7073 Background: Mesutoclax (ICP-248) is a next-generation BCL2 inhibitor, and orelabrutinib is a marketed BTK inhibitor for CLL/SLL, MCL, and MZL. However, the clinical activity of their combination in these malignancies remains undefined. This analysis evaluated the combination of mesutoclax and orelabrutinib across B-cell malignancies. Methods: Patients with relapsed and refractory (R/R) MCL, MZL were enrolled in a phase 1 study (NCT05728658), and treatment-naive (TN) CLL/SLL were enrolled in a phase 2 study (NCT06378138). R/R MCL and MZL patients received continuous daily mesutoclax (125 mg) and orelabrutinib (150mg) from cycle 1 day 1 continuously until disease progression or unacceptable toxicity. For CLL/SLL patients, induction therapy with orelabrutinib (150 mg QD, Cycles 1-17) was administered first, followed by mesutoclax (100 mg or 125 mg QD, Cycles 3-14). The orelabrutinib treatment continued beyond cycle 17 if the uMRD (≤10-4) was not achieved. Mesutoclax was implemented with a ramp-up schedule in all patients to mitigate the risk of TLS. Results: As of 05 Jan 2026, 60 patients were enrolled and treated in the studies: 8 R/R MCL, 10 R/R MZL, and 42 TN CLL/SLL (mesutoclax 100 mg, n=21; 125 mg, n=21). In R/R patients, the median number of prior lines of therapy was 1 (1-4). 6 (33.3%) were refractory to the last line of therapy. For TN CLL/SLL, 76.2% (32/42) of patients had moderate or high TLS risk, and 14.3% (6/42) had TP53 mutation or del (17p). Among 5 MCL and 8 MZL patients who had at least one disease evaluation, the overall response rate (ORR) was 100%, with CRR of 100% and 50%, respectively. Five patients (38.5%) achieved peripheral blood (PB) uMRD. In the 21 CLL/SLL patients receiving mesutoclax 125 mg, the ORR was 100% and the CRR was 38.1%, and the peripheral blood uMRD rate at 36-week was 65%. The median time to CR was 3.7 months in R/R group and 7.1 months in TN group. The 12-month PFS rate was 100% in CLL/SLL, while data for MCL and MZL are immature due to short follow-up. As the safety data cutoff (31 Dec 2025), the combination of mesutoclax and orelabrutinib was well tolerated with a favorable safety profile, and no new safety signals were identified compared to either agent as monotherapy. Most TEAEs were grade 1-2, with no TEAEs leading to drug discontinuation or death reported. The most common grade ≥3 TEAEs include neutrophil count decreased (35%), platelet count decreased (11.7%). Notably, no grade ≥3 anemia was reported. No clinical or laboratory TLS occurred. Conclusions: Mesutoclax in combination with orelabrutinib demonstrated a tolerable safety profile across B cell malignancy subtypes (MCL, MZL, CLL/SLL). Significant 100% ORR and deep response were observed in patients receiving mesutoclax 125mg combined with orelabrutinib. This all oral, chemo-free regimen has the potential to establish a novel therapeutic option for B-NHLs. Clinical trial information: NCT05728658 .

Importance:Epigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL. Objective:To evaluate efficacy and safety of tucidinostat plus R-CHOP vs R-CHOP alone as first-line treatment for patients with DEL. Design, Setting, and Participants:This randomized, double-blind, placebo-controlled phase 3 trial enrolled patients from May 21, 2020, through July 25, 2022, with follow-up to June 26, 2025. The trial was conducted at 40 study centers in China; a total of 423 eligible patients were enrolled. Interventions:Patients were randomly assigned in a 1:1 ratio to receive oral tucidinostat (20 mg on days 1, 4, 8, and 11 of each 21-day cycle) or matching placebo, plus 6 cycles of R-CHOP. Patients with a complete response after combination therapy received either tucidinostat or placebo maintenance up to 24 weeks. Main Outcomes and Measures:The primary end point was event-free survival. Secondary end points included complete response rate, progression-free survival, disease-free survival, overall survival, and tolerability. Results:Among 423 patients randomized (median age, 63 years; 47.5% male), the median follow-up duration from randomization was 41.3 months. The tucidinostat group demonstrated a 28% lower risk of disease progression, relapse after complete response, death, or initiation of new therapy for residual disease compared with the placebo group (stratified hazard ratio, 0.72 [95% CI, 0.54-0.96]; P = .02), with a 2-year event-free survival rate of 60.3% vs 50.5%, respectively. The complete response rate was 73.0% vs 61.8% (difference, 11.1% [95% CI, 2.3%-20.0%]), respectively. Increased toxicity associated with treatment was observed in the tucidinostat group but generally manageable with supportive care. Conclusions and Relevance:Tucidinostat plus R-CHOP significantly improved event-free survival, with manageable toxicity in patients newly diagnosed with DEL. This trial is the first to demonstrate the benefit of an epigenetic modulator in DLBCL, offering a new first-line therapeutic approach dually targeting MYC and BCL2 oncoprotein for this high-risk population. Trial Registration:ClinicalTrials.gov Identifier: NCT04231448.

