ABSTRACT Background GATA binding protein 2 (GATA2) plays a crucial role in the differentiation, proliferation, and maintenance of hematopoietic stem cells (HSCs). GATA2 mutations have been identified in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), but the impact of somatic GATA2 mutations on prognosis remains controversial, especially on patients who undergo allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Objectives The aim of this retrospective case–control study was to explore the prognostic significance of somatic GATA2 mutations in MDS/AML patients who underwent allo‐HSCT. Study Design Propensity score matching (PSM) analysis was used to match patients with wild‐type GATA2 as the control group (ratio 1:3). A total of 14 patients with somatic GATA2 mutations and 39 patients with wild‐type GATA2 were enrolled. Results The baseline characteristics were comparable between the two groups. However, patients with GATA2 mutations had a higher frequency of WT1 mutations and relapse rate (p = 0.036 and p = 0.008, respectively). Compared to patients with wild‐type GATA2, patients with GATA2 mutations had shorter progression‐free survival (PFS) and overall survival (OS), and post‐transplant PFS (p < 0.001, p = 0.030, and p = 0.004, respectively). Subgroup analysis showed that the PFS, OS, post‐transplant PFS, and OS of patients with GATA2 non‐zinc finger domain 1 (non‐ZF1) mutations (p < 0.001, p = 0.004, p < 0.001, and p = 0.049, respectively), but not those of patients with somatic GATA2 ZF1 mutations, were shorter than that of patients with wild‐type GATA2. Moreover, somatic GATA2 mutations and WBC count ≥ 20.86 × 109/L were independent adverse prognostic factors for PFS (p = 0.005 and p = 0.020, respectively). Relapse before transplantation was an independent adverse prognostic factor for OS (p = 0.009). Conclusions Our preliminary study revealed that somatic GATA2 mutations, especially non‐ZF1 mutations, may be associated with unfavorable outcomes in patients with MDS/AML, even for patients who underwent allo‐HSCT.

Introduction The bone marrow microenvironment plays crucial roles in the pathogenesis of multiple myeloma. Previous studies have shown that there are differences in the metabolomics of bone marrow suspension and plasma, but there is rare research on bone marrow biopsy tissue. This study aims to establish a new metabolomics approach to analyze bone marrow biopsy tissues and explore its diagnostic value.Methods We collected bone marrow biopsy tissues from 19 newly-diagnosed multiple myeloma(MM), 29 monoclonal gammaglobulinemia of undetermined significance(MGUS) and 30 lymphoma without bone marrow invasion as the controls. Metabolomics analysis was conducted using high-performance liquid chromatography-mass spectrometry. Diagnostic Biomarkers and associated pathway were analyzed.Results The metabolic profiles differed between the controls and MGUS or MM. For MGUS versus MM comparison, Phenylalanyl-Valine and N-Acetylornithine were significantly down-regulated in the MM while N-Acetylornithine has the best diagnostic value with the sensitivity and specificity of 87.5% and 71.4%. For the controls vs. MM comparison, N-Acetylornithine and Aspartyl-Arginine differed markedly. Compared with the controls group, N-Acetylornithine was significantly down-regulated in the MM group, and the AUC of N-Acetylornithine for MM was 0.933, with sensitivity and specificity of (90.0% and 93.3%). N-Acetylornithine displayed the same trends as the comparison between MGUS and MM. Furthermore, when comparing MGUS and MM, Arginine biosynthesis was identified as significantly disrupted in which N-Acetylornithine was involved.Conclusions We establish a novel method for metabolomic profiling of bone marrow biopsy tissue and provide evidence of metabolic alterations, particularly reduced N-acetylornithine levels, in MGUS and MM patients.

This retrospective single-center cohort included 480 immunoglobulin light-chain amyloidosis (AL) and 61 light chain deposition disease (LCDD) patients from Peking University First Hospital to compare clinical profiles and outcomes. AL frequently presented with multisystem (≥ 3 organs, 31.0%) and cardiac involvement (60.8%). LCDD was kidney-dominant (eGFR < 50 mL/min/1.73m², 85.2%) with higher clonal burden (dFLC > 180mg/L, 44/60 [73.3%] with available data), a trend toward higher CR rate (65.8% vs 48.8% AL, P = 0.058), and 100% ≥ PR to daratumumab in a small subgroup (n = 11). PI-based therapy was the main backbone (66.3% vs 66.0%). LCDD had superior OS ( P < 0.001), while AL showed better renal survival in high-risk strata (albumin < 30g/L, eGFR < 50, 24h-UTP > 5g; all P < 0.05). These findings support disease-specific management: deep hematologic remission for AL and renal protection plus clone-directed therapy for LCDD.

