bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Observation of Sequential Prophylaxis with Letermovir Injection and Tablets for Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Pang Aiming , Zheng Yawei , Chen Shulian , Shen Yuyan , Zhao Xiaoli , Ni Xiaofei , Zhang Lining , Wang Jiali , Cao Wenbin , Chen Xin , Cao Yigeng , Jiang Erlie 
Published: December 2024

Objective: To evaluate the efficacy and safety of sequential prophylaxis with letermovir injection and tablets for Cytomegalovirus(CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Methods: The study included 18 patients who completed allo-HSCT at the Blood Disease Hospital, Chinese Academy of Medical Sciences from December 2023 to March 2024. Letermovir injection was initiated on day 0 post-transplant, followed by a switch to letermovir tablets for sequential prophylaxis up to day 90. The primary outcome was the CMV breakthrough rate at 90 days post-transplant, and the second outcomes were the incidence of viral infections such as EBV and the status of hematopoietic reconstitution.
Results: At 90 days post-transplant, among the 18 allo-HSCT patients who received sequential prophylaxis with letermovir injection and tablets, no CMV infection was observed in all patients, resulting in a CMV infection breakthrough rate of 0%. Four patients had EB virus (EBV) viremia (22.22%), of which one patient developed PTLD (5.6%). The median time for neutrophil engraftment was 15 (11-18) days; no related liver and kidney function damage was observed during the medication process.
Conclusion: Preliminary research results indicate that sequential prophylaxis with letermovir injection and tablets is safe and effective for post-allo-HSCT CMV infection.
Modulating the Vasoactive Intestinal Peptide (VIP) Pathway Reprograms Superior CAR T Cells
Authors: Lin Heather K. , Blake Dejah , Wells Kory , Freeman Ruby , Mudigonda Abhijay , Liu William , Evans Alysa N , Goyal Subir , Liu Tongrui , Funk Christopher Ronald , Sinha Tanisha , Christensen Elyse , Mahmood Naeman , Fei Fan , Heller Brad , Chun Paul , Passang Tenzin , Ravindranathan Sruthi , Dougan Jodi , Porter Christopher C. , Paulos Chrystal , Patgiri Anupam , Yang Lily , Waller Edmund K. , Rafiq Sarwish 
Published: December 2024

Chimeric antigen receptor (CAR) T cell therapy is a highly potent cellular immunotherapy that still faces significant obstacles that limit clinical success. Novel immunomodulatory approaches to improve the CAR T cell phenotype, metabolic fitness, and the engagement of endogenous immunity are necessary to create effective CAR T products. Vasoactive intestinal peptide (VIP) is a neuropeptide that dampens adaptive immune responses and is abundantly produced by several hematologic malignancies. Here, we have engineered CAR T cell therapies that secrete a synthetic short peptide drug that antagonizes VIP receptors (CAR/VIPRa).
CAR/VIPRa T cells are less activated and less exhausted by the manufacturing process, which lends to better viability and preservation of memory phenotypes. Furthermore, VIPR antagonism increases the number of mitochondria and enriches the utilization of oxidative phosphorylation. This metabolic reprogramming results in quiescent CAR/VIPRa T cells that have greater potential and plasticity to achieve improved energetic profiles after antigen stimulation. In vivo, CAR/VIPRa T cells demonstrate significantly greater expansion with less exhausted phenotypes and are enriched for memory phenotypes in xenograft tumor models. Additionally, the small peptide drug produced by CAR/VIPRa T cells increases the number of endogenous tumor-infiltrating T cells in syngeneic tumor models. To investigate clinical relevance, CAR/VIPRa T cells manufactured from patient-derived T cells recapitulated lower activation profiles and enrichment for memory phenotypes.
Collectively, this approach to antagonize the VIP/VIPR pathway serves to improve CAR T cell phenotype and function before and after tumor engagement to drive enhanced anti-tumor efficacy. Therefore, CAR/VIPRa T cells are uniquely equipped to overcome many key obstacles that are required for success of CAR T therapy in the clinic.