6567 Background: Accurate cytogenetic characterization is critical for risk stratification in myelodysplastic syndromes (MDS). Conventional karyotyping and fluorescence in situ hybridization (FISH) are limited in resolution, target specific loci, and cannot detect copy-neutral loss of heterozygosity (CN-LOH). LeukoPrint, a CE-IVD-marked shallow whole-genome sequencing (sWGS, 1×coverage) test, enables genome-wide detection of copy number alterations (CNAs) and CN-LOH. Previously validated in acute myeloid leukemia and multiple myeloma, it improved CNA detection and prognostic accuracy. This study evaluated its ability to enhance diagnostic yield and refine prognostic precision in a large MDS cohort. Methods: Bone marrow samples from 461 MDS patients were profiled for genome-wide CNA/CN-LOH using LeukoPrint. Results were compared with conventional karyotyping and FISH to assess detection yield and concordance. The impact of additional LeukoPrint findings on Revised International Prognostic Scoring System (IPSS-R) cytogenetic risk stratification and MDS subclassification was evaluated. Results: LeukoPrint detected cytogenetic abnormalities in 63.3% of patients, comprising CNAs in 50.3%, CN-LOH in 23.9%, with 10.8% harboring both. Recurrent CNAs included del(5q) (10.0%), del(20q) (10.0%), +8 (8.9%), and del(7q) (7.8%), among others. CN-LOH frequently affected regions that overlapped common CNA loci, such as 5q (3.7%), 7q (3.7%), and 17p (0.7%). Compared with conventional cytogenetics, LeukoPrint showed 94.4% concordance (κ=0.854) with FISH for five key loci (−5/del(5q), −7/del(7q), +8, del(20q), −Y) and a higher detection rate than karyotyping (65.7% vs 39.2%). For the 11 IPSS-R defined cytogenetic abnormalities (del(3q), del(5q), del(7q), del(11q), del(12p), del(17p), del(20q), +8, +19, -7, and -Y), it identified all karyotype-detected lesions and increased detection yield by 49.4%. These newly identified abnormalities led to IPSS-R cytogenetic risk reclassification in 32.4% (33/102) of comparable cases, predominantly upgrading patients to higher-risk categories. Specifically, 26 patients were reassigned from Good to Intermediate (n = 17), Poor (n = 2), or Very Poor (n = 7); 5 from Intermediate to Poor (n = 4) or Very Poor (n = 1); and 1 from Poor to Very Poor. Furthermore, by detecting additional aberrations such as del(17p) or 17p CN-LOH, LeukoPrint enabled more accurate molecular classification, including the reclassification of one case from MDS-IB1 to MDS-biTP53. Conclusions: sWGS-based LeukoPrint substantially enhances cytogenetic detection in MDS, outperforming conventional karyotyping and FISH. By identifying additional clinically relevant cytogenetic abnormalities, it improves prognostic risk stratification and refines disease classification, supporting its integration into routine MDS cytogenetic assessment.

Abnormal Wnt/β-catenin pathway activation drives colorectal cancer (CRC) tumorigenesis, yet effective targeted therapies remain elusive. Given HPCAL1's established dual tumor-suppressive and oncogenic roles in other cancers, this study investigates its function in CRC to assess the therapeutic potential. Bioinformatic analyses of publicly available CRC datasets supported by in-house cohort studies linked high HPCAL1 expression in primary CRC tissues with clinicopathological factors associated with metastasis and worsened patient outcomes. Knockdown and overexpression studies in cell lines showed that HPCAL1 positively contributes to CRC cell motility and invasion, as well as proliferation in vitro and in vivo in xenografts. RNA sequencing linked HPCAL1 expression with the Wnt/β-catenin pathway, demonstrating positive correlations with Wnt ligands in CRC models and clinical samples. Biochemical approaches showed HPCAL1 augmented the activation and nuclear localization of β-catenin. Moreover, HPCAL1 formed distinct complexes with β-catenin in tandem with the TCF7 or p65 transcription factors, in turn, differentially transactivating Wnt6, Wnt7A, and Wnt11 ligands. Notably, the anticancer activity of desloratadine against CRC cells, a pharmacological inhibitor of HPCAL1, functioned by curtailing Wnt6, Wnt7A, and Wnt11 expression and suppressing Wnt/β-catenin signaling. Collectively, these findings indicate that HPCAL1 is a significant contributor to the clinical aggressiveness of CRC with oncogenic effects intrinsically linked with sustaining canonical Wnt pathway activation. Furthermore, drug targeting experiments provide proof-of-principle evidence for promoting HPCAL1 as a therapeutic target for countering activated Wnt/β-catenin signaling in colorectal cancer.

BackgroundAcute myeloid leukemia (AML) is a hematologic malignancy characterized by heterogeneity, poor prognosis, and limited biomarkers for risk prediction. Mitochondria pathway related genes (MPRGs), as central regulators of cellular metabolism and immune microenvironment dynamics, may provide useful information for prognostic assessment and biological characterization in AML.MethodsMPRGs were obtained from the MitoCarta3.0 database. Univariate Cox and Kaplan-Meier methods were conducted to analyze their prognostic relevance. LASSO penalized regression followed by stepwise multivariate Cox analysis yielded an optimal gene panel in the TCGA-LAML dataset. External validation was performed across three GEO datasets (GSE10358, GSE106291, GSE71014). Finally, the role of UCP2 was examined in vitro by assessing UCP2 knockdown effects on MOLM-13 cell behavior.ResultsA prognostic signature comprising seven MPRGs (UCP2, FAM162A, ACCS, HSD1, ACSF2, PPIF, and SDHA) was established. High-risk patients exhibited significantly shorter survival. The MPRGs risk score served as an independent predictor of prognosis. Moreover, elevated risk scores correlated with heightened immune checkpoint molecule expression and an immunosuppressive tumor microenvironment. UCP2 knockdown attenuated both proliferative capacity and migratory potential in MOLM-13 AML cells.ConclusionIn summary, the MPRG-based signature provides independent prognostic value in AML and reflects its association with an immunosuppressive microenvironment. These findings provide additional evidence that mitochondrial pathway-related genes are associated with AML prognosis and immune microenvironment features. UCP2 may represent a biologically relevant candidate gene in AML, although further mechanistic and clinical validation is required.