Background and Objectives: Conventional assays for M-protein detection in multiple myeloma (MM), including serum immunofixation electrophoresis (sIFE) and serum free light-chain (sFLC) assays, have limitations in selected clinical settings. This pilot study aimed to develop and preliminarily validate a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based workflow using Kunitz trypsin inhibitor (KTI) as an internal standard for patient-specific serum M-protein light-chain tracking, particularly in low-level post-treatment samples in which conventional assays may be negative or difficult to interpret. Materials and Methods: A total of 55 serum samples from 25 patients with MM were analyzed. Serum immunoglobulin light-chain species were enriched using mixed κ/λ affinity beads, followed by reduction, KTI-based calibration, and MALDI-TOF MS analysis. Quantitative performance was evaluated using purified IgG1 κ standards. Time-matched sIFE and sFLC ratio results were used for descriptive comparison. Results: After KTI-based calibration, patient-specific M-protein light-chain molecular masses could be consistently identified. The assay showed good linearity over the range of 0.20–10.00 μg/mL, with a calibration equation of y = 6.0228x + 0.1063 and an R2 of 0.9961. The limit of detection and limit of quantification were 0.002 μg/mL and 0.008 μg/mL, respectively. Intra-day and inter-day precision were acceptable, and recovery ranged from 96.0% to 101.2%. In selected low-level or discordant samples, including cases with therapeutic interference, polyclonal background, or non-secretory disease, MALDI-TOF MS provided exploratory complementary monitoring information. Conclusions: This KTI-calibrated MALDI-TOF MS workflow showed preliminary analytical performance within the validated low-concentration range and may serve as a complementary approach for patient-specific serum M-protein light-chain monitoring in selected clinical settings of MM. Larger independent studies are required before its clinical utility can be established.

BACKGROUND Our previous retrospective study suggested that peripheral-blood stem-cell infusion before 2:00 p.m. was associated with a lower incidence of acute graft-versus-host disease (aGVHD) than later infusion, but retrospective analyses are susceptible to confounding. Whether infusion timing affects aGVHD has not been tested in a randomized trial. METHODS In this multicenter, open-label trial, we randomly assigned patients 12 to 60 years of age with hematologic malignancies undergoing a first allogeneic peripheral-blood stem-cell transplantation to stem-cell infusion at 12:00 pm (±30 minutes) or 6:00 pm (±30 minutes). The primary end point was grade II to IV aGVHD within 100 days after transplantation. RESULTS A total of 198 patients underwent randomization (99 in each group). Grade II to IV acute GVHD occurred in 11.1% of patients in the 12:00 pm group and 23.2% in the 6:00 pm group (subdistribution hazard ratio for 6:00 pm vs. 12:00 pm, 2.18; 95% CI, 1.06 to 4.48; P = 0.029). The corresponding incidences of grade III to IV acute GVHD were 2.0% and 12.2% (subdistribution hazard ratio, 6.25; 95% CI, 1.39 to 28.15; P = 0.006). There were no significant differences in hematopoietic recovery, TRM, or relapse between groups. CONCLUSIONS Among patients undergoing allogeneic peripheral-blood stem-cell transplantation, infusion at 12:00 pm resulted in a lower incidence of grade II to IV acute GVHD than infusion at 6:00 pm (ClinicalTrials.gov number, NCT06294678 .)

Renal involvement is an uncommon but clinically important manifestation of B-cell neoplasms, and direct comparisons between indolent and aggressive entities remain limited. This single-center retrospective biopsy-confirmed and tissue-selected study compared 28 biopsy-confirmed patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBL), with 14 patients in each group, treated at Peking University First Hospital between June 2010 and June 2025. The aggressive comparator group included 13 DLBCL cases and one case annotated as HGBL with MYC and BCL2 rearrangements. Clinical features, timing of renal involvement recognition, dominant clinical entry points, pathological patterns, treatment strategies, and hematologic and renal responses were analyzed. CLL/SLL was associated with higher white blood cell and absolute lymphocyte counts, whereas DLBCL/HGBL showed higher lactate dehydrogenase and β2-microglobulin levels. The interval to renal involvement recognition was longer in CLL/SLL than in DLBCL (24.00 vs. 2.00 months, p = 0.007). At renal involvement recognition or biopsy, 24 h urinary protein excretion was nominally higher in the CLL/SLL group than in the DLBCL/HGBL group (3.90 vs. 1.58 g/24 h). CLL/SLL more often presented with proteinuria/edema, hematuria, or renal dysfunction and showed heterogeneous infiltrative lesions with concurrent glomerular or vascular involvement. DLBCL/HGBL more frequently presented with flank pain or renal mass-related manifestations and was dominated by direct infiltrative or mass-forming lesions. Treatment patterns differed markedly, whereas no significant difference in the distribution of renal responses was detected; however, this comparison was underpowered and should be interpreted descriptively. In this biopsy-confirmed, tissue-selected cohort, CLL/SLL and DLBCL/HGBL showed different observed patterns of renal involvement recognition, tissue acquisition, and renal pathological presentation. These findings support tissue-based evaluation of renal abnormalities in B-cell neoplasms but should be interpreted as descriptive and hypothesis-generating in view of the small sample size and the influence of diagnostic and biopsy pathways.