Clinical Trial Success Rate in Lymphoma: Fate of Trials and Agents from 2000 to 2023
Authors: Luo Zhiping , Li Meng , Flowers Christopher R. , Chihara Dai 
Published: December 2024

Introduction:Only 7.5% of investigational agents tested in phase 1 trials resulted in new drug approvals by the FDA for hematologic malignancies from 2011 to 2020 (©BIO 2024). Although approximately half of investigational agents tested in phase 1 trials progress to phase 2 trials, just 27.8% transition to phase 3 trials, illustrating the low success rate transitioning agents from early phase trials. However, comprehensive studies examining development success of agents for patients with lymphoma have not been performed.
Methods: We conducted a retrospective analysis of clinical trials investigating lymphoma treatments between January 1, 2000, and May 25, 2023. Clinical trial data were obtained from the Biomedtracker® database and were supplemented with information from ClinicalTrials.gov to ensure data completeness and accuracy. We identified phase 1, 2, and 3 trials conducted during this period focused on or including patients with lymphoma and reviewed agents approved by FDA for patients with lymphoma from 2006 to 2024. We assessed the numbers of patients enrolled and trial enrollment period and calculated the phase transition success rates for the identified trials to assess the efficiency and success of the clinical development process.
Results: A total of 2,222 phase 1 trials were conducted during the study period of which patients of lymphoma were eligible for participation in 1,868 phase 1 trials that evaluated 858 agents. 1,132 phase 1 trials evaluated single agents and 736 trials evaluated combinations. Overall, 60,809, 68,325 and 53,848 patients were treated in phase 1, 2 and 3 trials. The median duration of opening to closing the trial was 42, 44 and 49 months in phase 1, 2 and 3, respectively. During this period, 1,769 phase 2 trials and 188 phase 3 trials were conducted to further assess the safety and efficacy in lymphoma. From 2006 to 2024, 44 new agents (including rituximab biosimilar) in 91 indications received approval from FDA. and common lymphoma subtypes that received new agent approval were follicular lymphoma (n=15), chronic lymphocytic leukemia (n=16), diffuse large B-cell lymphoma (n=11) while little to no new agents approved for peripheral T-cell lymphoma (n=4), classical Hodgkin lymphoma (n=3), Burkitt lymphoma (n=1), and primary CNS lymphoma (n=0). For 26 agents, FDA granted accelerated approval which requires phase 3 confirmatory trial. The success rate from phase 1 to phase 2, phase 2 to phase 3, and phase 3 to approval for lymphoma were 94.7%, 10.6% and 48.4%, respectively. The overall success rate from agents evaluated in phase 1 to approval was 5.1% (95%CI: 3.7%-6.6%).
Conclusions:Our study defines the clinical development landscape and timelines of new therapies for lymphoma and illustrates the unmet need for further clinical trials focusing on rare subtypes. Success rate in lymphoma is still low suggesting the critical role of better pre-clinical data conducting phase 1 trials.
Morbidity and Mortality of Major Adverse Cardiovascular Events in Hospitalized Acute Myeloid Leukemia Patients
Authors: Eltaher Basant , Shah Purva , Kharel Himal , Mahmoud Amir , Abdelhay Ali 
Published: December 2024

Introduction: Patients with acute myeloid leukemia (AML) undergo different intensive chemotherapy regimens, with possible side effects including cardiovascular toxicity. This could be challenging when managing AML with its complex pathophysiology.
Methods: This is a retrospective analysis conducted using ICD-10 codes from the National Inpatient Sample (NIS) between 2016 and 2020 and analyzed with STATA BE software. Our aim is to identify major adverse cardiovascular events (MACE) in patients with AML. Descriptive analysis was used to illustrate baseline characteristics of hospitalized patients with AML. Logistic regression was further employed to examine the association between AML and MACE. Underlying comorbidities including hypertension, hyperlipidemia, diabetes, chronic kidney disease (CKD), smoking, and thrombophilia were adjusted for.