Orelabrutinib is a potent, irreversible, and highly-selective BTK inhibitor that has been approved for the treatment of relapsed/refractory chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). This randomized, phase 3 study (ClinicalTrials.gov identifier: NCT04578613) compared orelabrutinib with chemoimmunotherapy in patients with treatment-naïve CLL/SLL. From February 20, 2021, to July 8, 2024, 192 eligible patients were randomly assigned (1:1) to receive either orelabrutinib (91 patients) or chlorambucil plus rituximab (101 patients), comprising the intention-to-treat population. At a median follow-up of 21.4 months (data cutoff, May 17, 2024), the primary endpoint of progression-free survival (PFS) per independent review committee (IRC) was not reached (NR; 95% CI, not estimable [NE]-NE) with orelabrutinib versus 19.4 months (95% CI, 16.6-NE) with chlorambucil plus rituximab (hazard ratio [HR], 0.32; 95% CI, 0.18-0.58; p < 0.0001; crossing the efficacy boundary). The IRC-assessed overall response rate (90.1% vs 79.2%; p = 0.041) and duration of response (HR, 0.30; 95% CI, 0.15-0.60; p = 0.0003) also favored orelabrutinib over chlorambucil plus rituximab. In the safety population, treatment-related adverse events occurred in 82 of 91 patients (90.1%) receiving orelabrutinib and 89 of 98 patients (90.8%) receiving chlorambucil plus rituximab, with 32 (35.2%) and 59 (60.2%) at grade 3 or worse, respectively. Orelabrutinib maintained or improved patient-reported outcomes compared with chemoimmunotherapy. In summary, orelabrutinib significantly improved PFS and response versus chemoimmunotherapy in patients with treatment-naïve CLL/SLL, with a manageable safety profile, supporting it as an effective alternative first-line option.

BackgroundAutonomic nervous system involvement is common in systemic amyloidosis, yet the clinical relevance of heart rate variability (HRV) in immunoglobulin light-chain (AL) amyloidosis remains incompletely defined.MethodsIn this retrospective cohort study, 56 patients with biopsy-proven AL amyloidosis and 33 age- and sex-comparable healthy controls underwent 24 h Holter monitoring. Time- and frequency-domain HRV parameters were recorded. Associations of HRV with cardiac involvement assessed by cardiac magnetic resonance (CMR), Mayo 2004 stage, and short-term treatment response were evaluated using group comparisons and multivariable regression.ResultsCompared with controls, patients with AL amyloidosis had significantly higher mean heart rate and lower SDNN, total power (TP), and all frequency-domain components (ULF, VLF, LF, and HF) (all P < 0.05). Patients with CMR-defined cardiac involvement showed a higher prevalence of HRV abnormalities and lower SDNN, SDANN, pNN50, TP, ULF, VLF, and LF than CMR-negative patients (all nominal P < 0.05). In multivariable models, troponin remained independently associated with CMR-positive status, whereas HRV indices did not retain independent significance. By Mayo 2004 stage (I/II/III: 11/20/25), SDANN and VLF declined progressively with advancing stage (P < 0.05), and SDANN remained independently associated with higher stage after adjustment for troponin. In the exploratory subset with paired follow-up Holter recordings (n = 33), most HRV parameters did not change significantly after therapy; however, the coefficient of variation (CV) showed a statistically significant increase following treatment (P = 0.037).ConclusionReduced HRV is a prominent feature of AL amyloidosis and is independently associated with Mayo stage after adjustment for cardiac biomarkers. These findings position HRV as a non-invasive marker of autonomic involvement that complements established cardiac biomarkers in characterising disease severity in AL amyloidosis; whether this translates into independent prognostic value requires evaluation in prospective outcome studies.

Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by complement-mediated hemolysis, thrombophilia, and bone marrow failure. Despite anti-C5 therapy (e.g., eculizumab), many patients remain anemic due to residual intravascular hemolysis and C3-mediated extravascular hemolysis (EVH). HSK39297, a novel oral Factor B inhibitor, targets proximal complement activation and enables a once-daily administration regimen, offering potential advantages over existing therapies. This phase 2 trial evaluated the efficacy and safety of HSK39297 monotherapy in complement inhibitor- naïve PNH patients. Methods In this open-label, multicenter study (NCT06561841), 47 adults with PNH (granulocyte clone >10%, lactate dehydrogenase [LDH] >1.5× upper limit normal [ULN], hemoglobin [Hb] <100 g/L) were randomized 1:1:1 to receive HSK39297 (cohort A: 75 mg/125 mg twice daily [BID], cohort B: 100 mg BID, or cohort C: 200 mg once daily [QD]) for 24 weeks. The primary endpoint was the proportion of patients achieving Hb increase of ≥20 g/L without red blood cell (RBC) transfusions between weeks 4 and 24. Secondary endpoints included LDH reduction > 60% or normalization, changes in Hb levels, reticulocyte count, indirect bilirubin, PNH clone size, C3 fragment deposition, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scores, and safety. Pharmacokinetics and pharmacodynamics were assessed. Results At week 24, 42 of 47 patients (89.4%) met the primary endpoint (cohort A: 87.5%; B: 86.7%; C: 93.8%). Transfusion avoidance was achieved in 95.7% of patients. Mean Hb increased by 50.7 g/L. LDH levels reduced by ≥60% or normalized in all patients (47/47, 100%). C3d+ RBC levels remained low (0.34% at week 24). Consistent improvements were observed in other markers of hemolysis and FACIT-Fatigue scores. Adverse events (AEs) occurred in 72.3% of patients ,mostly of which were grade ≤2（CTCAE5.0）. 59.6% of patients experienced drug-related AEs, with headache (34.0%) being the most frequently reported. No breakthrough hemolysis or thromboembolic events were reported. The 200 mg QD cohort showed sufficient exposure to sustained complement inhibition at the trough. Conclusions HSK39297 monotherapy significantly improved hematologic and clinical outcomes in complement inhibitor- naïve PNH patients, demonstrating robust efficacy across all doses and a favorable safety profile. The 200 mg QD regimen demonstrated optimal efficacy and pharmacokinetics and is therefore proposed for further investigation in phase 3 trials.