BackgroundThe global epidemiological trends of chronic lymphocytic leukemia (CLL) provide a crucial macrolevel foundation for guiding precision medicine. However, translating broad risk factors and burden disparities into actionable clinical strategies requires a bridge to molecular pathogenesis. This study analyzes the global CLL burden to not only delineate its public health landscape but also inform the development of biomarker-based prevention and early detection frameworks.MethodsLeveraging data from the Global Burden of Disease Study 2021, we evaluated primary pre-pandemic trends in CLL incidence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2019 using estimated annual percentage change (EAPC), joinpoint regression, and decomposition analysis to identify key drivers of trends and inequalities. Predictive modeling (ARIMA) was employed to project future burden. Critically, the epidemiological insights-particularly regarding identified risk factors (e.g., smoking, high BMI) and high-burden populations-were framed as a strategic map to prioritize hypotheses for subsequent biomarker discovery research in CLL etiology and progression. We additionally analyzed three independent Gene Expression Omnibus (GEO) transcriptomic cohorts including CLL patients and nonleukemic controls. Differential expression analysis across cohorts identified 67 overlapping CLL-related genes, which underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Using least absolute shrinkage and selection operator (LASSO)-regularized logistic regression in a training cohort, we derived a 14-gene predictive signature and validated its discriminative performance in independent datasets.ResultsThe analysis revealed a mild decline in global age-standardized incidence but significant declines in mortality (31.3%) and DALYs (32.9%), alongside marked socioeconomic disparities. Decomposition analysis quantified the dominant role of population aging in driving DALY increases in Western Europe (+11403.53%) and epidemiological factors in Central Asia (+633.72%). Smoking and high body mass index were reaffirmed as modifiable risk factors. Projections indicate declining incidence and mortality but rising prevalence through 2040. These findings pinpoint specific demographics and risk exposures as high-priority targets for biomarker investigation and stratified screening. At the molecular level, differential expression analyses across three GEO cohorts identified 67 overlapping CLL-related genes, which were significantly enriched in immune cell differentiation, leukocyte adhesion, T/B cell receptor signaling, and cytokine/growth factor pathways. A LASSO-based model further distilled these into a 14-gene signature that effectively discriminated CLL from non-CLL samples in the training cohort and retained stable predictive performance in independent validation sets.ConclusionThis study synthesizes the global epidemiology of CLL into a framework that informs clinical and translational research. By combining global burden analysis with a complementary transcriptomic investigation, it provides epidemiological context and candidate molecular features for future biomarker-based risk stratification and early identification strategies in CLL.

OBJECTIVE:Clinical data on incorporating selinexor into conditioning regimens before allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain limited. We evaluated the feasibility and safety of selinexor-containing conditioning in patients with high-risk myeloid malignancies. METHODS:This retrospective single-center case series included 12 consecutive patients receiving selinexor-containing conditioning before allo-HSCT. Toxicities, engraftment, graft-versus-host disease (GVHD), relapse, non-relapse mortality (NRM), and survival were descriptively evaluated. PFS and OS were estimated using Kaplan-Meier methods; competing-risk methods were used for relapse, NRM, and GVHD; and follow-up was estimated using reverse Kaplan-Meier. RESULTS:All patients completed planned selinexor administration, with manageable toxicity and no unexpected organ toxicity. Neutrophil engraftment was achieved in all evaluable patients and platelet engraftment in the majority. Median follow-up was 42 months (95% CI, 25-42 months). Median PFS and OS were 9.0 months (95% CI, 2.0-25 months) and 10.0 months (95% CI, 2-30 months), respectively. At 12 months, the cumulative incidences of relapse and NRM were both 33.3% (95% CI, 10.3%-58.8%). Day + 100 overall aGVHD incidence was 41.7% (95% CI, 15.2%-66.5%), and 12-month overall cGVHD incidence was 25.0% (95% CI, 6.0%-50.5%). CONCLUSION:In this single-center retrospective experience, incorporation of selinexor into conditioning regimens prior to allo-HSCT was feasible and associated with manageable toxicity in in selected patients with high-risk myeloid malignancies. Given the small sample size and absence of a comparator cohort, these findings should be interpreted cautiously. Prospective studies are warranted to further define the role of selinexor in the transplant setting.