Results: This study consisted of 103,697 hospitalized AML patients with a mean age of 61 years, most of whom were of white race (69%) and male gender (55.6%). The most common underlying comorbid condition was hypertension (34%), followed by hyperlipidemia (30.5%), smoking (25%), congestive heart failure (17.3%), and chronic kidney disease (16.4%). Cardiovascular-related death accounted for 34%. AML patients not in remission (AMLniR) made up most of our cohort (73.6%) and were generally older than AML in remission (AMLiR) and AML with relapse (rAML) (mean age of 63 years vs 54.6 and 54.1 in other two groups, respectively). rAML had higher rates of death (11%) compared to AMLiR (2.8%) and AMLniR (8.2%). Hospitalized patients with relapse were more likely to undergo bone marrow transplant (23.6%).
The effect size of the association between AMLniR and AMLiR with MACE rounded to 1 (p=0.98 and p=0.043, respectively). This could be due to underlying cardiac risk factors rather than the presence of AML. Interestingly, AML with relapse were less likely to have major cardiovascular events (Odds ratio (OR) 0.9, 95% CI, 0.86-0.98; p value &lt;0.01), possibly related to younger age observed in this group. Patients who underwent bone marrow transplant and received chemotherapy had less odds of developing major adverse cardiovascular events (OR 0.8, 95% CI, 0.7-0.95 and OR 0.6, 95% CI, 0.5-0.63). MACE in AML patients ((OR 2, 95% CI, 1.9-2.12,), AMLniR (OR 1.46, 95% CI, 1.2-1.9), and rAML (OR 2.5, 95% CI, 2-3.2) were associated with increased in-hospital deaths. However, AMLiR had lower likelihood of deaths (OR 0.6, 95% CI, 0.45-0.74).
Conclusion: Hospitalized AML patients with relapse had lower rates of major cardiovascular events, possibly due to the younger age of this group. Bone marrow transplant and chemotherapy were associated with less major cardiovascular events, while AMLniR and rAML were associated with increased in-hospital mortality. More research is needed to evaluate MACE in AML patients undergoing intensive chemotherapy.
Recombinant Human Thrombopoietin Combined with Thrombopoietin Receptor Agonists Can Facilitate the Recovery of Platelet after Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma
Authors: Xu Xuezhu , Liu Rui , Yang Ruoyu , He Aili , Zhao Wanhong , Wang Fangxia 
Published: December 2024

Abstract
Background
Autologous hematopoietic stem cell transplantation (ASCT) has been widely used in the treatment of hematologic tumors and has achieved significant efficacy, especially for multiple myeloma (MM). The high-dose conditioning regimen of ASCT always causes myelosuppression which might lead to neutropenia and thrombocytopenia. In clinical practice, thrombopoietin receptor agonists (TPO-RAs) and recombinant human thrombopoietin (rh-TPO) have been applied to refractory thrombocytopenia after ASCT and has shown a certain efficacy, respectively. But very few clinical data are available regarding the use of TPO-RAs combined with rh-TPO after ASCT for NDMM patients.
Aims
To compare the effect of rh-TPO plus TPO-RA (hetrombopag) on white blood cell and platelet (PLT) recovery, adverse events, post-operative complications, and cost effectiveness after autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma (NDMM).
Methods
Ninety-five cases with NDMM had been enrolled from January 2018 to December 2023. The hematopoietic reconstitution was compared between these 35 cases receiving rh-TPO combined with TPO-RA after stem cell reinfusion as observation group and 60 cases only receiving rh-TPO classified as the control group.
Results
There were no significant differences in the baseline clinical characteristics between two groups. In the observation group, the median time to platelet was the 10th day after stem cell reinfusion, which were significantly shorter than those of the control group (P＜0.001). The mean units of platelet transfusion in the observation group were significantly lower than those in the control group (1.0 vs 1.5 units, P=0.007). All the patients tolerated rh-TPO and TPO-RA well and no thrombotic events occurred. Survival analysis showed no decrease in time to progression (TTP) or overall survival (OS) by TPO-RA administration. There were no statistical differences in the incidence of adverse events, total expense and hospital stay between two groups (P &gt; 0.05).
