bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Analysis Defines Increased Circulating, Monocyte-Derived Macrophages That Promote Immune Suppression in Mouse Models of FGFR1-Driven Leukemogenesis and Defines a Multigene Signature That Predicts AML Outcomes
Authors: Fang Hui , Zhang Ting , Lu Xiaocui , Matsunaga Atsuko , Eisfeld Ann-Kathrin , Hedrick Catherine , Hu Tianxiang 
Published: December 2024

Background: The development of FGFR1-driven stem cell leukemia and lymphoma syndrome (SCLL) is accompanied by an increase in highly heterogenous myeloid derived suppressor cells (MDSCs), which leads to suppression of all immune effector cells in mouse models of the disease. This murine model provides the opportunity to define the genetic events that underly leukemia induced immune evasion.
Methods: A combination of CyTOF and scRNA-Seq was used to define the phenotypes and genotypes in leukemia induced macrophages. Pharmaceutical inhibition and correlative analysis was performed to examine the function and clinical significance of these macrophages.
Results: CyTOF analysis demonstrated an increase in levels of circulating macrophages in the peripheral blood during leukemia progression, which was further confirmed by flow cytometry. The connection between MDSC and macrophages was defined. These macrophages were derived not only from Ly6CHi M-MDSC, but also from the Ly6CInt and Ly6CLo monocytic populations. Consistently, single cell sequencing analysis demonstrated accumulation of non-classical monocytes (ncMono) during leukemia progression, which also show increased expression of macrophage markers. Trajectory analysis revealed a transition from cMono to ncMono, and potential genes orchestrating this transition process have been identified. Furthermore, T cell suppression assays demonstrated the immune suppressive abilities of leukemia-induced circulatory macrophages. Importantly, treatment of leukemic mice with the CSF1R inhibitor GW2580, which suppresses macrophage function and reduces their viability, leads to improved survival accompanied by reduced levels of leukemia cells and increased T-cell levels. This suggests that the leukemia induced macrophages are responsible, at least in part, for the suppression of immune effector cells. In newly diagnosed AML patients, those showing a high ncMono score, which was generated based on a specific ncMono gene signature, correlated with poorer survival, compared with those with a low ncMono score.
Conclusion. Overall, we demonstrate that a major part of the immune suppression in SCLL leukemia models involves suppression of T-cell function by circulating macrophages, and targeting macrophages in this system improves survival of mice engrafted with leukemia cells. In addition, we have also defined specific genetic reprogramming that is associated with the transition of monocytes into macrophages during leukemogenesis, potentially providing opportunities to target and reverse the immune suppressive microenvironment to improve AML outcome.
Efficacy and Safety of Beceltinib Capsules in the Treatment of Persistent or Chronic Primary Immune Thrombocytopenia: A Multicenter, Randomized, Open-Label, Phase 1/2 Study
Authors: Zhou Hu , Song Xuewen , Sheng Zengmei , Zhang Feng , Wu Guocai , Zhao Lidong , Zhou ZePing , Shou Lihong , Chen Lili , Wang Xiaotao , Huang Jian , Fu Rong , Chen Dan , Huang Ruibin , Jiao Zongjiu , Lu Jian , Ruan Yajun , Jiao Yu 
Published: December 2024

Abstract:
Introduction:
Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by abnormally low blood platelet count, resulting in an increased risk of bleeding. Beceltinib, an oral irreversible covalent inhibitor of Bruton's tyrosine kinase, has shown potential as a therapeutic approach for ITP. This study aimed to evaluate the efficacy and safety of Beceltinib in adult patients with persistent or chronic ITP.
Methods:
In this multicenter, randomized, open-label, phase 1/2 study, adult patients with primary ITP who had previously failed standard therapy or could not tolerate it were enrolled. Patients were randomly assigned to receive either 50mg, 75mg, or 100mg of Beceltinib twice daily for 24 weeks. The primary endpoint was the proportion of patients achieving platelet counts of ≥50×109/L for at least two consecutive weeks during the treatment period. The secondary efficacy end points were sustained platelet response which defined as the proportion of patients with at least 4 platelet counts≥50×109/L during the last 6 visits within 24 weeks without rescue medication use. Safety monitoring, including adverse events, physical examinations, and bleeding risk assessments, was conducted throughout the trial. Pharmacokinetics and pharmacodynamics of Beceltinib were also explored.
Results:
A total of 32 patients were enrolled in the study, and 13 patients (40.6%) achieved the primary endpoint which is two consecutive platelet counts of at least 50 x 109/L during 24-week treatment period. Out of the responders, 11 patients (84.6%) demonstrated a sustained response, indicating that majority of the patients who positively responded to Beceltinib exhibited continued efficacy. The median cumulative response duration was 22 weeks (interquartile range, 12 to 31). The median time to the first platelet counts of at least≥50×109/L was 3 week (range, 1 to 9). Patients who had responded to glucocorticoids in the past showed better primary platelet response (61.5%, 8 of 13) and sustained platelet response (53.8%, 7 of 13). Dose adjustments were made in some patients, and the effective rate varied across different dose levels. The incidence of adverse reactions was 43.8%, with most being mild (grades 1 or 2). The study demonstrated that Beceltinib was generally well-tolerated by ITP patients.
Conclusion:
This study suggests that Beceltinib may have potential efficacy and safety for the second-line treatment of ITP. The findings provide new treatment options for clinical practice. Further studies are needed to validate these results and assess the long-term effects of Beceltinib in ITP patients.
Clinical Feature and Predictive Model for Transplanted Patients with Functional High-Risk Multiple Myeloma
Authors: Yu Tongyong , Li Juan 
Published: December 2024