While variant TP53 is an adverse prognosis factor in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), current clinical prognosis and variation feature analysis of TP53 alterations remain limited. We evaluated 333 MDS/AML patients with TP53 mutations, single nucleotide polymorphisms (SNPs), and wild-type TP53 to characterize clinical features and identify prognostic factors using next-generation sequencing (NGS) data. Interpretation requires caution due to sample size limitations, particularly in subgroup analyses. Multivariate analysis identified age, gender, cytogenetic risk, transplantation, white blood cell (WBC) count, TP53 status, and TP53 variant allele frequency (VAF) > 40

Secondary hemophagocytic lymphohistiocytosis (HLH) syndrome, a fatal disorder characterized by NK/T-cell deficiency, cytokine storm, and organ damage, is rare in chronic lymphocytic leukemia (CLL). Ibrutinib, the first generation of irreversible Bruton's tyrosine kinase inhibitor, has been the first-line therapy for CLL. As an off-target effect, it can also block IL-2 inducible T-cell kinase (ITK), which is essential in maintaining normal NK and T-cell functions. Up to now, 4 cases reported secondary HLH developed in CLL patients shortly after ibrutinib therapy, which indicated ibrutinib might be associated with HLH via NK/T cell damage as a result of ITK inhibition. We herein report the first case describing EBV-driven HLH developed in a CLL patient under long-term ibrutinib monotherapy (4 year), also showing concurrent NK and T cell deficiency. Therefore, the relationship between the long-term use of ibrutinib and the pathophysiology of HLH, as well as the mediating role of NK/T cell disorder caused by ITK blockade therein, deserves attention and further studies.

Background:Angioimmunoblastic T-cell lymphoma (AITL), representing the second most prevalent subtype of peripheral T-cell lymphoma, currently lacks standardized frontline therapeutic strategies. Methods:In this study, we evaluated the survival outcomes and prognostic factors in 154 patients with AITL treated with one of four regimens: CHOP (cyclophosphamide, vincristine, epirubicin, prednisone), CHOPE (CHOP + etoposide), CPET (chidamide, prednisone, etoposide, thalidomide), or GDPT (gemcitabine, cisplatin, dexamethasone, thalidomide). Among them, 144 patients had complete survival follow-up data. Survival differences across groups were analyzed using the log-rank test, while variations in clinical parameters were assessed via chi-square tests and one-way ANOVA. Univariate and multivariate Cox regression analyses were conducted to identify factors associated with progression-free survival (PFS) and overall survival (OS). Results:The 5-year OS and PFS rates for the entire cohort were 36.6% (95% CI: 0.275-0.488) and 32.2% (95% CI: 0.233-0.451), respectively. Patients who were younger (<60 or <70 years), had Ann Arbor stage I/II disease, or exhibited lower Eastern Cooperative Oncology Group (ECOG) performance status scores demonstrated significantly improved OS and PFS following treatment. Notably, among patients with ECOG <2, those treated with the CPET regimen achieved longer PFS and OS compared to those receiving CHOP or CHOPE. In contrast, for patients with ECOG ≥2, no significant survival differences were observed across treatment regimens. Both univariate and multivariate analyses identified ECOG performance status as an independent prognostic factor for survival outcomes. Conclusion:For patients with a low ECOG performance status, the CPET regimen may offer promising survival outcomes.

The dysregulation of human genes and proteins following SARS-CoV-2 infection significantly impacts the clinical symptoms and prognosis of COVID-19, particularly in immunocompromised individuals such as patients with hematological tumors. Despite this, a comprehensive multi-omics understanding of human host immune responses remains incomplete. Here, we conducted a multi-omics analysis of 89 peripheral blood samples (RNA sequencing) and 98 serum samples (proteome mass spectrometry) from 52 patients with COVID-19, including patients with hematological tumors and non-tumor individuals. By integrating transcriptomic, proteomic, and interactome data, we compared differentially expressed genes (DEGs) and proteins (DEPs) across infection stages and clinical outcomes to gain insights into the mechanisms of SARS-CoV-2 infection. Our analysis revealed distinct and overlapping transcriptomic and proteomic responses to SARS-CoV-2 infection. DEGs were predominantly associated with innate immune responses and viral processes, while DEPs were linked to actin cytoskeleton organization and protein kinase regulation. Notably, DEGs and DEPs often exhibited opposing regulatory patterns, suggesting post-transcriptional and post-translational mechanisms. Tumor patients showed more severe proteomic perturbations, with a higher proportion of DEPs functioning as key hub proteins in cellular networks. Network-based drug repositioning identified potential therapeutic targets, including HSPA8, SRC, STAT1, APOE, and APP. Clinical analysis indicated that patients with long COVID experienced more severe coagulation abnormalities, immunosuppression, and myocardial injury, while acutely deceased patients exhibited abnormally activated immune responses. Our study provides a comprehensive resource for understanding the molecular mechanisms of SARS-CoV-2 infection in patients with hematological tumors. By integrating multi-omics data, we highlight the importance of proteomic changes in disease progression and identify potential therapeutic targets for COVID-19 and long COVID.

