bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-Cell and Spatial Transcriptomics Link Malignant T Cells to Macrophages in the Tumor Immune Microenvironment of Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma
Authors: Wang Jinuo , Zhang Zhongmin , Cheng Fei , Wu Wenjun , Wang Zhaoming , Tian Luyi , Cai Zhen
Published: December 2024

Introduction: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare and highly aggressive disease that most reported in Asia. However, the specific mechanisms and factors within the tumor microenvironment (TME) that drive this malignant disease remain largely unknown. In this study, we performed a comprehensive analysis of TME in patients with MEITL by single-cell RNA sequencing and spatial transcriptomic, which might help further elucidate the tumor biology and gain an insight to treatments beyond chemotherapy and transplantation.

Methods: A retrospective analysis of the clinical features and pathological data of 20 patients with MEITL treated at the First Affiliated Hospital of Zhejiang University School of Medicine from January 2019 to October 2023 was conducted. Four samples from 4 representative patients were subjected to single-cell RNA sequencing and spatial transcriptomic analysis.

Results: Among the 20 patients with MEITL, there were 13 males and 7 females, with a median age of 55.2 (16-75) years. Nineteen cases (19/20) had lesions located in the jejunum or ileum. Abdominal pain, diarrhea, and fatigue were the main clinical symptoms, with intestinal perforation as the main complication. Immunohistochemistry results showed that most monomorphic epitheliotropic intestinal T-cell lymphoma tumor cells were positive for CD3 (20/20), CD8 (17/20), and CD56 (19/20) expression, while negative for CD5 (19/20) and EBER (18/20) expression. 17 patients died during follow-up due to disesae progression or infection secondary to interstital disease. The estimated one-year OS were 10%. Analysis of single-cell and spatial transcriptomic data revealed that various cells, including MEITL tumor cells, intestinal epithelial cells, and macrophages, were distributed in the intestinal pathological tissue. NK cells were absent among TEM of MEITL. The tumor cells maintain the phenotypes of both T and NK cells. There was a high degree of spatial correlation between tumor cells and macrophages. Further differential gene enrichment analysis of macrophages revealed a positive spatial correlation between tumor cells and M1 macrophages, while the numbers of M1 macrophages under high power field were also related to patients' survival.

Conclusions: Monomorphic epitheliotropic intestinal T-cell lymphoma has an insidious onset, often presenting with acute abdomen, and has a very poor prognosis. According to single-cell sequencing and spatial transcriptomic results, the TME of MEITL is complex with various cells while in absence of NK cells. The high spatial correlation between tumor cells and macrophages suggests the underlying interactions of these two cells during the pathogenesis of MEITL.
Complications of Modern Immunotherapy (CAR-T and BsAb), a Single Centre Experience
Authors: Sokolova Tereza , Zavrelova Alzbeta , Belada David , Zak Pavel , Radocha Jakub
Published: December 2024

Introduction: immunotherapy represents a revolutionary therapeutic approach in the current era of malignant disease treatment. However, this therapy has its own pitfalls and risks, including immune complications such as Cytokine Release Syndrome (CRS), Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), immunosuppression and subsequent infections.

Aim: The analysis aimed to evaluate the incidence of infectious and immune complications (CRS, ICANS) in patients treated with modern immunotherapy (Chimeric Antigen Receptor T-Cell Therapy (CAR-T) and bispecific antibodies (BsAb) of the antiCD20 and antiBCMA/GPRC5D groups), to compare the findings across agents and to detect IgG antibody levels along with the incidence of infectious complications.

Methods. This was a retrospective analysis of all incomers treated with BsABs and CAR-T. Data were extracted from the hospital information system.