Objective: Despite these therapeutic advancements, a subset of patients continues to exhibit poor outcomes, highlighting the complexity and heterogeneity of the disease. These subsets of patients with MM who relapsed early, even without any high-risk features at baseline, were defined as functional high-risk (FHR) MM. And the prognosis of FHR MM was worse than high-risk (HR) MM. Therefore, it is important to distinguish patients with FHR MM from patients with standard risk (SR). In this study, we explored risk factors for clinical features to identify through comparing FHR with SR. Additionally, we sought to develop a prognostic model to predict FHR MM patients with transplantation according to risk factors.
Methods: We conducted a retrospective analysis of clinical data from MM patients diagnosed between January 1, 2007, and March 22, 2024, who underwent autologous hematopoietic stem cell transplantation (ASCT) with a minimum follow-up of 24 months after transplantation. The cases were randomly divided into a training set (151 cases, 70%) and a validation set (65 cases, 30%). Univariate and multivariate analyses were performed to identify independent risk factors for FHR MM. A predictive model was constructed using logistic regression analysis and internally validated.
Results: A total of 357 MM patients were included in our study, with 49 (13.73%) classified as FHR, 167 (46.78%) as SR, and 141 (39.50%) as GHR. The FHR groups had the shortest survival compared with the HR and the SR groups, including PFS and OS. The median PFS was 22.5 months, 49.7 months, and 111.2 months in the FHR, HR, and SR groups, respectively. The median OS was 39.7 months, 71 months, and 132.1 months in the FHR, HR, and SR groups, respectively. Univariate and multivariate analyses revealed that LDH ≥190U/L (OR=2.70, P=0.015), PET-CT SUVmax≥7.5 at onset of MM (OR=3.13, P=0.035), the proportions of PET-CT SUVmax decline after induction therapy ≥80% (OR=4.79, P=0.044), PLT &lt;80*10^9/L (OR=10.55, P=0.012), and ferritin ≥650μg/L (OR=4.76, P=0.031) were independent risk factors for FHR MM. Additionally, Pattern B of M-protein decline (OR=0.39, P=0.012) and achieving CR after ASCT (OR=0.37, P=0.009) were identified as independent protective factors. A predictive model incorporating these factors demonstrated areas under the ROC curves of 0.753 for the training set and 0.857 for the validation set. Calibration plots, Decision Curve Analysis (DCA) curves, and Hosmer-Lemeshow test results indicated that the model has good predictive accuracy.
Conclusion: This study developed a predictive nomogram model for FHR MM patients with transplantation, which shows promising predictive capabilities.
Different Large Granular Lymphocyte Count Drew Distinguish Characteristics in Large Granular Lymphocytic Leukemia
Authors: Yu Ying , Li Yuxi , Cui Rui , Sun Jingwen , Lyu Rui , Wang Tingyu , Wenjie Xiong , Yan Yuting , Qiu Lu-Gui , Yi Shuhua 
Published: December 2024