Background Cord blood (CB) is widely used in treating haematologic disorders due to its broad availability, tolerance to significant histocompatibility antigen disparities, and low incidence of chronic graft-versus-host disease (cGVHD). The cord blood transplantation (CBT) with anti-thymocyte globulin (ATG)-containing conditioning regimens shows promise in this regard.Methods We conducted a retrospective review of data from patients who underwent CBT at our centre from August 2003 to December 2022. Patients undergoing CBT with ATG were matched with those who received HLA-haploidentical haematopoietic stem cell transplantation (haplo-HSCT). Propensity score matching (PSM) was utilized to form 105 matched pairs (140 patients) for comprehensive trial analysis.Results The cumulative incidence of neutrophil and platelet engraftment was significantly lower in the CBT group. Patients in the CBT group exhibited significantly lower incidences of grade II-IV acute GVHD (aGVHD) and cGVHD compared to the haplo-HSCT group (8.57% vs. 29.52%, p = 0.012; 20% vs. 39.05%, p = 0.031). The overall survival (OS) rate for the CBT and haplo-HSCT groups showed no significant difference. In patients with leukaemia, the CBT cohort showed better OS, GVHD-free and relapse-free survival (GRFS), as well as a lower incidence of disease relapse, although there was no statistical difference.Conclusion Our single-centre retrospective long-term follow-up investigations indicated that although the implantation rate of CBT is lower than that of haplo-HSCT, patients undergoing CBT with ATG-containing conditioning regimens may have a comparable overall survival with a lower risk of GVHD compared to those undergoing haplo-HSCT.

OBJECTIVE:To analyze the predictive role of WT1 expression levels pre- and early post-transplantation on relapse and overall survival (OS) in patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) during their first complete remission (CR1). METHODS:A retrospective analysis was conducted on the clinical data of 107 adult AML patients who underwent allo-HSCT during their CR1 at our center between May 2012 and December 2021. The predictive role of bone marrow WT1 expression levels before transplantation and at 3 and 6 months post-transplantation on relapse and OS was explored in combination with relevant clinical factors. RESULTS:The median follow-up time for the 107 patients was 70 (range: 11-117) months. Among the patients, 15 cases died. Kaplan-Meier survial analysis showed that the 3-year overall survival (OS) rate was 85.0%. 20 patients experienced relapse, with a median time to relapse of 8 (range: 0.5-44) months and a 1-year cumulative relapse rate of 13.1%. The overall median value of WT1 before transplantation, 3 months after transplantation, and 6 months after transplantation was 0.26% (range: 0%-23.64%), with an upper quartile value of 0.74%. No statistically significant differences in WT1 expression levels were observed among the pre-transplantation, 3-month post-transplantation, and 6-month post-transplantation time points (P =0.227). Univariate analysis showed that patients with WT1 levels >0.74% at 3 months post-transplantation had a higher 1-year relapse rate (P =0.029) and lower 3-year OS rate (P <0.001) compared to patients with WT1 levels ≤0.74%. Other significant factors affecting 1-year relapse included stem cell source (P =0.041) and chronic graft-versus-host disease (cGVHD) (P =0.013). For 3-year OS, additional influencing factors were genetic high risk (P =0.048) and stem cell source (P =0.016). Multivariate analysis revealed that WT1 level >0.74% at 3 months post-transplantation had a trend to affect 1-year relapse rate (HR=3.309, 95%CI : 0.958-11.431, P =0.058), while the absence of cGVHD was an independent risk factor for 1-year relapse (HR=3.473, 95%CI : 0.749-16.100, P =0.037). Only WT1 level >0.74% at 3 months post-transplantation was an independent risk factor for 3-year OS (HR=6.886, 95%CI : 2.402-19.738, P <0.001). CONCLUSION:High WT1 expression level at 3 months post-transplantation in AML patients undergoing allo-HSCT during CR1 affects the 1-year relapse rate and 3-year OS, and is an independent risk factor affecting 3-year OS. These findings suggest that dynamic monitoring of WT1 expression levels has certain value in prognostic assessment of AML patients who received allo-HSCT during CR1.