Abstract: Comprehensive detection of copy number aberrations (CNAs) is critical for precise prognostic risk stratification in multiple myeloma (MM), yet conventional cytogenetic methods remain limited. We developed LeukoPrint, a shallow whole-genome sequencing (sWGS) assay for genome-wide CNA profiling. Using this platform, we analyzed CNA profiles of 423 patients with MM across 3 hospitals and compared LeukoPrint with karyotyping and fluorescence in situ hybridization (FISH) to evaluate its diagnostic performance and clinical utility in prognostic assessment. Compared with karyotyping, LeukoPrint demonstrated a significantly higher abnormality detection rate (75.2% vs 11.2%) and identified CNAs in 73.3% of karyotyping-negative cases. Concordance with FISH for key prognostic CNAs (amp(1q), del(1p), del(13q), del(17p)) was 94.0%. Based on these findings, we propose replacing karyotyping with LeukoPrint combined with FISH for routine diagnostics. Integrating LeukoPrint with FISH results into the Mayo Stratification for Myeloma and Risk-Adapted Therapy risk model reclassified 11.5% of standard-risk patients as high-risk, identifying candidates for intensified therapy. Furthermore, LeukoPrint genome-wide profiling revealed distinct CNA patterns between hyperdiploid and nonhyperdiploid MM, informing biological heterogeneity. LeukoPrint significantly outperforms conventional karyotyping and closely matches FISH for critical CNA markers, offering an alternative for cytogenetic profiling and prognostic risk stratification in MM.

OBJECTIVE:To analyze the immunophenotype and clinical characteristics of mature T-cell lymphoma (TCL) and clonal T cells of undetermined significance (T-CUS), and to explore the application value of flow cytometry in the differential diagnosis of TCL and T-CUS. METHODS:Multi-parameter flow cytometry (MFC) was used to analyze the immunophenotypic characteristics of 93 TCL patients (TCL group) and 46 patients with T-CUS but no T-lymphoproliferative disease (non-TCL group) admitted to the Department of Hematology of Henan Provincial People's Hospital from October 2019 to June 2024, and the clinical and laboratory data of patients in TCL group and T-CUS group (non-TCL patients) were collected. RESULTS:In terms of flow cytometry immunophenotype, the TCL group and the T-CUS group had similar immunophenotypes, with CD8+ tumor cells being the most, followed by CD4+, and CD4+/CD8+ and CD4-/CD8- being rare. There were significant statistical differences in the positive expression rates of CD3, CD4 and CD8 between the two groups, which showed that the expression rates of CD3 and CD8 in the TCL group were lower than those in the T-CUS group (CD3: 72.00±42.04 vs.94.05±21.61; CD8: 56.04±48.22 vs.79.86±36.33) (P <0.05), while the expression rates of CD4 were higher than those in the T-CUS group ［（38.35±48.53） vs. （10.76±31.15）, (P <0.01)］. TRBC1 showed a restricted expression pattern (monoclonal expression) in all cases, and the positive expression rate of TRBC1 in the TCL group was slightly higher than that in the T-CUS group, but there was no significant statistical difference between the two group (P >0.05). According to the laboratory results, the levels of RDW-CV and LDH in the TCL group were higher than those in the T-CUS group ［RDW-CV: 17.6(11.9-24) vs.14.1(10.9-19.1); LDH: 459(129-90 704) vs.310(99-11 722)］, and the difference was statistically significant (P <0.05). The results of T-cell receptor (TCR) gene rearrangement, karyotype analysis and EBV nucleic acid quantitative detection were obtained in the two groups, and the Kappa test showed that the positive rate of TCR gene rearrangement in the TCL group was significantly higher than that in the T-CUS group (92.1% vs. 52.6%) (P <0.001). CONCLUSION:TRBC1 can be used as an ideal indicator for rapid detection of T cell clonality, Multi-parameter flow cytometry (MFC) combined with TCR gene rearrangement testing has good clinical value in distinguishing T-cell lymphoma from T-cell clonal proliferation of uncertain significance.