Introduction
Large granular lymphocytic leukemia (LGLL) is a rare disorder characterized by the clonal expansion of large granular lymphocytes (LGLs). While, an LGL count greater than 2×10^9/L is common, some researchers consider &gt; 0.5×10^9/L necessary. However, the WHO and other studies do not specify a clear LGL count, leading to ambiguity. Diagnosing patients with low LGL counts, especially &lt; 0.5×10^9/L, remains challenging. Establishing a precise clinical diagnostic parameter for LGLL is urgently needed.
Methods
From July 2005 to July 2022, 175 patients were diagnosed with LGLL at Blood Hospital of CAMS & PUMC.，excluding patients with aplastic anemia (AA) or other hematologic malignancies. Then patients categorized into low (&lt;0.5× 10^9/L), intermediate (0.5-2× 10^9/L), and high (&gt;2× 10^9/L) LGL count groups (27.4%, 31.4%, and 41.1% of patients, respectively).
Results
Among the 175 enrolled LGLL patients, 20 (11.4%) had NK-LGLL and 155 (88.6%) had T-LGLL. The median proportion of LGL cells was 55.8% (range: 4.1%-98.2%), with a median LGL count of 1.1 × 10^9/L (range: 0.10-71.21 × 10^9/L). The low LGL count group had 48 patients (27.4%), the intermediate group had 55 patients (31.4%), and the high group had 72 patients (41.1%). Anemia (75.0% vs. 83.6% vs. 48.6%, P&lt;0.001), thrombocytopenia (27.1% vs. 20.6% vs. 5.6%, P&lt;0.001), and pure red cell aplastic anemia (29.2% vs. 43.6% vs. 13.9%, P=0.001) were significantly more prevalent in the low and intermediate LGL count groups than in the high LGL count group (Table 1). Notably, Treg cell proportion was higher in the low and intermediate LGL count group compared to the high LGL count group (P=0.015). Overall, the low and intermediate LGL count groups exhibited lower overall response rates (ORR) and worse overall survival (OS) compared with the high LGL count group (ORR: 86.8% vs. 64.3% vs. 91.4%, P=0.005; OS: 3-year OS rate 86.5% vs. 90.9% vs. 100%, P=0.029). However, no evidence of a difference in ORR and OS among the three LGL count groups was observed under treatment subgroups.
Conclusions
Generally, while LGL counts reveal unique clinical and biological features, they should not be obligatory for diagnosing LGLL.
Impact of Mono- and Bi-Allelic TP53 Aberrations on Transformation of Human HSPCs
Authors: Lind Karin , Dutta Sayantanee , Cosenza Marco , Eder Thomas , Foßelteder Johannes , Pabst Gabriel , Schöll Wolfgang , Prokesch Andreas , Reinisch Andreas , Woelfler Albert , Zebisch Armin , Grebien Florian , Korbel Jan O. , Sill Heinz 
Published: December 2024

Introduction
Clonal hematopoiesis with mono-allelic TP53 mutations confers a high-risk for progression to myeloid neoplasms, particularly in the context of exposure to cytotoxic stress. During leukemic transformation, bi-allelic TP53 aberrations frequently evolve - however, the exact molecular mechanisms driving transformation are not well understood. Here, we use genetically engineered human HSPCs to investigate the impact of mono- and bi-allelic TP53 aberrations on HSPC function and genomic integrity.
Methods
Cord blood derived HSPCs were engineered using a CRISPR-Cas9 and adeno-associated viral vector-mediated knock-in strategy to generate TP53R175H/WT, TP53R175H/KO, TP53R273H/WT, TP53R273H/KO, TP53KO/WT and TP53KO/KO aberrations, respectively. To control for gene editing, the AAVS1 safe harbor locus was targeted. To understand the functional impact of different TP53 allelic states, cell cycle analysis, colony formation and serial replating as well as bulk mRNA sequencing were performed. The emergence of structural chromosomal variants was investigated by single-cell template strand sequencing upon doxorubicin exposure.
Results
Successful editing of HSPCs at the TP53 locus was confirmed at the genomic DNA, RNA and protein levels, respectively. Bi-allelic TP53 aberrant HSPCs showed an increase of cells in S-phase and formed significantly more colonies with a high proportion of BFU-E as compared to control cells. Mono-allelic TP53 aberrant cells lost their replating capacity after three passages whereas bi-allelic ones were not exhausted after five replatings. Transcriptome analysis revealed the induction of an inflammatory signature in cells with both, mono-and bi-allelic TP53 aberrations, with a skewed expression rate of erythroid and myeloid genes. Single-cell template strand sequencing indicated that mono-allelic TP53 aberrations, especially in conjunction with doxorubicin treatment, already induced a substantial increase of structural genomic variants including chromothripsis.
Conclusions
Our data indicate that already mono-allelic TP53 aberrations induce an inflammatory signature and structural chromosomal alterations in human HSPCs. Alterations of the second TP53 allele increase the proliferative and self-renewing capacity of HSPCs further promoting their leukemic transformation and progression. These data contributes towards a better understanding of human, TP53 aberrant leukemogenesis.
Single-Cell Analysis Reveals Altered Tumor Microenvironments of Relapse/ Refractory and Remission-Associated Acute Myeloid Leukemia Treated By ABC-14 Regimen
Authors: Huang Xin , Li Minming , Wu Ping , Deng Chengxin , Lu Zesheng , Wang Yulian , Geng Suxia , Luo Chengwei Luo , Lai Peilong , Du Xin , Weng Jianyu 
Published: December 2024