Background: BTK inhibitors (BTKis) have become the standard-of-care therapies for both frontline and relapsed/refractory Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma (CLL/SLL). As a second-generation BTKi, zanubrutinib has demonstrated superior efficacy and a favorable safety profile in head-to-head clinical trials compared to the first-generation BTKi, ibrutinib. The objective of this study was to assess the real-world efficacy of single-agent zanubrutinib in patients with CLL/SLL. This study presents the largest multicenter, real-world data on zanubrutinib monotherapy in Chinese CLL/SLL patients (NCT06489184). Methods: This was a retrospective observational study of adult patients with CLL/SLL who initiated single-agent zanubrutinib treatment between June 2014 and March 2024 at fourteen sites across China, followed up through April 1, 2024. All patients had at least one month of follow-up. Duration of treatment (DOT), reasons for discontinuation, real-world progression-free survival (rwPFS), overall survival (OS), and dose reduction were reported. Results: A total of 322 patients received zanubrutinib monotherapy in the first line (1L, n = 180), second line (2L, n = 105), and third line or greater (≥3L, n = 36), and included one patient for whom the treatment line was unknown. The median (range) age of patients was 64.7 (34-92) years, and most patients were male (63%). Moreover, del(17p) or TP53 mutation was found in 62/266 (23.3%) tested patients. Unmutated IGHV was reported in 116/222 (52%). After a median (range) follow-up of 25.0 (1.0-119.3) months, 20.3% of patients discontinued zanubrutinib, mostly due to progressive disease (31 patients, 9.6%). Seventeen patients (5.3%) discontinued treatment due to patient preference, and 14 patients (4.3%) discontinued treatment due to adverse events (AEs). The most common AEs leading to discontinuation were infections (including COVID-19) (1.6%) and bleeding (1.3%). No cardiac AEs led to discontinuation; only one patient discontinued treatment due to blood pressure elevated. A total of 255 patients were still on zanubrutinib treatment. The 24-month duration of treatment rate was 84.4% in all patients (1L: 88.4%, 2L: 87.4%, ≥3L: 64.3%). The 24-month rwPFS rates were 95.9% for 1L, 90.8% for 2L, and 78.9% for ≥3L, while the OS rates were 97.4%, 96.3%, and 89.1%, respectively. Fifty-seven patients initiated zanubrutinib before June 2020 (when zanubrutinib was approved in China for CLL/SLL therapy on June 3, 2020), 12 patients in 1L, 30 patients in 2L, 15 patients in 3L, being patients from clinical trials. The median DOT of these patients was 71.6 months, and their median rwPFS were 109.6 months, 72-month rwPFS rate was 60.4%, the median OS has not been reached, and the 72-month OS rate were 86.3% . Dose reduction due to AEs occurred in 12 patients; among them, 4 patients experienced platelet count decreased, 3 patients experienced bleeding, and 2 patients experienced cardiac AEs (one with palpitations and atrioventricular block first degree, and one with paroxysmal atrial tachycardia and atrial fibrillation). Conclusion: The real-world efficacy of zanubrutinib monotherapy for CLL/SLL is consistent with clinical trials. These results strongly support zanubrutinib as a valuable treatment option for CLL/SLL patients, especially in those receiving first-line therapy, and discontinuation and dose reduction due to cardiac AEs are less common. Further investigation is warranted to fully elucidate the long-term benefits of zanubrutinib in the management of CLL/SLL.

The identification of human-herpesvirus protein-protein interactions (PPIs) is an essential and important entry point to understand the mechanisms of viral infection, especially in malignant tumor patients with common herpesvirus infection. While natural language processing (NLP)-based embedding techniques have emerged as powerful approaches, the application of multi-modal embedding feature fusion to predict human-herpesvirus PPIs is still limited. Here, we established a multi-modal embedding feature fusion-based LightGBM method to predict human-herpesvirus PPIs. In particular, we applied document and graph embedding approaches to represent sequence, network and function modal features of human and herpesviral proteins. Training our LightGBM models through our compiled non-rigorous and rigorous benchmarking datasets, we obtained significantly better performance compared to individual-modal features. Furthermore, our model outperformed traditional feature encodings-based machine learning methods and state-of-the-art deep learning-based methods using various benchmarking datasets. In a transfer learning step, we show that our model that was trained on human-herpesvirus PPI dataset without cytomegalovirus data can reliably predict human-cytomegalovirus PPIs, indicating that our method can comprehensively capture multi-modal fusion features of protein interactions across various herpesvirus subtypes. The implementation of our method is available at https://github.com/XiaodiYangpku/MultimodalPPI/.

