.1% (16/17) treatment discontinuations occurred within the first 2 years on zanubrutinib. The median time on zanubrutinib treatment prior to discontinuation was 8.0 months (range, 1.0 - 29.0). No patient discontinued zanubrutinib due to cardiovascular AE. Until the cut-off date, the median follow-up was 23.0 months (95%CI: 20.0 - 26.0). The median rwEFS was not reached. The estimated 48-months rwEFS rate was 77%. There was no significant difference in rwEFS between 1L and 2L subgroups (p=0.39). Overall survival was also not reached. Only two cases of Richter transformation (RT) occurred. Noticeably, among the 2L subgroup 34.5% (19/55) patients were switched from previous ibrutinib treatment. The reasons for BTKi switch were as follows: 57.9% (11/19) for AEs (including 3 skin rash, 2 infection, 1 pleural infusion, 3 myelosuppression and 2 bleeding cases), 21.1% (4/19) for PD, 10.5% (2/19) for inadequate efficacy (stable disease) and 10.5% (2/19) for economic considerations. After switching to zanubrutib, 54.5% (6/11) AEs were recovered and 45.5% (5/11) were improved to lower degrees. Among the 6 patients with PD or SD after ibrutinib, 4 patients (66.7%) responded to zaubrutinib with only 1 PD and 1 RT in the follow-up. Conclusion: Our findings suggest that the real-world efficacy and safety profile of zanubrutinib for CLL/SLL is consistent with previous clinical trials. Real-world data support zanubrutinib continuous treatment as a preferred regimen for CLL/SLL patients. Discontinuation of zanubrutinb due to PD or AE is not common. Economic burden is the main reason for dose reduction or the treatment discontinuation. For patients who cannot tolerate ibrutinib or have inadequate response to ibrutinib, switching to zanubrutinib could be a desirable option which could alleviate most ibrutinib-related AEs with further improvement of response in certain patients. Future validation is warranted to fully elucidate the long-term benefits of zanubrutinib in the management of CLL/SLL.

CAR-T cell therapy demonstrates significant efficacy in hematologic malignancies, with target selection critically determining therapeutic outcomes. However, the available tumor surface antigens are limited, especially in the treatment of solid tumors. A potential solution to overcome this limitation entails employing antibodies recognizing peptide-major histocompatibility complex (pMHC) structures, enabling CAR-T cell to detect intracellular tumor antigens through a T cell receptor (TCR)-like recognition mechanism. This study focuses on HBV-associated hepatocellular carcinoma (HBV-HCC), where HBV DNA integration into the host genome generates specific viral antigen epitopes presented by MHC class I molecules, representing attractive targets for CAR-T cell therapy. We engineered CAR-T cells with a TCR-like antibody (HBs183 CAR-T) specific for the immunodominant HBV envelope epitope Env183-191 presented by HLA-A *0201, and evaluated the antigen-specific cytotoxicity and safety profile of the CAR-T cells through in vitro functional assays and in vivo evaluation in heterogenous tumor models (subcutaneous and intraperitoneal xenografts). Our research provides a reference for CAR-T cell therapy targeting intracellular antigens, particularly specific antigens derived from viral infections, as targets for CAR-T treatment, and offers a preliminary concept validation for the CAR-T treatment of HBV-HCC tumors.