Conclusions
Our data shows that the treatment protocol of TPO-RA (hetrombopag) combined with rh-TPO may boost a faster platelet growth rate. Importantly, no additional adverse effects occurred when the addition of TPO-RA.
Thromboprophylaxis By Direct Oral Anticoagulants Versus Low Molecular Weight Heparin in Patients Undergoing Surgery for Gynecological Cancer: A Systematic Review and Meta-Analysis
Authors: Dave Prashil , Uddin Anwar , Shastri Dipsa , Irfan Sohaib , Winer Andrew 
Published: December 2024

Introduction: Anticoagulants are used prophylactically to prevent venous thromboembolism (VTE) in the perioperative period for patients undergoing surgery for gynecological cancer. However, they carry a substantial risk of bleeding. This meta-analysis aims to study the efficacy and safety of Apixaban and Rivaroxaban compared to the traditional Enoxaparin.
Methods: PRISMA guidelines were followed, and PubMed, Cochrane, and Google Scholar were searched using MeSH terms ‘gynecological cancer’ AND ‘DVT prophylaxis’ OR ‘thromboprophylaxis’ OR ‘Enoxaparin’ from January 2004 to December 2023. Five studies were included in analysis. Demography, type and duration of surgery, treatment efficacy, and safety data was extracted. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions and 95% Confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.3.3).
Results: A total of 1797 patients from the five studies (Apixaban n=326, Rivaroxaban n=343, Enoxaparin n=1138) reporting the perioperative outcomes of Apixaban and Rivaroxaban versus Enoxaparin therapy were included, of which 2 were clinical trials (40%), and 3 were retrospective analyses (60%). The mean age for Apixaban and Rivaroxaban was 57.3 years, and the mean age for Enoxaparin was 59.1 years. The mean BMI for Apixaban, Rivaroxaban and Enoxaparin was 27.1. The pooled composite venous thromboembolism relative risk for Apixaban vs Enoxaparin was 0.64 (95% CI 0.22-1.89, 12=0%, p=1.00). The pooled composite VTE, the relative risk for Rivaroxaban vs. Enoxaparin, was 0.58 (95%CI 0.24-1.41, 12=0%, p=0.69). The pooled DVT relative risk for Apixaban vs Enoxaparin was 1.11 (95% CI 0.1-12.75, 12=75%, p=0.13). The pooled major bleeding relative risk for Rivaroxaban vs Enoxaparin was 4.31 (95% CI, 1.18-15.79, 12=0%, p=0.47). No pooled major bleeding relative risk for Apixaban vs. Enoxaparin could be calculated as only one study mentioned outcome.
Conclusions: Our analysis suggests that direct oral anticoagulants offer superior efficacy compared to Enoxaparin for preventing venous thromboembolism. However, Rivaroxaban is associated with a significantly higher risk of bleeding compared to Enoxaparin. Further clinical trials and randomized studies to evaluate the comparative effectiveness and safety of these anticoagulants in various patient populations are essential. Such studies are important for the development of comprehensive international guidelines for VTE management, ensuring optimal evidence-based treatment.
Investigating Prognostic Value of Immunoglobulin Next-Generation Sequencing in B Cell Non-Hodgkin Lymphoma Patients Undergoing Chimeric Antigen Receptor T-Cell Therapy
Authors: Zhang Yi-Lun , Sheng Lingshuang , Shen Rong , Wu Wen , Zheng Xin , Wang Li , Cheng Shu , Xu Peng-Peng , Jian Qi-Jie , Peng Bo , Zhang Ke , Pang Fei , Wang Kai , Yan Zi-Xun , Zhao Wei-Li 
Published: December 2024

Background
In B cell non-hodgkin lymphoma (B-NHL), circulating tumor DNA (ctDNA)-based liquid biopsy for minimal residual disease (MRD) detection correlates strongly with post-treatment relapse. Immunoglobulin next-generation sequencing (Ig-NGS) is more sensitive and cost-effective compared to targeted capture sequencing. Improved biomarkers are essential to guide autologous chimeric antigen receptor T-cell (CAR-T) therapy, particularly in early stages. Currently, there is a lack of research on the prognostic value of Ig-NGS MRD in B-NHL patients undergoing CAR-T therapy.