This study investigated autoimmune diseases (ADs) clinical characteristics, their association with B-cell lymphoma (BCL), and related frequent genetic mutations. A retrospective review of 2,040 BCL patients at Henan Provincial People’s Hospital (2016–2022) identified 98 with concurrent ADs. Hashimoto’s thyroiditis was the most common AD identified, followed by Sjögren’s syndrome, rheumatoid arthritis, and autoimmune hemolytic anemia. The median interval from initial AD diagnosis to BCL development was 9 years, varying significantly across AD subtypes (P = 0.038). Marginal zone lymphoma (MZL) were more frequent in patients with Sjögren’s syndrome (P < 0.001) and inflammatory bowel disease (P = 0.03). BCL with concurrent ADs occurred more frequently in female patients (P = 0.009). These patients also exhibited higher levels of β2-microglobulin ≥ 2.5 mg/L (P = 0.001), demonstrated more frequent bone marrow infiltration (P = 0.017), and demonstrated a higher prevalence of gastrointestinal tract involvement (P = 0.033). However, the presence of concurrent ADs did not significantly affect overall BCL patient prognosis (P = 0.188). The next-generation sequencing (NGS) results indicate that the top four mutated genes identified in the AD-associated DLBCL cohort are B2M, BIRC3, RB1, and PLCG2. In the DLBCL cohort, the predominant mutated genes are KMT2C, EGR1, BCL2, and DDX3X. AD-associated BCL predominantly affects females, with more common bone marrow involvement. Hashimoto’s thyroiditis is the most prevalent AD type, with a 9-year median interval from AD diagnosis to BCL development. Concurrent ADs do not significantly impact BCL survival. Mutations in BIRC3, RB1, B2M, PLCG2, and EP300 are present in patients with AD-associated DLBCL.

QuestionDoes adding the histone deacetylase inhibitor tucidinostat to R-CHOP improve clinical outcomes in patients with newly diagnosed MYC/BCL2 double-expressor lymphoma?FindingsIn this randomized phase 3 clinical trial that included 423 patients, event-free survival was significantly improved with tucidinostat plus R-CHOP compared with placebo plus R-CHOP (hazard ratio, 0.72), with a generally manageable safety profile.MeaningThese findings support the use of an epigenetic modulator (tucidinostat) combined with R-CHOP as a first-line treatment for MYC/BCL2 double-expressor lymphoma, a biologically distinct entity of diffuse large B-cell lymphoma associated with poor prognosis after standard R-CHOP immunochemotherapy. ImportanceEpigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL.ObjectiveTo evaluate efficacy and safety of tucidinostat plus R-CHOP vs R-CHOP alone as first-line treatment for patients with DEL.Design, Setting, and ParticipantsThis randomized, double-blind, placebo-controlled phase 3 trial enrolled patients from May 21, 2020, through July 25, 2022, with follow-up to June 26, 2025. The trial was conducted at 40 study centers in China; a total of 423 eligible patients were enrolled.InterventionsPatients were randomly assigned in a 1:1 ratio to receive oral tucidinostat (20 mg on days 1, 4, 8, and 11 of each 21-day cycle) or matching placebo, plus 6 cycles of R-CHOP. Patients with a complete response after combination therapy received either tucidinostat or placebo maintenance up to 24 weeks.Main Outcomes and MeasuresThe primary end point was event-free survival. Secondary end points included complete response rate, progression-free survival, disease-free survival, overall survival, and tolerability.ResultsAmong 423 patients randomized (median age, 63 years; 47.5% male), the median follow-up duration from randomization was 41.3 months. The tucidinostat group demonstrated a 28% lower risk of disease progression, relapse after complete response, death, or initiation of new therapy for residual disease compared with the placebo group (stratified hazard ratio, 0.72 [95% CI, 0.54-0.96]; P = .02), with a 2-year event-free survival rate of 60.3% vs 50.5%, respectively. The complete response rate was 73.0% vs 61.8% (difference, 11.1% [95% CI, 2.3%-20.0%]), respectively. Increased toxicity associated with treatment was observed in the tucidinostat group but generally manageable with supportive care.Conclusions and RelevanceTucidinostat plus R-CHOP significantly improved event-free survival, with manageable toxicity in patients newly diagnosed with DEL. This trial is the first to demonstrate the benefit of an epigenetic modulator in DLBCL, offering a new first-line therapeutic approach dually targeting MYC and BCL2 oncoprotein for this high-risk population.Trial RegistrationClinicalTrials.gov Identifier: NCT04231448 This randomized clinical trial conducted in China evaluates the efficacy and safety of the histone deacetylase inhibitor tucidinostat plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) vs R-CHOP alone as first-line treatment for patients with MYC/BCL2 double-expressor lymphoma.

BackgroundMultiple myeloma (MM) associated anemia affects over 60% of patients and correlates with poor prognosis. While most studies focus on the impact of microenvironment on erythropoiesis in MM, the stage-specific erythroid cell defects and their underlying molecular mechanisms remain poorly characterized.MethodClinical data were collected from 300 patients with newly diagnosed multiple myeloma (NDMM) and 300 healthy controls. Phenotypic and transcriptomic profiles of bone marrow early and late erythropoiesis were compared between healthy donors (HDs) and NDMM patients with anemia (NDMM-A). Furthermore, in vitro erythroid culture assays were performed to verify the intrinsic erythropoietic impairments in NDMM-A patients.ResultsPrimary erythropoiesis profiles from bone marrow revealed a global reduction in erythroblasts across all maturation stages, along with significantly impaired colony-forming capacity of erythroid progenitors in NDMM patients. Transcriptomic profiling identified stage-specific dysregulation in the early and late erythropoiesis of NDMM-A patients. Erythroid progenitors exhibited downregulation of cell-cycle regulators (e.g., CDC20, AURKB) and key erythropoietic transcription factors (e.g., GATA1, GFI1B), accompanied by upregulation of immune-response genes (OAS3, OAS2). Conversely, terminal erythroblasts showed upregulation of genes involved in oxidative phosphorylation and the p53 pathway. In vitro assays confirmed intrinsic defects in erythroblasts derived from NDMM patients’ CD34+ cells, including poor proliferation, increased apoptosis rate, and defective enucleation.ConclusionThese findings demonstrate that both cell-intrinsic impairments and external responses drive stage-specific erythropoietic failure in NDMM, providing new insights for therapeutic strategies.