Invasive fungal disease (IFD) remains a life-threatening complication in patients with hematological diseases. Isavuconazole was approved by the FDA for primary treatment of invasive aspergillosis and mucormycosis. While clinical trials have demonstrated its efficacy, data on its use in hematology patients remain limited. This study aims to evaluate the real-world effectiveness and safety of isavuconazole in this population. We conducted a single-center, retrospective study of hematology patients who received isavuconazole for IFD between 1 June 2022, and 31 July 2024, at West China Hospital, Sichuan University. A total of 66 patients with proven (n = 9), probable (n = 17), or possible (n = 40) IFD were included in the study. Acute leukemia (AL) was the most common underlying disease, affecting 27 patients (40.9%), followed by non-Hodgkin’s lymphoma (NHL) and myelodysplastic syndrome (MDS). Over 80.0% of patients received oral isavuconazole. At 6 weeks of follow-up, a favorable response was observed in 57.6% of patients, increasing to 71.2% at 12 weeks. Factors associated with achieving complete response in isavuconazole treatment included receiving isavuconazole as primary treatment (OR = 0.10, p = 0.01) and reaching complete/partial remission (CR/PR) of the primary hematological disease (OR = 0.07, p = 0.003). The all-cause mortality rates were under 30.0%. The use of isavuconazole as primary antifungal therapy (p < 0.05) and achieving CR/PR in the underlying hematological disease (p < 0.05) were two independent predictors of improved clinical outcomes. Adverse events were reported in 33.3% of patients, and no adverse events led to discontinuation of treatment. Our study demonstrated that isavuconazole is an effective and well-tolerated treatment for IFD in hematology patients. The oral formulation provided comparable efficacy and enhanced compliance, potentially leading to improved outcomes and optimizing the management strategy. The generalizability of our findings may be limited by the single-center, retrospective nature; further validation through prospective, multi-center studies is needed.