Results. Eighteen patients were treated with CAR-T (here (14/18) 77.8% with a diagnosis of non-Hodgkin's lymphoma (NHL), (4/18) 22.2% with a diagnosis of multiple myeloma (MM)) and 63 patients were treated with BsAb (here (38/63) 60.3% with a diagnosis of NHL, (25/63) 39.7% with a diagnosis of MM). The target antigen was BCMA/GPRC5D in 35.8%, CD20 in 46.9% and CD19 in 17.3%. The overall incidence of CRS was 63%, with a maximum severity of grade 2, in 21% of patients, and with the most significant prevalence in CAR-T, 94.5%. The incidence of ICANS was observed in 38.9% of patients, exclusively with CAR-T therapy for B-NHL. Infectious complications were observed in 74.1% of patients overall, with a median incidence of 79 days after therapy. The most common type of infection, given the epidemiological situation, was COVID-19 (44%), followed by respiratory infections (30%), urinary infections (3%), sepsis (8%), aspergillosis (2%), and unspecified infections (13%). Any grade infection was observed in both BsAb groups (antiBCMA/GPRC5D and antiCD20) with an overall proportion of infectious complications (88% vs. 81.6%) and a similar proportion of each grade (grades 3-5: 32% vs. 31.6%). The median IgG concentration at 3 months post-treatment was 3.65 g/L in the antiBCMA/GPRC5D BsAb group, 3.13 g/L in the CAR-T group and 5.15 g/l in the antiCD20 BsAB gourp. Percentage of patients indicated for substitution across immunotherapy groups; antiBCMA/GPRC5D BsAb (76%), CAR-T (38.9%), antiCD20 BsAb (21.1%).

Conclusion: Infectious complications remain a significant source of morbidity and mortality in patients treated with modern immunotherapy. Patients treated with antiCD20 and antiBCMA/GPRC5D showed different levels of IgG antibodies, but the observed incidence of infectious complications was similar in both types.
Study on Clinical and Laboratory Characteristics of Acute Erythroid Leukemia with EPOR Amplification
Authors: Fu Wenjing , Zhang Qiguo , Gong Wenyu , Bao Wenqiang , Xu Shiyun , Ling Chun , Jin Qichuan , Chen Bing
Published: December 2024

Objective: To enhance the understanding of acute erythroid leukemia (AEL) with erythropoietin receptor (EPOR) amplification and to improve its precise diagnosis and individualized treatment strategies.

Methods: A thorough analysis of the clinical and laboratory characteristics of two cases of de novo acute erythroid leukemia were performed and literatures were reviewed.

Results: Case 1: A 57-year-old male presented with dizziness and fatigue for one week. The proportion of erythroblasts in bone marrow aspirations was 3.2%, 40.5%, and 55% in three separate punctures, with proerythroblasts accounting for 18.4%, 23.5%, and 41% respectively. Bone marrow biopsy showed extremely hypercellular areas, with up to 80% erythroblasts in focal areas, predominantly proerythroblasts. Flow cytometry revealed that approximately 14.72% of cells were erythroblasts expressing CD36, CD117, CD33, and partially CD13. The granulocyte proportion was relatively normal. Chromosome analysis revealed a complex karyotype, and only a TP53 gene c.559+2T>G splice site mutation was detected using myeloid neoplasm-related gene mutation panel, with a VAF of 35.0%. FISH analysis showed no deletion of the TP53 gene. The diagnosis of acute erythroid leukemia was made, and the patient received two courses of decitabine plus arsenic trioxide and decitabine alone. However, bone marrow examination showed no remission, and the patient had a complex karyotype with clonal evolution, resulting in a survival of 3 months.

Case 2: An 80-year-old male presented with chest tightness, dyspnea, and fatigue for 10 days. Bone marrow aspiration showed hypercellular marrow, with 94% erythroblasts, including 35% proerythroblasts, 52% basophilic erythroblasts, 5.5% polychromatophilic erythroblasts, and 1.5% orthochromatic erythroblasts. Flow cytometry revealed that approximately 11.69% of nucleated cells were blast/early erythroid cells expressing CD33, CD117, CD36, CD71, and CD105. Chromosome analysis showed a complex karyotype. Myeloid neoplasm-related gene mutation panel showed TET2 mutation (+), TPMT mutation (+), and a TP53 p.K132E missense mutation with a VAF of 59.4%. Copy number variation (CNV) analysis revealed EPOR amplification and IKZF gene deletion. The patient survived for 7 days.