BackgroundHigh-risk multiple myeloma (HRMM) is a subtype that accounts for approximately 15-20% of MM patients and is characterized by early relapse or treatment refractoriness, even in the context of autologous stem cell transplantation and novel pharmacological agents. Currently, the risk stratification of HRMM predominantly relies on genetic markers; however, this framework exhibits limitations in facilitating early detection and accurate prognostication, thereby inadequately addressing the clinical requirements for precision management. The recently articulated concept of Cardiovascular-Kidney-Metabolic (CKM) syndrome, particularly in its stages 3-4,which correlate with increased all-cause mortality, underscores the complex interrelationships among metabolic, cardiac, and renal factors and presents a promising avenue for a novel prognostic indicator in MM. The development of a composite prognostic model that integrates tumor burden, genetic risk, and CKM stage stratification has the potential to significantly improve outcome prediction for HRMM and inform individualized therapeutic strategies.MethodsThis study examined clinical data from 301 patients treated at Henan Provincial People's Hospital from January 2017 to December 2024, all of whom received ≥4 chemotherapy cycles and first-line therapy. Patients with ASCT, unclear diagnoses, or incomplete genetic data were excluded. Ultimately, 241 patients were split into experimental (192) and validation groups (49) in an 8:2 ratio. Logistic and LASSO regressions identified model predictors, evaluated with ROC, calibration, and decision curves, and Bootstrap resampling. Statistical analysis used SPSS version 22.0.ResultsWe analyzed 241 non-transplanted NDMM patients with a median age of 56.9, categorizing them into 54 (22.4%) high-risk and 187 (77.6%) non-high-risk groups based on overall survival of less than 3 years. The high-risk group exhibited more aggressive disease, a higher tumor load, and 14.8% had soft tissue-related extramedullary disease (EMD-S), compared to 4.3% in the non-high-risk group (P=0.011). They also had a higher median bone marrow plasma cell percentage (32.5% vs. 24.8%, P < 0.05) and significant differences in CKM (P = 0.023) and high-risk FISH genetics (HRCA > 2) (P = 0.011).This study used logistic regression to analyze variables like age, gender, height, weight, hemoglobin, PLT, LDH, creatinine, BMPC%, peripheral blood plasma cell ratio, ISS, R-ISS, EMD-S, HRCA, CKM, chemotherapy regimen, and date of death/follow-up, collected after diagnosis but before treatment. It found age (>65), PLT, LDH, ISS, EMD-S, BMPC%, CKM, and HRCA as significant risk factors (P < 0.1). These were included in a LASSO regression model, showing age, platelets, LDH, ISS, EMD-S, CKM, and HRCA significantly influenced predictions. The predictive model is: logist(p) = –2.23 + 0.98 × age + 0.50 × ISS2 + 0.90 × ISS3 + 2.06 × EMD-S – 0.003 × PLT + 0.49 × LDH + 0.35 × CKM1 – 0.005 × CKM2 + 1.18 × CKM3-4. The main risk factors identified were EMD-S (OR = 7.85), age (OR = 2.66), and CKM 3-4 (OR = 3.25).Kaplan-Meier analysis stratified by CKM stage demonstrated statistically significant differences (p =0.011).The model evaluation reveals an ROC curve area of 0.731 (0.640-0.822) for the experimental group, while the validation group's ROC area is currently unavailable due to data limitations. The calibration curve shows a Brier Score of 0.145 and a Hosmer-Lemeshow Test result of P=0.3. Internal validation using bootstrap resampling (500 iterations) yielded a corrected C-statistic of 0.73 (0.630-0.81), confirming model stability. Decision curve analysis (DCA) indicated a net benefit exceeding both the all and none lines between thresholds of 0.2 and 0.6, highlighting good clinical utility. Various validation methods confirmed the model's high clinical utility, offering robust decision support for physicians.ConclusionThis study developed a predictive model to identify HRMM in non-transplanted NDMM patients using accessible clinical data, enhancing early detection and prognosis. Our model incorporates novel metrics like CKM, EMD-S, and HRCA to better assess disease aggressiveness and quantify the combined impact on the cardio-renal-metabolic system.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous and aggressive malignancy that usually lacks B-cell associated antigens. Here, we identified three cases of PTCL-NOS that uniformly expressed T-cell specific antigens (CD2 and CD3) and the B marker CD20 (CD20+ PTCL-NOS). Molecular studies showed clonal rearrangement of the chain T-cell receptor genes without evidence of a clonal rearrangement of the immunoglobulin gene. All three patients were diagnosed with the advanced stages and had bone marrow (BM) involvement, of which one patient was confirmed by PET-CT and the other two patients were confirmed by BM biopsy. However, we surprisingly found that BM-infiltrated lymphoma cells did not express CD20. Whole-exome sequencing analysis revealed that the most common mutations were on the DDX3X and TET2 genes. Although all the patients had relatively low Ki67 indices, they achieved poor response to the first-line treatment with CHOP-like chemotherapy. Subsequently, one patient was treated at a local hospital with an unspecified regimen, and the other two patients ultimately received rituximab combined chemotherapy as a salvage treatment after receiving multiple second-line therapies. However, the outcomes of these patients remained unsatisfactory. Therefore, it currently appears to be quite challenging to provide appropriate and effective treatment for patients with CD20+ PTCL-NOS.