Background Myelofibrosis (MF) is characterized by abnormal clonal expansion of hematopoietic stem cells driven by mutations JAK2, CALR and MPL genes and resultant bone marrow fibrosis. Thrombocytopenia is a poor prognostic feature and limits the use of JAK1/JAK2 inhibitor ruxolitinib (Rux). Flonoltinib Maleate (FM), a new generation of JAK2 /FLT3/CDK6 inhibitor, can stabilize platelet level and improve bone marrow fibrosis via suppressing the TGF-β signal passway. In FIH trial (NCT05153343), FM achieved SVR35, best SVR35, and TSS50 of 81.8%, 93.3% and 73.3%, respectively at week-24 in MF patients. Bone marrow fibrosis improvement was also observed in 36.4% MF patients. To further explore the efficacy and safety of FM compared with Rux, a multicenter randomized, open-label, phase IIb trial were conducted in JAKi-naïve MF patients (pts) (NCT06457425). Methods 75 pts aged ≥18 years with primary MF, post-PV MF or post-ET MF, DIPSS with int-2 or high risk MF were randomized 1:1:1 to FM 50 mg low dose (FM L), 100 mg high dose (FM H) once daily or Rux BID (dosage per label) for 28-day as a cycle for core 24 weeks treatment. Key eligible criteria included platelet count ≥50 x 109/L, ANC ≥1.0 x 109/L, palpable ≥5 cm below LCM or spleen volume ≥450 cm³ by MRI/CT, PB blasts <10%. Primary endpoint was rate achieving 35% (SVR35%) by MRI or CT at week 24 by IRC. Key secondary endpoint was 50% or more reduction in total symptom score (TSS50) at week 24. Results As of Jul 29 2025, 75 MF Pts (median age was 63.0, 52% were male) have been enrolled across 24 centers, with 25 patients allocated to FM L, 26 to FM H and 24 to Rux. Baseline characteristics were generally similar across three arms, exception of the higher proportions grade 3 bone marrow fibrosis (60.0%,76.9% vs 50.0%), high risk MF by IPSS (68.0%,73.1% vs. 50.0%) and CALR mutations (32.0%, 34.6% vs. 12.5%) in FM L and FM H arms compared with RUX arm. 6 severe myelodepletive phenotype pts with PLT < 100×109/L and HGB < 100g/L at baseline enrolled in FM arms. 51 pts completed 12-week and 32 pts completed core 24-week evaluation (CT/MRI by IRC), respectively. At 12 weeks, the SVR35 were superior and achieved respective 80.0% of pts on FM L (12/15) and 100% on FM H (18/18) compared to 50.0% on Rux. The TSS50 rates were 66.7% for FM L, 83.3% for FM H vs.61.1% for Rux treated patients. Notably, CARL mutations pts achieved significantly high SVR35% response in FM L and FM H groups than Rux [66.7% (4/6), 100% (6/6) and 0% (0/2)]. At 24 weeks, pts with FM L and FM H remained significantly benefits versus Rux in SVR 35% [90.0%(9/10), 100.0% (11/11) vs, 54.5%(6/11)] and TSS 50% (80.0%,100% vs.63.6%). 87.5% (7/8) patients with CALR mutation in FM arms achieved SVR35 or CI. Pts with PLT< 100×109/L or PLT> 100×109/L treated with FM arms had higher mean platelet count and greater increase from baseline versus Rux, particularly in early treatment cycles. However, pts with baseline PLT> 100×109/L Rux experienced a rapid decline in PLT, leading to an early dose adjustment. Furthermore, in FM treated group, the proportion of patients with an improvement in bone marrow fibrosis (> 1 grade) and remained stable condition were higher than Rux treated group with 93.8% (15/16) and 60% (6/10), respectively. For FM L, FM H, and Rux arms, the most >10% common Grade ≥3 hematological TEAEs were anemia (37.5%, 52% vs. 34.8%), No Grade ≥3 non-hematological TEAEs were reported in 3 arms. Relatively high incidence of grade ≥3 anemia in both FM arms was partly related to 6 severe myelodepletive phenotype pts at baseline. The incidence of Grade ≥3 anemia in FM L, FM H and Rux for patients with baseline platelet count >100×109/L were respectively 30.0%, 47.8% and 34.8%. Dose reduction occurred in 6 pts (30%) in FM L, 17 pts (73.9%) in FM H and 16 pts (69.6%) in Rux. Only one discontinuation occurred in Rux arms due to disease progression. Conclusions FM demonstrated excellent clinical benefits in MF pts for spleen response and improved symptom compared with RUX and manageable toxicities, suggesting FM as a potential profound innovation in treating MF through a novel mechanism of JAK2 inhibition. The updated results for the phase 2b of 75 MF patients will be completed in December 2025. A pivotal phase III multicenter, randomized, positive control, double blind clinical trial in China is currently in discussion with regulatory authority.