Method
We recruited B-NHL patients scheduled for CAR-T therapy, collecting tissue and/or peripheral blood samples prior to leukapheresis. Plasma and peripheral blood mononuclear cells were immediately separated and used for dominant clonotypes identified by Ig-NGS assay (Origimed, Shanghai, China) as the baseline assessment. Post-therapy, serial peripheral blood samples were collected at days 7, 14, 28, and every 3 months for MRD assessment via Ig-NGS assay. Imaging examinations were performed at 3, 6 and 12 months after therapy.
Result
In a cohort of 51 B-NHL patients treated with CAR-T therapy, including 45 diffuse large B-cell lymphoma patients, two follicular lymphoma patients, two primary bone marrow B-cell lymphoma patients, and two high-grade B-cell patients, clonality was identified in 94% (48/51) of patients, with at least one identifiable clonotype (median 2; range 1-3). In matched baseline samples, the dominant clonotypes identified in tissue samples were detectable in 83% (19/23) of ctDNA samples and 71% (15/21) of gDNA samples. After a median follow-up of 12 months post-treatment, the objective response rate was 78% (40/51). In post-CAR-T therapy surveillance, MRD was detected in 50% (11/22) of patients, significantly correlated with poorer progression-free survival than MRD negative patients (1-year PFS: 36% vs. 100%, P&lt;0.001). MRD positivity had a sensitivity and specificity for progression of 64% (7/11) and 100% (11/11), respectively. The median lead time from MRD detection to clinical relapse was 23 days (range: 2-166 days).
Conclusion
Our research provides substantive evidence that Ig-NGS testing on ctDNA, rather than gDNA from peripheral blood, is more suitable for MRD monitoring. ctDNA effectively serves as a reliable indicator for impending disease progression. A positive plasma MRD result directly correlates with a significantly heightened risk of disease progression. Consequently, MRD surveillance following CAR-T therapy holds potential for timely evaluation and early re-initiation of treatment upon molecular relapse, thereby optimizing therapeutic strategies.
Establishment of Bruton Tyrosine Kinase Inhibitor-Resistance Related Gene Signature to Predict Prognosis and Identification of TRIP13 As a Chemotherapeutic Target in Diffuse Large B-Cell Lymphoma
Authors: Ding Yangyang , Huang Keke , Sun Cheng , Liu Zelin , Zhu Jinli , Jiao Xunyi , Liao Ya , Feng Xiangjiang , Guo Jinjin , Zhu Chunhua , Zhai Zhimin , Xiong Shudao 
Published: December 2024

Background: Bruton tyrosine kinase inhibitor (BTKi) combined with rituximab-based chemotherapy benefits diffuse large B-cell lymphoma (DLBCL) patients. However, drug resistance is a major cause of relapse and death in DLBCL. This study aims to explore the relationship between BTKi-resistance related genes (BRRGs) and DLBCL prognosis, and to clarify the function and mechanism of key resistance genes.