The preliminary study (2023 ASH Poster #1522) demonstrated that ABC-14 regimen (Azacitidine, Venetoclax, and Chidamide) was comparable to “3+7” regimen in the induction therapy of newly diagnosed AML, while overcoming the limitations of drug resistance of VA regimen (Azacitidine and Venetoclax), even with better for the subtype of AML-M4/M5, and reducing the toxicity of the traditional “3+7” regimen. However, it is important to identify deeper characterization of the disease that can be used to better guide ABC-14 regimen therapy decisions and improve clinical outcomes. Here, we utilize single-cell RNA sequencing (scRNA-seq) to analyze AML bone marrow (BM) samples from diagnosis (6 cases), remission (3 cases), short time relapse (2 cases), and refractory (4 cases) timepoints, which provide insights into AML tumor and microenvironment.
Bone marrow samples aspirates from AML patients and healthy individuals were obtained from the Guangdong Provincial People's Hospital under ethical guidelines with informed consent. scRNA-seq data analysis including cell clustering and cell-type annotation, CNV estimation in single cells, differentially expressed genes (DEGs) testing, GO/KEGG enrichment analysis.
We focused on the distinct clusters of primary refractories, short time relapse, and continuous complete remission (CCR) associated AML blasts, monocytes, T cells, and macrophages with differential expression of genes. Relapse-associated group have more CD16+Mono, exhausted TIGIT+CD8+T cells and C1QB+macrophages, while CCR-associated group have more CD14+IFIT1+Mono, CD14+S100A12+Mono, CD14+HLA-DPB1+Mono, CD14+AQP9+Mono. Post-therapy residual blasts and primary refractory group exhibits downregulation of signal transduction by p53 class mediator genes. Also, a post-therapy T-cell cluster associated with relapse group exhibits downregulation of antigen processing and presentation of peptide antigen via MHC Class II and T-cell activation genes.
Altogether, this study characterizes ABC-14 regiment treated AML relapsed /refractory and CCR associated groups to provide insights into the BM microenvironment landscape. Our results will facilitate a better understanding and the development of novel therapeutic strategies for relapsed/refractory AML patients.
Impact of CD3 Expression on Outcome of Pediatric Anaplastic Large Cell Lymphoma
Authors: Obeid Ahmed , Hafez Hanafy , Semary Samah Fathy , Nageb Eman , Soliman Sonya Fahmy , Zaky Iman , Kamal Mohammed , Lehmann Leslie E. , Elhaddad Alaa 
Published: December 2024

Background: Anaplastic large cell lymphoma (ALCL) constitutes 10-15% of childhood non-Hodgkin lymphoma. Despite different treatment strategies, event-free survival has remained stable. CD3 expression, a T-cell marker, can be lost or diminished in some ALCL cases, which may affect the prognosis, especially in relapse settings according to some studies. The purpose of this study is to determine the effect of CD3 expression on survival and its relation to the other prognostic variables in pediatric ALCL.
Methods: A retrospective analytical study was conducted on 89 newly diagnosed pediatric ALCL patients (under 18 years old) treated at Children's Cancer Hospital Egypt (CCHE-57357) from July 2007 to December 2019. Immunohistochemistry was utilized to confirm the diagnosis and determine CD3 expression in tumor cells. Survival results - event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS) - were analyzed concerning CD3 expression and other risk factors.
Results: The median age was 10.7 years with a male-to-female ratio of 1.8-1. The majority of patients (85.4%) were ALK positive. CD3 was positive in 31 (34.8%) patients. The median follow-up period was 60 months. The five-year OS, EFS and RFS rates for the entire group were 84.3%, 73.1%, and 81.5%, respectively. CD3 positivity was linked to more central nervous system (CNS) involvement (p=0.03) but did not significantly correlated with other patient features or survival outcomes.
Conclusion: This study indicates that CD3 expression may not affect the survival in newly diagnosed pediatric ALCL. However, stage, B symptoms, and particular organ involvement were linked to lower relapse-free survival. Additional studies are needed to validate these findings in larger cohorts.
Construction and Verification of Prediction Model of Frailty Risk in Elderly Patients with Hematological Neoplasms
Authors: Zhao Jinying , Qianqian Zhang , Liu Yating , Li Bing , Xie Wenjun , Jiang Erlie , Wang Xin 
Published: December 2024