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome driven by cytokine storms (e.g., IFN-γ, IL-6, IL-10). Lymphoma-associated HLH (LA-HLH), particularly linked to aggressive T/NK-cell neoplasms, demonstrates dismal prognosis and mandates urgent suppression of both hyperinflammation and malignancy. While JAK inhibitors (e.g., ruxolitinib) target the JAK-STAT pathway central to HLH cytokine signaling, their utility in PTCL-associated HLH is limited by substantial hematologic toxicity and lack of proven antitumor efficacy in PTCL. Golidocitinib, a potent and selective JAK1 inhibitor, has shown promising anti-tumor activity with favorable safety profile in relapsed/refractory (r/r) peripheral T-cell lymphoma (PTCL), representing a mechanistically rational strategy to disrupt pathogenic signaling in high-risk LA-HLH. This was a retrospective study of patients with PTCL-associated HLH treated with golidocitinib monotherapy or combination therapy. Methods: In this single-center study, sixteen patients with relapsed/refractory PTCL-associated HLH meeting HLH-2004 criteria were enrolled between July 1, 2024, and June 26, 2025, receiving golidocitinib-based therapy (8 monotherapy, 8 combined with chemotherapy). Lymphoma response was assessed per Lugano 2014 criteria, and HLH response was evaluated according to the response criteria defined in the Histiocyte Society HLH-2004 protocol. Results: Baseline characteristics included a median age of 56 years (range 28–61), 9 males; lymphoma subtypes comprised extranodal NK/T-cell lymphoma (n=6), angioimmunoblastic T-cell lymphoma (n=5), NK-cell leukemia (n=2), hepatosplenic T-cell lymphoma (n=2), and PTCL-NOS (n=1). 87.5% patients (14/16) had Ann Arbor stage III–IV disease; median prior lines of anti-lymphoma therapy were 2 (range 1–4); 10 patients (62.5%) had ECOG PS ≥2. Systemic HLH manifestations included fever (≥38.5°C) in all patients, cytopenia in 8 (50%) patients, hepatic impairment in 7 (43.8%) patients; elevated biomarkers included EBV-DNA in 10 patients (62.5%) and elevated sCD25 in 11/11 tested patients (100%). Anti-lymphoma efficacy demonstrated an ORR of 46.7% (7/15) and CR rate of 13.3% (2/15) with a median time to response of 2 months (1-3). Among 10 patients with elevated EBV-DNA, 60% (6/10) achieved undetectable levels post-treatment. Rapid anti-HLH activity was observed, HLH response rate was 85.7% (6/7) and 77.8% (7/9) at week 2 and week 4 respectively. Clinical improvements included resolution of fever, hematologic recovery (7 patients at both timepoints), and hepatic function normalization (7 patients at both timepoints). Significant reductions in inflammatory markers were observed, including neutrophil to lymphocyte ratio (NLR), IL-6, CRP, TNF-α, ferritin, and triglycerides. At data cutoff (median follow-up: 3.1 months, range 0.8–6.3), 62.5% of patients (10/16) remained on treatment, with median PFS and OS were not reached. Treatment-related adverse events (TRAEs) were manageable, with the most common being thrombocytopenia (42.8%), CMV reactivation (28.6%), abnormal liver function (14.3%). Grade ≥3 TRAEs lung infection (14.3%) and CMV reactivation (14.3%); serious TRAEs comprised CMV reactivation (28.6%), lung infection (14.3%), and thrombocytopenia (14.3%). No treatment-related deaths occurred. Conclusion： This study demonstrates that golidocitinib-based regimens provide dual anti-HLH and antitumor efficacy in relapsed/refractory PTCL-associated HLH, with rapid clinical improvement (e.g., fever resolution, biomarker normalization) and an ORR of 46.7%. Most patients achieved systemic and hematologic recovery with a manageable safety profile and no treatment-related deaths. These findings highlight the potential of JAK1 inhibition in this high-risk cohort, warranting prospective validation to confirm efficacy and optimize therapeutic strategies.