ABSTRACT A dysfunction of human host genes and proteins in coronavirus infectious disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key factor impacting clinical symptoms and outcomes. Yet, a detailed understanding of human host immune responses is still incomplete. Here, we applied RNA sequencing to 94 samples of COVID-19 patients with and without hematological tumors as well as COVID-19 uninfected non-tumor individuals to obtain a comprehensive transcriptome landscape of both hematological tumor patients and non-tumor individuals. In our analysis, we further accounted for the human-SARS-CoV-2 protein interactome, human protein interactome, and human protein complex subnetworks to understand the mechanisms of SARS-CoV-2 infection and host immune responses. Our data sets enabled us to identify important SARS-CoV-2 (non-)targeted differentially expressed genes and complexes post-SARS-CoV-2 infection in both hematological tumor and non-tumor individuals. We found several unique differentially expressed genes, complexes, and functions/pathways such as blood coagulation (APOE, SERPINE1, SERPINE2, and TFPI), lipoprotein particle remodeling (APOC2, APOE, and CETP), and pro-B cell differentiation (IGHM, VPREB1, and IGLL1) during COVID-19 infection in patients with hematological tumors. In particular, APOE, a gene that is associated with both blood coagulation and lipoprotein particle remodeling, is not only upregulated in hematological tumor patients post-SARS-CoV-2 infection but also significantly expressed in acute dead patients with hematological tumors, providing clues for the design of future therapeutic strategies specifically targeting COVID-19 in patients with hematological tumors. Our data provide a rich resource for understanding the specific pathogenesis of COVID-19 in immunocompromised patients, such as those with hematological malignancies, and developing effective therapeutics for COVID-19. IMPORTANCE A majority of previous studies focused on the characterization of coronavirus infectious disease 2019 (COVID-19) disease severity in people with normal immunity, while the characterization of COVID-19 in immunocompromised populations is still limited. Our study profiles changes in the transcriptome landscape post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hematological tumor patients and non-tumor individuals. Furthermore, our integrative and comparative systems biology analysis of the interactome, complexome, and transcriptome provides new insights into the tumor-specific pathogenesis of COVID-19. Our findings confirm that SARS-CoV-2 potentially tends to target more non-functional host proteins to indirectly affect host immune responses in hematological tumor patients. The identified unique genes, complexes, functions/pathways, and expression patterns post-SARS-CoV-2 infection in patients with hematological tumors increase our understanding of how SARS-CoV-2 manipulates the host molecular mechanism. Our observed differential genes/complexes and clinical indicators of normal/long infection and deceased COVID-19 patients provide clues for understanding the mechanism of COVID-19 progression in hematological tumors. Finally, our study provides an important data resource that supports the increasing value of the application of publicly accessible data sets to public health.