Background:Tazemetostat, the first enhancer of zeste homolog 2 (EZH2) inhibitor approved by the U.S. Food and Drug Administration, has shown efficacy in a global population with relapsed or refractory (R/R) follicular lymphoma (FL). This phase 2 study was primarily designed as a registration-intent bridging trial of tazemetostat in Chinese patients with EZH2-mutant (EZH2 mut) R/R FL; the study also included evaluation in the EZH2 wild-type (EZH2 wt) population. Methods:This multicentre, single-arm, phase 2 study was conducted at 19 sites in China. Eligible patients (aged ≥18 years) with histologically confirmed grade 1-3a FL were categorised by EZH2 status: mutant (EZH2 mut, bridging cohort) and wild-type (EZH2 wt), and received oral tazemetostat 800 mg twice daily in continuous 28-day cycles until investigator-assessed disease progression, intolerable toxicity, withdrawal of consent, or other protocol-specified criteria. The EZH2 mut cohort primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Efficacy in the EZH2 mut cohort was assessed in patients who received at least one dose of tazemetostat and had centrally confirmed FL. Efficacy in the EZH2 wt cohort and safety in both cohorts were assessed in all patients who received at least one dose of tazemetostat. This study is registered with ClinicalTrials.gov, NCT05467943. Findings:Between July 29, 2022, and Aug 31, 2023, 22 patients with EZH2 mut R/R FL were enrolled (three lines [3L] of prior therapy, 31.8%; four lines [4L] of prior therapy or more, 27.3%). As of Aug 31, 2024 (median follow-up 14.4 months), IRC-assessed ORR was 63.6% (95% confidence interval [CI], 40.7%-82.8%), clinical benefit rate (CBR) was 90.9% (70.8%-98.9%), median duration of response (DoR) was not reached (18-month DoR rate, 51.6% [18.2%-77.3%]), and median progression-free survival was 15.4 (8.2-not estimable) months. All patients experienced treatment-related adverse events (TRAEs), and 13.6% had grade ≥3 TRAEs; most common TRAEs were haematological toxicities. For the EZH2 wt cohort, 20 patients were enrolled (3L, 35.0%; ≥4L, 45.0%). Tazemetostat also demonstrated efficacy benefit and a manageable safety profile in the EZH2 wt cohort, with an investigator-assessed ORR of 35.0% (95% CI, 15.4%-59.2%), CBR of 85.0% (62.1%-96.8%), and median DoR of 8.4 (1.9-15.7) months. Interpretation:These results suggest that tazemetostat has a clinically meaningful efficacy and was well tolerated in Chinese patients with R/R FL. Larger trials are warranted. A multicentre, randomised, phase 3 trial of tazemetostat combined with lenalidomide plus rituximab vs. lenalidomide plus rituximab in patients with R/R FL is ongoing (NCT04224493). Funding:HUTCHMED.

Interdigitating dendritic cell sarcoma (IDCS) is an exceedingly rare hematological neoplasm arising from dendritic cells that presents significant diagnostic and therapeutic challenges, particularly in cases of disseminated disease. Here, a 33-year-old woman presented with discomfort of the left pharynx accompanied by nasopharyngeal and cervical mass for 3 months. The histopathology confirmed the diagnosis of IDCS as the neoplastic cells were spindle or ovoid in shape, forming fascicles or whorls, and were positive for S-100, vimentin and CD163 but negative for CD21, CD23, CD35 and CD1a. The patient underwent autologous hematopoietic stem cell transplantation (auto-HSCT) after achieving partial remission (PR) from six courses of chemotherapy based on the ABVD regimen and one cycle of radiotherapy. Encouragingly, the mass disappeared after cladribine containing regimen pretreated auto-HSCT and the patient has been in complete remission (CR) state for over 5 years. Therefore, the long survival of this patient might suggest that ABVD regimen with a sequential cladribine-containing preparative regimen prior to auto-HSCT may improve the prognosis of disseminated IDCS. However, this represents only a single-case experience, and further studies with larger sample sizes are required for validation.