Chimeric antigen receptor T (CAR-T) cell therapy targeting B cell mature antigen (BCMA) has shown remarkable clinical benefits in treating multiple myeloma (MM). Bortezomib, a proteasome inhibitor approved as a first-line agent for MM for two decades, has demonstrated potent antitumor activity. In this study, we found that bortezomib treatment stabilizes the expression of BCMA and conceived the hypothesis that BCMA CAR-T therapy combined with bortezomib would enhance the anti-MM efficacy. The in vitro experiments revealed that pretreatment of both MM tumor cell line MM1.S and tumor cell line NALM-6 forced expression of BCMA with low concentrations of bortezomib up-regulated BCMA expression. When encountered with BCMA CAR-T cells, the cytotoxicity to these bortezomib-treated tumor cells was increased, indicating that the up-regulated BCMA induced by bortezomib contributes to the enhanced activities of the CAR-T cells. Further, in the in vivo experiment, the combined treatment significantly enhanced the anti-MM ability and prolonged the survival rate. Moreover, safety analysis found that there is no tissue damage or loss of weight, suggesting the favorable tolerability of this combination strategy. Our study provided a surety and efficacious strategy for the BCMA-targeted CAR-T cancer immunotherapy enhancement.

Radiotherapy (RT) exhibits a dose-dependent duality in its impact on antitumor immunity. While high-dose irradiation induces immunogenic cell death (ICD) and enhances immune responses, conventional RT is limited by toxicity and may paradoxically promote immunosuppression via myeloid-derived suppressor cells (MDSCs) infiltration and M2 macrophage polarization. To address this challenge, we leveraged ex vivo high-dose irradiation to generate tumor-derived exosomes (cExo) enriched with immunostimulatory components. Proteomic analysis revealed that cExo were enriched with damage-associated molecular patterns (DAMPs), including high mobility group box 1 protein (HMGB1) and calreticulin (CRT), as well as major histocompatibility complex I (MHC I), thereby enhancing dendritic cells (DCs) activation and antigen cross-presentation. Building upon these findings, we developed a hybrid nanoplatform (cExo-Lip) by fusing immunogenic cExo with liposomes loaded with plasmid IL-12 (pIL-12). This design compensates for the limited immunogenicity of low-dose irradiation by delivering MHC I and DAMPs via cExo, thereby enhancing DCs maturation and cytotoxic T lymphocyte (CTLs) priming. Moreover, sustained IL-12 expression further remodels the tumor immune microenvironment by reprogramming M2 macrophages toward a tumoricidal M1 phenotype and enhancing CTLs activation, thereby synergistically amplifying RT-induced immune responses. In B16F10 melanoma mouse models, combining 6 Gy RT with pIL-12@cExo-Lip resulted in 91.07% tumor suppression. Our approach uniquely capitalizes exosomes treated by ex vivo high-dose irradiation for the first time to overcome the limitations of clinical dose constraints and synergizes RT's immune-priming potential with cytokine delivery to combat the challenges in clinical cancer radiotherapy and enhance its therapeutic efficacy.

This study aims to analyze the risk factors for the development of multidrug-resistant (MDR) and carbapenem-resistant (CR) bacteria bloodstream infection (BSI) in a patient with acute leukemia (AL) and the mortality in gram-negative bacteria (GNB) BSI. This is a retrospective study conducted at West China Hospital of Sichuan University, which included patients diagnosed with AL and concomitant GNB BSI from 2016 to 2021. A total of 206 patients with GNB BSI in AL were included. The 30-day mortality rate for all patients was 26.2

Background:Dihydrolipoamide S-acetyltransferase (DLAT) is a subunit of the pyruvate dehydrogenase complex (PDC), a rate-limiting enzyme complex, that can participate in either glycolysis or the tricarboxylic acid cycle (TCA). However, the pathogenesis is not fully understood. We aimed to perform a more systematic and comprehensive analysis of DLAT in the occurrence and progression of tumors, and to investigate its function in patients' prognosis and immunotherapy. Methods:The differential expression, diagnosis, prognosis, genetic and epigenetic alterations, tumor microenvironment, stemness, immune infiltration cells, function enrichment, single-cell analysis, and drug response across cancers were conducted based on multiple computational tools. Additionally, we validated its carcinogenic effect and possible mechanism in glioma cells. Results:We exhibited that DLAT expression was increased in most tumors, especially in glioma, and affected the survival of tumor patients. DLAT was related to RNA modification genes, DNA methylation, immune infiltration, and immune infiltration cells, including CD4+ T cells, CD8+ T cells, Tregs, and cancer-associated fibroblasts. Single-cell analysis displayed that DLAT might regulate cancer by mediating angiogenesis, inflammation, and stemness. Enrichment analysis revealed that DLAT might take part in the cell cycle pathway. Increased expression of DLAT leads tumor cells to be more resistant to many kinds of compounds, including PI3Kβ inhibitors, PKC inhibitors, HSP90 inhibitors, and MEK inhibitors. In addition, glioma cells with DLAT silence inhibited proliferation, migration, and invasion ability, and promoted cell apoptosis. Conclusion:We conducted a comprehensive analysis of DLAT in the occurrence and progression of tumors, and its possible functions and mechanisms. DLAT is a potential diagnostic, prognostic, and immunotherapeutic biomarker for cancer patients.