Introduction The incidence of CLL in China is estimated at 1/10 to 1/20 of its incidence in Western countries. Moreover, the geographic diversity in CLL biology was noticed. Ibrutinib, the first-in class Bruton tyrosine kinase inhibitor (BTKi) was approved in China in 2017. The long-term efficacy and safety of BTKi in Chinese CLL patients has rarely been reported. This real world study aims to analyze long-term survival and outcomes of ibrutinib in Chinese patients with CLL and explore the risk factors for PFS and OS. Methods This study (NCT06489184) included 257 CLL patients aged 18 years and older who received ibrutinib monotherapy for at least one month from Mar.18, 2014.to Apr.1, 2024. The Kaplan-Meier curves were constructed to evaluate PFS, OS, and the differences between the treatment groups were compared using the log-rank test. Cox proportional hazards model comparisons were also conducted to explore the prognostic factors of PFS and OS, and backward stepwise logistic regression method was used in the multivariate analysis to identify independent predictors. A P < 0.05 was considered statistically significant; all P values were two-sided. TP53 aberration includes either TP53 mutation or del17p. Results A total of 257 patients were enrolled in the study, with 137 treatment-naïve (TN) patients and 120 R/R CLL. The median age was 64(range: 34-92) and 180 (70.0%) were male. Regarding the biological characteristics, 59.1% (152) of the patients were at Rai stage III/IV, 34.6% (89/257) with complex karyotype (CK), 36.6% (94/257) with unmutated IGHV. TP53 mutation was detected in 27.2% (70/257) patients, del17p was 20.6%(53/257), and TP53 aberration was 34.2%(88/257). The median follow up was 40 months in the overall population, the longest follow up was till to 122 months, median estimated PFS and OS were 83 and 104 months respectively. For TN patients, the median follow-up was 38(1-122) months, and median PFS and OS was not reached. In TN group 51 patients discontinued the drug, 21(41.2%) due to PD, 17(33.3%) due to AE, 12 (23.5%) due to patient decision, and 1(2.0%) due to unknown reason. Univariate analysis identified TP53 aberration and unmutated IGHV associated with impaired PFS and OS, on the other hand, del(13q) was favorable prognostic parameter for PFS and OS. Using multivariate analysis, TP53 aberrations (HR:2.732; 95%CI:0.108-0.860; P= 0.020), del(13q) (HR:0.304; 95%CI:0.108-0.860; P=0.025) and unmutated IGHV(HR:2.777; 95%CI:1.151-6.701; P=0.023) was the independent adverse risk factors for PFS, and del(13q) (HR:0.283; 95%CI:0.087-0.917; P= 0.025) and unmutated IGHV(HR:3.389; 95%CI:1.242-9.253; P=0.017) was the independent adverse risk factors for PFS. For R/R patients, the median follow-up was 40.5 (1-119) months. Median PFS and OS were 55 and 83 months, respectively. In R/R group, 79 patients discontinued the drug. 34(43%) due to PD, 19(24.1%) due to AE, 13(16.5%) due to the patients' decision, 11(13.9%) due to death, and 2(2.5%) due to unknown reasons. Univariate analysis identified TP53 aberration, IGHV unmutated and RAI III/IV associated with impaired PFS and OS, and del(13q) was favorable factor for PFS and OS. Multivariate analysis showed that TP53 aberration (HR:1.988; 95%CI:1.043-3.789; P=0.037) and unmutated IGHV (HR:0.488; 95%CI:0.247-0.963; P=0.038) were independent adverse risk factors for PFS, and Rai stage III/IV (HR:2.541; 95%CI:1.015-6.360; P=0.046) and unmutated IGHV (HR:0.440; 95%CI:0.206-0.939; P=0.034) were independent adverse risk factors for PFS. Among the 73 dead patients, 23 were in TN group and 50 in R/R group. The causes of deaths in TN group were CLL PD (6, 26.1%), Richter Transformation (RT) (3,13%) COVID-19 and infection (6, 26.1%), other (4,17.4%), cardiovascular disease (CVD, 3,13%), and unknown (1,4.3%). However, COVID-19 and infection (13, 26%) was the most common death reason in R/R group, and CLL PD (12, 24%), RT (7,14%), unknown (7,14%), other (4,8%), cardiovascular disorders (3,6%), secondary malignancies (SM, 3,6%) and cerebral infarction (1,2%). Conclusion To our best of knowledge, this is the first multicenter real-world data in China to analysis ibrutinib monotherapy in CLL patients. Ibrutinib showed long-term effect in both TN and R/R CLL, but discontinuation due to patient decision remains a noteworthy issue in CLL treatment in China.

Acute myeloid leukemia (AML) is a malignant lymphohematopoietic tumor that ranks among the most frequent indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT). This article aims to provide a comprehensive analysis of the application of allo-HSCT for AML and identify prognostic factors to enhance future treatment effect. This retrospective study collected data from 323 patients diagnosed with AML at Peking University First Hospital who underwent allo-HSCT between September 2003 and July 2022. The annual number of transplantations has steadily increased. Our center has observed a rise in the proportion of cytogenetic high-risk and measurable residual disease (MRD) positive patients since 2013, as well as an increase in the number of haploidentical transplantations. The overall leukocyte engraftment time has decreased over the past 20 years. Furthermore, both overall survival (OS) and disease-free survival (DFS) have significantly improved, while non-relapse mortality (NRM) has significantly decreased since 2013. Multivariate analysis identified transplantation before 2013, patients in complete remission (CR) 2 or non-CR, and recipients older than 50 years as risk factors for NRM, while patients in non-CR and patients with positive MRD are risk factors for recurrence. These findings offer insights into AML treatment outcomes in China, highlighting changes in transplantation practices and the need to reduce post-transplant relapse. Effective interventions, such as MRD monitoring and risk stratification schemes, are crucial for further enhancing transplant outcomes.

Patients with hematological malignancies who experience severe infections are at risk of developing dangerous complications due to excessive inflammatory cytokines. To improve the prognosis, it is crucial to identify better ways to manage the systemic inflammatory storm after infection. In this study, we evaluated four patients with hematological malignancies who developed severe bloodstream infections during the agranulocytosis phase. Despite receiving antibiotics, all four patients presented elevated serum IL-6 levels as well as persistent hypotension or organ injury. Adjuvant therapy with tocilizumab, an IL-6-receptor antibody, was administered, and three of the four patients showed significant improvement. Unfortunately, the fourth patient died due to multiple organ failure caused by antibiotic resistance. Our preliminary experience suggests that tocilizumab, as an adjuvant therapy, may help alleviate systemic inflammation and reduce risk of organ injury in patients with elevated IL-6 levels and severe infection. Further randomized controlled trials are needed to confirm the effectiveness of this IL-6 targeting approach.