Introduction Treating acute myeloid leukemia (AML), a diverse group of hematological cancers affecting bone marrow and blood, remains difficult, with a five-year survival rate of about 30%. Although screening for genetic mutations and fusion genes has become essential in AML diagnosis and risk stratification, the clinical significance of copy number aberrations (CNAs) remains poorly understood. To this end, we conducted a multicenter prospective clinical trial (ChiCTR2300077695) to characterize the genomic landscape of CNAs using shallow whole-genome sequencing (sWGS), termed LeukoPrint, in AML. Interim results from the first 205 patients (pts) are reported here. Methods In this prospective multicenter clinical trial, we aim to enroll 600 newly diagnosed AML pts (excluding APL) across 13 participating hospitals in China. Bone marrow samples were collected and underwent CNA profiling via LeukoPrint (1× sWGS) at three stages: pretreatment, post-induction, and relapse. CNAs only those greater than 5 Mbp were analyzed. Conventional karyotyping analysis was performed in parallel for this cohort, and its diagnostic performance was compared with LeukoPrint. European Leukemia Net (ELN)-defined CNAs were used for risk stratification, consistent with standard cytogenetic analysis protocols. The trial received approval from the Ethics Committees of all participating hospitals, and all pts provided informed consent. By April 9, 2025, 205 pts were enrolled in this study, with 136 in the younger group (aged 18–59) and 69 in the older group (aged ≥60). All pts underwent CNA profiling using LeukoPrint at least twice, at pretreatment and post-induction phases. Results Using LeukoPrint, we detected 193 CNAs in 87 pts (42.4% of the cohort). No notable difference in detection rates was observed between younger and older groups (41.9% vs. 43.5%). CNAs were frequently identified in chromosomes 7, 8, 11, and Y (each with >5% prevalence), with the most common recurrent CNAs occurring at 8q24.21 (13% prevalence), the locus containing the MYC oncogene. Recurrent deletions were predominantly observed in 5q31.3 and 7q36.1, the genomic regions harboring the oncogenes ACSL6, CD74, and EZH2. LeukoPrint outperformed karyotyping in CNA detection (42.4% vs. 27.3%), enhancing results for 51 pts (24.9% of the cohort). Notably, 38 pts, initially classified with normal karyotypes or failed karyotyping, were reclassified as carrying CNAs. Applying the 2022 ELN criteria, three pts initially classified as low- or intermediate-risk based on genetic mutations, fusions, and karyotypes were reclassified as high-risk following LeukoPrint analysis in place of karyotyping. Clinical follow-up in two cases confirmed poor outcomes in one, supporting LeukoPrint's prognostic value. LeukoPrint demonstrates strong potential for prognostic prediction by monitoring dynamic change of molecular response in 115 pts. A significantly higher proportion of pts with post-induction CNAs were identified as non-responders than those without CNAs (6 vs. 3). Similarly, the proportion of pts without detectable post-induction CNAs was 95.5% in complete remission (CR, n=22), 83.3% in CR with partial hematologic recovery (CRh, n=6), 71.4% in CR with incomplete hematologic recovery (CRi, n=7), 0% in partial remission (PR, n=3), and 0% in non-responders (NR, n=3). Copy-neutral loss of heterozygosity (CN-LOH) occurs when one allele is lost and the remaining allele is duplicated, resulting in no net change in copy number. This genomic alteration, such as TP53 CN-LOH, can have significant clinical impact but is undetectable by traditional karyotyping or fluorescence in situ hybridization (FISH). LeukoPrint identified CN-LOH in 43 (20.9%) of 205 pts in this cohort. Notably, CN-LOH was detected in 25 out of 114 pts without detectable CNAs, revealing that LeukoPrint provides additional insights into chromosomal aberrations in 12% (25/205) of pts. Combined with 24.9% from standard LeukoPrint analysis, LeukoPrint enhanced CNA detection in at least 36.9% of pts. Conclusions LeukoPrint outperforms traditional karyotyping in detecting CNAs, improving data accuracy in over one-third of pts in this cohort. It enables dynamic monitoring of treatment response and disease progression, demonstrating strong correlation with clinical outcomes. These findings suggest that LeukoPrint holds significant promise as a complementary or alternative tool for conventional cytogenetic methods in AML.

Acute myeloid leukemia (AML), a heterogeneous malignancy with complex molecular mechanisms, urgently requires improved prognostic biomarkers and therapeutic targets. This study investigated Hippocalcin-like 1（HPCAL1）, a calcium-binding protein with dual functionality dependent on cancer type, as a potential prognostic marker and investigated its interaction with the tumor immune microenvironment in AML. Through analyses of multiple independent cohorts (GSE13159, GSE34184, GSE24395 and institutional data), we revealed that significant HPCAL1 overexpression in AML samples was correlated with poor survival outcomes. ESTIMATE analysis revealed increased immune activity in the HPCAL1-high group, which was supported by differential expression profiling, which identified 617 genes enriched in inflammatory/immune pathways. Coexpression network and protein interaction analyses further implicated HPCAL1 in immune regulation, particularly through NOD-like receptor signaling, as confirmed by GSEA/GSVA. Single-cell RNA sequencing analysis of the GSE130756 dataset revealed monocyte-specific HPCAL1 expression with altered cellular communication patterns in AML, whereas deconvolution analysis revealed that increased monocyte proportions in HPCAL1-high samples were associated with adverse prognoses. Our findings establish HPCAL1 as a novel prognostic indicator in AML, potentially by mediating its effects through immune microenvironment modulation and monocyte population dynamics. These results provide a foundation for future mechanistic studies exploring the role of HPCAL1 in AML pathogenesis and its therapeutic potential.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous B-cell malignancy influenced by immune dysregulation, posing significant clinical challenges. Lymphocyte subsets (e.g., CD4 + T helper 1/ T helper 2 cells) and their cytokines (IFN-γ/IL-4) are readily measurable immune markers involved in DLBCL pathogenesis and may independently predict prognosis. However, the prognostic value of these two combined clinical laboratory findings in newly diagnosed DLBCL patients remains uninvestigated. Here, we retrospectively analyzed 94 newly diagnosed DLBCL patients treated at our institution between 2017 and 2023. The prognostic influences of lymphocyte subsets, cytokines levels and other factors on progression-free survival (PFS) and overall survival (OS) were studied by Kaplan–Meier analysis and Cox regression (univariate/multivariate). Then we constructed an immune-related prognostic score model (IRPS) and validated it in another independent cohort. The results suggested that a high IFN-γ/IL-4 ratio and elevated CD4 + T cell count were favorable risk variables for both PFS and OS in DLBCL patients. Besides, multivariate analysis showed that age was marginally associated with the worse OS whereas low CD8 + T cell count was associated with the inferior PFS. Moreover, elevated pretreatment IFN-γ/IL-4 ratio was significantly correlated with better clinical response efficacy. Compared to those treatment-responsive patients, lower level of IFN-γ/IL-4 ratio was discovered in patients experienced with progression during the subsequent treatment cycles. Additionally, a new immune-related prognostic score model was constructed based on age, CD4 + T cell count and IFN-γ/IL-4 ratio, where high-risk patients had worse overall survival than low-risk patients. Meanwhile, the IRPS could refine the International Prognostic Index (IPI) score well and validation of the IRPS in another independent cohort confirmed its effectiveness. IFN-γ/IL-4 ratio is a practical prognostic marker in newly diagnosed DLBCL, and the IRPS model shows potential for predicting PFS and OS in DLBCL, enabling improved risk stratification.