Multiple myeloma (MM) remains an incurable hematologic malignancy, despite the development of numerous innovative therapies during the past two decades. Immunotherapies are changing the treatment paradigm of MM and have improved the overall response and survival of patients with relapsed/refractory (RR) MM. B cell maturation antigen (BCMA), selectively expressed in normal and malignant plasma cells, has been targeted by several immunotherapeutic modalities. Chimeric antigen receptor (CAR) T cells, the breakthrough in cancer immunotherapy, have revolutionized the treatment of B cell malignancies and remarkably improved the prognosis of RRMM. BCMA-targeting CAR T cell therapy is the most developed CAR T cell therapy for MM, and the US Food and Drug Administration has already approved idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel) for MM. However, the development of novel BCMA-targeting CAR T cell therapies remains in progress. This review focuses on BCMA-targeting CAR T cell therapy, covering all stages of investigational progress, including the innovative preclinical studies, the initial phase I clinical trials, and the more developed phase II clinical trials. It also discusses possible measures to improve the efficacy and safety of this therapy.

Hematologic malignancies are one of the most common cancers, and the incidence has been rising in recent decades. The clinical and molecular features of hematologic malignancies are highly heterogenous, and some hematologic malignancies are incurable, challenging the treatment, and prognosis of the patients. However, hematopoiesis and oncogenesis of hematologic malignancies are profoundly affected by epigenetic regulation. Studies have found that methylation-related mutations, abnormal methylation profiles of DNA, and abnormal histone deacetylase expression are recurrent in leukemia and lymphoma. Furthermore, the hypomethylating agents and histone deacetylase inhibitors are effective to treat acute myeloid leukemia and T-cell lymphomas, indicating that epigenetic regulation is indispensable to hematologic oncogenesis. Epigenetic regulation mainly includes DNA modifications, histone modifications, and noncoding RNA-mediated targeting, and regulates various DNA-based processes. This review presents the role of writers, readers, and erasers of DNA methylation and histone methylation, and acetylation in hematologic malignancies. In addition, this review provides the influence of microRNAs and long noncoding RNAs on hematologic malignancies. Furthermore, the implication of epigenetic regulation in targeted treatment is discussed. This review comprehensively presents the change and function of each epigenetic regulator in normal and oncogenic hematopoiesis and provides innovative epigenetic-targeted treatment in clinical practice.

Natural killer (NK) cells, a unique component of the innate immune system, are inherent killers of stressed and transformed cells. Based on their potent capacity to kill cancer cells and good tolerance of healthy cells, NK cells have been successfully employed in adoptive cell therapy to treat cancer patients. In recent years, the clinical success of chimeric antigen receptor (CAR)-T cells has proven the vast potential of gene-manipulated immune cells as the main force to fight cancer. Following the lessons learned from mature gene-transfer technologies and advanced strategies in CAR-T therapy, NK cells have been rapidly explored as a promising candidate for CAR-based therapy. An exponentially growing number of studies have employed multiple sources of CAR-NK cells to target a wide range of cancer-related antigens, showing remarkable outcomes and encouraging safety profiles. Clinical trials of CAR-NK cells have also shown their impressive therapeutic efficacy in the treatment of hematological tumors, but CAR-NK cell therapy for solid tumors is still in the initial stages. In this review, we present the favorable profile of NK cells as a potential platform for CAR-based engineering and then summarize the outcomes and strategies of CAR-NK therapies in up-to-date preclinical and clinical investigations. Finally, we evaluate the challenges remaining in CAR-NK therapy and describe existing strategies that can assist us in devising future prospective solutions.