Objective: Develop and validate a nomogram for the prediction of frailty among elderly patients with HN.
Methods: A total of 505 elderly patients with HN from 17 hospitalsin China from April 2023 to November 2023 were included in the study. Characteristic features and disease-related information were collected, and geriatric assessments were conducted.Patients were divided by the Geriatric 8 questionnaire into frail and non-frail.The Chi-square test and Mann Whitney U test were used to compare the characteristics of the two groups. Univariate analysis and binary logistic regression were used to explore factors affecting frailty, and a risk prediction model was established in the form of a nomogram.Internal validation was carried out by the bootstrap using receiver operating characteristics, calibration curve,and decision analysis curve.
Results: The incidence rate of frailty in elderly patients with HN was 56.6%(286/505).The nomogram model (including eyelesof chemotherapy, self care ability, nutritional status, and hemoglobin level ) showed good predicting performance in both training and validation sets. In the validation cohort, the AUC was 0.867(95%C10.833~0.897), Youden index was 0.557, and the sensitivity and specificity were 85.71% and 69.95%, respectively. The average absolute error of the coincidence degree betwcen the predicted value and the real value was 0.01.
Conclusion: The nomogram showed good predicting value on elderly patients with HN, which can provide a reference for clinical doctors and nurses to identifythe frailty risk.
MagnetisMM-32: Evaluation of Elranatamab Vs EPd, PVd, or Kd in Patients with Relapsed or Refractory Multiple Myeloma and Prior Anti-CD38-Directed Therapy
Authors: Schuster Steven , Ito Satoshi , Hoyle Margaret , Yver Anne , Hong Fangxin , Finn Gregory 
Published: December 2024

BACKGROUND
Elranatamab (ELRA), a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody, has shown efficacy and manageable safety as a monotherapy in patients with relapsed or refractory multiple myeloma (RRMM). This study will evaluate ELRA monotherapy vs elotuzumab-pomalidomide-dexamethasone (EPd), pomalidomide-bortezomib-dexamethasone (PVd), or carfilzomib-dexamethasone (Kd) in patients with RRMM to determine whether ELRA can provide superior clinical benefit.
STUDY DESIGN AND METHODS
MagnetisMM-32, a phase 3, open-label, multicenter, randomized study, will enroll ≈492 patients. Patients will receive ELRA (Arm A) or investigator's choice of EPd, PVd or Kd (Arm B), until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Patients treated with ELRA will receive 2 step-up priming doses followed by weekly doses in a 28-day cycle. Patients who achieve a PR or better for ≥2 months will be eligible for reduced dosing frequency. Patients will be randomized 1:1 (stratified by prior line of therapy [1 vs 2 vs 3/4] and International Staging System disease stage [1/2 vs 3]).
Key inclusion criteria include age of ≥18 years, prior multiple myeloma diagnosis with measurable disease (per IMWG criteria), evidence of progressive disease or failure to achieve a response to last line of multiple myeloma therapy, 1 to 4 prior lines of therapy including an anti-CD38 antibody-containing regimen (for ≥2 consecutive cycles) and a lenalidomide-containing regimen (for ≥2 consecutive cycles), adequate bone marrow function, and an ECOG performance status of ≤2. Key exclusion criteria include stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior BCMA-directed or CD3-redirecting therapy; and unable to receive EPd, PVd, or Kd.
The primary and key secondary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per IMWG criteria and overall survival (OS), respectively. Other secondary endpoints include PFS by investigator, objective response rate, duration of response, time to response by BICR, PFS on next line of therapy per IMWG criteria, MRD negativity rate, safety, pharmacokinetics of ELRA, immunogenicity, and health-related quality of life outcomes. The primary endpoint and OS will be compared statistically between treatment arms by stratified log-rank tests. Clinical trial information: NCT06152575. Study funding: Pfizer.