Conclusion: The proportion of erythroblasts in bone marrow smears of acute erythroid leukemia can be underestimated due to aspiration dilution, emphasizing the importance of bone marrow biopsy pathology combined with immunohistochemistry. Acute erythroid leukemia with EPOR amplification exhibits more significant erythroblast proliferation and a more aggressive clinical course.
FLAG/IDA/Venetoclax Induction in Patients with FLT3+ Acute Myeloid Leukemia
Authors: Abdelmessieh Peter , Ridgway Forrest , Shestovska Yuliya , Khanal Rashmi , Styler Michael , Ojala Anne , Ballas Brittany , Sorrentino Michele , Varshavsky-Yanovsky Asya , Fung Henry C.
Published: December 2024

Introduction

Induction chemotherapy (IC) in acute myeloid leukemia (AML) in younger and fit patients has combined an anthracycline (i.e., daunorubicin or idarubicin) with the antimetabolite, cytarabine. This is termed the 7 + 3 regimen. Response rates with this standard regimen approach 70-80%, but 30-40% of patients eventually relapse. Patients with FLT3 mutations have had poorer outcomes, however, the RATIFY trial, and more recently the QuANTUM-FIRST study, have shown that adding a targeted FLT3 inhibitor to the standard back bone of the 7+ 3 regimen improved response rates and overall survival. MD Anderson published a phase II study in which venetoclax was added to the standard anthracycline/cytarabine induction regimen of fludarabine, cytarabine, G-CSF, and idarubicin (FLAG-IDA/venetoclax). Results from this study showed an impressive 96% response rate for newly diagnosed (ND) AML patients. Based on these results, Fox Chase Cancer Center adopted this approach. Although this phase II study did include patients with FLT3, no studies have looked at outcomes with this protocol in patients with FLT3 mutations.

Methods

Patients between 2020 and 2024 who were treated with induction FLAG-IDA/venetoclax for AML, based on ELN 2022 criteria, were retrospective reviewed. Patients that had FLT3-ITD or TKD mutations were included in this review. All patients after induction either proceeded directly to allogenic stem cell transplant or proceeded to receive consolidation that included a FLT3 inhibitor.

Results

Overall, 9 patients were included in this study. Induction with FLAG-IDA/venetoclax lead to a 100% (N = 9/9) complete response rate on recovery marrow results per IWG criteria and FLT3 PCR negativity. MRD testing was not performed. There were no patient deaths during induction. Twenty-two percent (N=2/9) of patients relapsed despite receiving FLT3 directed therapy during the consolidation phase of their treatment. Data on long-term survival will require longer followup however thus far only 2 patients have had relapse. All patients were able to complete their induction course with no grade 3 or 4 cardiac events.

Conclusions

Based on our small review, FLAG-IDA/venetoclax appears to be an effective induction therapy for FLT3+ AML. Although the current standard of care for FLT3+ AML should include targeted therapy with FLT3 directed agents, this review shows it is not necessarily needed with induction. This is not surprising considering the combination of hypomethylating agents and venetoclax also showed excellent response rates. Adding FLT3+ inhibition to FLAG-IDA/venetoclax would be a promising study to explore in a phase I setting.
Multiple Supratherapeutic Doses of Iptacopan 400 Mg Twice Daily Are Well Tolerated in Healthy Participants: Safety Findings from a Randomized, Participant-Blinded, Placebo-Controlled, Phase I Study
Authors: Schmouder Robert L , Hackling Melissa , Shah Bharti , Bellibas S. Eralp , Kulmatycki Kenneth
Published: December 2024

Background: Iptacopan, the first oral proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement system, is approved as a monotherapy for adults with paroxysmal nocturnal hemoglobinuria and is being investigated in diseases such as immunoglobulin A nephropathy, C3 glomerulopathy and atypical hemolytic uremic syndrome. Iptacopan is administered at a therapeutic dose of 200 mg twice daily (bid). A Phase I, randomized, participant-blinded, placebo-controlled study (A2109) is being conducted to assess the safety, pharmacokinetics and pharmacodynamics of multiple supratherapeutic oral doses of iptacopan (400 mg and 800 mg bid) in healthy volunteers.

Aim: To report the safety findings from the completed Cohort 1 of the ongoing A2109 study, in which healthy participants received multiple 400 mg bid supratherapeutic doses of iptacopan or placebo.