Results: In this study, we analyzed transcriptome data from parental and ibrutinib-resistant clone cell lines (GSE138126) and identified 1186 differentially expressed genes (DEGs), with 552 upregulated and 634 downregulated in the ibrutinib-resistant group. The GSE31312 dataset was used as the training cohort, while GSE87371 and GSE10846 served as external validation cohorts. Univariate Cox regression analysis identified 247 BRRGs associated with overall survival (OS). LASSO regression and tenfold cross-validation further identified 10 key BRRGs (CARD16, TRIP13, PSRC1, CASP1, PLBD1, CARD6, CAPG, CACNA1A, CDH15, and NDUFA4) to construct a prognostic signature. The resistance score formula based on 10-BRRGs is: Resistance Score=(0.2242×CARD16)+(0.0064×TRIP13)+(0.0174×PSRC1)+(0.0276×CASP1)+(0.0118×PLBD1)+(0.0627×CARD6)+(−0.0394×CAPG)+(−0.0661×CACNA1A)+(−0.3578×CDH15)+(0.6447×NDUFA4). Patients were divided into high- and low-resistance score groups based on the median resistance score. Kaplan-Meier survival analysis showed that patients with high-resistance scores had worse OS compared to those with low-resistance scores in both the training and validation cohorts. Additionally, the BRRGs signature exhibited good predictive efficacy for 1-year, 3-year, and 5-year OS, with AUC values of 0.731, 0.761, and 0.777, respectively. Notably, tumor immune microenvironment, biological pathways, and chemotherapy sensitivity were different between high- and low-resistance score groups. Furthermore, we identified TRIP13 as a key resistance gene in this signature and found that TRIP13 was overexpressed in DLBCL and BTKi-resistant DLBCL cell lines. Knockdown of TRIP13 inhibited cell proliferation, promoted apoptosis, and enhanced the apoptotic effect of BTKi in vivo and in vitro. Mechanistically, these effects were mediated through the Wnt/β-catenin signaling pathway.
Conclusion: Our study presents a novel BRRGs signature that could serve as a promising prognostic marker in DLBCL. Additionally, TRIP13 might be a potential therapeutic target for resistant DLBCL.
KMT2A (MLL1) Rearrangements in Hematolymphoid Malignancies: A Genomic Landscape Study
Authors: Ghimire Krishna , Goodman Alexandra , Sampat Parth , Srivastava Nimisha , Nam Myungwoo , Ross Jeffrey 
Published: December 2024

Background: KMT2A (MLL1) gene is altered in a variety of hematolymphoid neoplasms and solid tumors. In acute myelocytic leukemia, the interactions between KMT2A gene fusion proteins and menin have been linked to leukemogenesis and represent new potential targets for anti-tumor therapies.
Methods: 4,190 cases of AML underwent comprehensive genomic profiling using the Foundation One Heme combined hybrid capture based DNA and RNA sequencing assay. All classes of genomic alterations (GA) were evaluated. The tumor mutation burden (TMB) and microsatellite stability (MSS) status were determined from the sequencing data.
Results: Of the 4,190 AML cases, there were 43.1% female and 56.9% male patients with a median age of 62 years. 520 (12.4%) of the AML cases featured a GA in the KMT2A gene 99.1% of which were large rearrangements (KMT2Ara). The KMT2Ara AML cases had a median age of 62 years and were 41.7% female and 58.3% male gender. In contrast, the KMT2A not rearranged (KMT2Anra) cases had a similar mean age and gender distribution. Of the KMT2Ara cases there were 43.1% KMT2A duplications, 52.7% fusions and 4.2% not otherwise specified rearrangements. 0.9% of the KMT2A altered AML cases were short variant mutations. There were no KMT2A (0%) amplifications or deletions. GA enriched in the KMT2Ara vs the KMT2Anra AML cases included significantly increased frequencies of GA in FLT3 (27.3% vs 19.9%; p=.0001), KRAS (16.0% vs 8.0%; P&lt;.0001) (overall; 1.1% KRAS G12C) and IDH2 (16.0% vs 7.2%; p&lt;.0001) and significantly decreased frequencies in GA in RUNX1 (15.8% vs 19.6%; p=.05), ASXL1 (10.5% vs 16.1%; p=.0008) and TET2 (10.1% vs 16.3%; p=.0002). Similar GA frequencies in NRAS (17.2% vs 17.7%) DNMT3A (16.0% vs 16.4%) and WT1 (10.7% vs 10.1%) were not significant. The median TMB in the KMT2Ara and KMT2Anra cases was identical at 0.8 mutations/Mb with only 0.2% of both groups having a TMB of &gt; 10 mutations/Mb. All (100%) of KMT2Ara and KMT2Anra AML cases were MS stable.
Conclusions: Rearrangements in the KMT2A gene in AML are common and may emerge as a new target of therapy for AML patients. This genomic landscape study reveals significant differences in import GA associated with AML in KMT2Ara and KMT2Anra cases.