Background: For multiple myeloma (MM), the proportions of patients reaching the subsequent line of therapy (LOT) decline gradually and real-world data describing the attrition rates of LOT in Chinese MM were limited. Herein, we investigated the attrition rates by subsequent LOTs and their relevant risk factors in MM patients in China.Methods: MM patients who had been hospitalized and received at least one LOT from January 2008 to August 2019 in West China Hospital Sichuan University were retrospectively recruited. Demographic and clinical characteristic data were obtained from the "HemaTank " Chinese Multiple Myeloma Database. The Cox proportional hazards regression model was applied to analyze the risk factors of frontline treatment attrition.Results: A total of 1,255 newly diagnosed MM were enrolled, with 573 (45.7%) patients receiving only one LOT and 682 (54.3%) patients receiving more than one LOT. Thalidomide with dexamethasone/prednisone was the most common frontline treatment before 2017, while bortezomib-based regimens constituted the majority of frontline treatment in 2017 and beyond. The attrition rates from the first to the fifth LOT exhibited a gradual upward trend (45.7%, 48.7%, 58.9% and 62.5%, respectively). Meanwhile, 54.3%, 27.9%, 11.5%, and 4.3% of all the enrolled MM patients received a second, third, fourth and fifth LOT. MM who underwent autologous stem cell transplantation (ASCT) showed lower attrition rates across all LOTs (range 12%-56.8%) than MM without ASCT (range 49.1%-64.5%). The multivariate Cox regression model revealed that ISS stage III (HR 2.07, p < .001), elevated LDH (HR 1.47, p = .006), and comorbidities such as amyloidosis (HR 1.63, p = 0 .01), hepatic disease (HR 1.36, p = .022), pulmonary disease (HR 1.38, p = .022), and cardiac disease (HR 1.62, p = .004) were independent risk factors for MM patients attritted from the frontline treatment.Conclusion: In this study, the attrition rates were generally high and increased gradually across all LOTs. Nearly half of MM patients received only one LOT, and higher tumor burden and more comorbidities may be associated with fewer subsequent LOTs. The high attrition rates highlight the importance of applying the most optimal frontline treatment regimen rather than salvaging subsequent LOTs.

Distant metastasis and primary tumor relapse are the two main hurdles to the success of surgical treatment for cancer patients. Circulating tumor cells (CTCs) and incomplete surgical resection are the primary cause of distant metastasis and recurrence of tumors respectively. Chimeric antigen receptor (CAR)-modified T cells targets residual carcinomas and CTCs hold the potential to inhibit primary recurrence and reduce tumor metastasis, but the experimental evidence is lacking. Here, we developed a surgery-induced tumor metastasis model in immunocompetent mice to investigate the efficacy of CAR-T cells therapy in preventing metastasis and local recurrence. We observed that subcutaneous tumor resection has induced a large number of CTCs intravasated into circulation. EpCAM-specific CAR-T was effective in clearing CTCs following surgical removal of the tumor. This resulted in less pulmonary metastasis and longer survival in mice when compared to mice treated with surgery followed by Mock-T cells. In addition, the local relapse was obviously inhibited at the surgical site followed by EpCAM-CAR-T cell treatment. This study demonstrated that CAR-T cell therapy can be an adjuvant treatment following surgery to prevent tumor metastasis and inhibit primary tumor relapse for cancer patients.

Chimeric antigen receptor-modified T (CAR-T) cell therapy has shown curable efficacy for treating hematological malignancies, while in solid tumors, the immunosuppressive microenvironment causes poor activation, expansion and survival of CAR-T cells, accounting mainly for the unsatisfactory efficacy. The artificial antigen-presenting cells (aAPCs) have been used for ex vivo expansion and manufacturing of CAR-T cells. Here, we constructed a K562 cell-based aAPCs expressing human epithelial cell adhesion molecule (EpCAM), chemokines (CCL19 and CCL21) and co-stimulatory molecular ligands (CD80 and 4-1BBL). Our data demonstrated that the novel aAPCs enhanced the expansion, and increased the immune memory phenotype and cytotoxicity of CAR-T cells recognizing EpCAM, in vitro. Of note, co-infusion CAR-T and aAPC enhances the infiltration of CAR-T cells in solid tumors, which has certain potential for the treatment of solid tumors Moreover, IL-2-9-21, a cytokine cocktail, prevents CAR-T cells from entering the state of exhaustion prematurely after continuous antigen engagement and boosts the anti-tumor activity of CAR-T cells co-infused with aAPCs. These data provide a new strategy to enhance the therapeutic potential of CAR-T cell therapy for the treatment of solid tumors.