Methods: Healthy individuals aged between 18 and 55 years were enrolled into Cohort 1 and were randomized 2:1 to receive iptacopan 400 mg bid or matching placebo. There was a 28-day screening period, a 14-day treatment period and a 5-day post-treatment washout period. The primary endpoint was safety, including adverse event (AE) reportings, vital signs, electrocardiogram (ECG) assessments and safety laboratory evaluations. Pre-dose safety data were collected at screening and baseline. On treatment, safety laboratory evaluations were performed on Days 2, 3, 7, 10, 14, 15, 16, 18 and 19; vital signs were measured daily; and ECG assessments were done on Days 1, 4, 7, 10, 14 and 19.

Results: Twelve healthy volunteers were enrolled into Cohort 1; 8 received iptacopan 400 mg bid and 4 received placebo.Two participants in the iptacopan arm had AEs during the treatment period; 1 had moderate headache and the other had a mild AE of elevated amylase levels. These 2 AEs were considered related to iptacopan; however, both resolved without the need for additional treatment. No participants discontinued iptacopan. One individual receiving placebo had 5 mild AEs during the treatment period (chills, bilateral hand pain, sensation of feeling flushed, headache and bilateral sclera erythema), which resolved without the need to discontinue treatment. The other 3 participants who received placebo had no AEs. During iptacopan treatment, there was no evidence of an effect on any laboratory parameter (including red or white blood cell count), ECG parameter or vital sign (including heart rate and blood pressure), and there was no adverse impact on liver, kidney or thyroid function.

Conclusions: Multiple supratherapeutic doses of iptacopan 400 mg bid for 14 days were well tolerated in healthy individuals. Based on these results, the study will progress to assess iptacopan 800 mg bid in Cohort 2.
Role of Myeloid-Derived Suppressor Cells (MDSCs) in the Prediction of Allogeneic Hematopoietic Stem Cell Transplantation Outcomes of Patients with Hematologic Malignancies
Authors: Thammahong Arsa , Wudhikarn Kitsada , Bunworasate Udomsak , Chanswangphuwana Chantiya
Published: December 2024

Background: Myeloid-derived suppressor cells (MDSCs), which include polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs), are known to suppress immune responses. Research on MDSCs following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological malignancies is limited. This study aimed to characterize MDSCs and their pattern of immune reconstitution, as well as to explore the association between MDSCs and allo-HSCT outcomes in patients with hematologic malignancies.

Methods: Forty-one patients who underwent allo-HSCT at King Chulalongkorn Memorial Hospital from 2021 to 2023 were included. MDSCs were identified in whole blood using immunophenotyping with flow cytometry. Signature cytokines were measured using the Luminex assay. The percentage of MDSCs among total CD45 positive cells and cytokine levels were analyzed in relation to transplantation outcomes.

Results: Among the 41 patients, the median age was 44 years (range: 18-62), and they were diagnosed with acute myeloid leukemia (41.46%), acute lymphoid leukemia (36.59%), myelodysplastic syndrome (7.32%), myeloproliferative neoplasm (12.20%), and lymphoma (2.44%). Peripheral blood stem cells were collected from human leukocyte antigen-matched related/unrelated donors (82.93%) and haploidentical donors (17.07%). Thirty-seven patients (90.24%) received myeloablative conditioning regimens. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitors plus methotrexate (68.29%) and post-transplant cyclophosphamide (31.71%). The median follow-up time was 188 days. Acute GVHD (aGVHD) occurred in 9 (21.95%) patients with a median onset time of 31 days, with only two patients experiencing grade II-IV aGVHD. The percentage of PMN-MDSC at day+14 and day+28 was significantly lower in aGVHD patients compared to non-GVHD patients (day+14: 0.0052% vs. 0.193%, p=0.003; day+28: 0.061% vs. 0.197%, p=0.018). Similarly, the CXCL2 level (a PMN-MDSC cytokine) was significantly lower in aGVHD patients. M-MDSC percentage and interleukin-10 (an M-MDSC cytokine) at day+28 were also significantly lower in aGVHD patients compared to non-GVHD patients (0.143% vs. 0.431%, p=0.023; 15.45 pg/ml vs. 25.07 pg/ml, p=0.011). Cytomegalovirus (CMV) reactivation was observed in 48.78% of patients, associated with increased M-MDSC at day+14 and decreased PMN-MDSC at day+14. For GVHD-free, relapse-free survival (GRFS) analysis, patients with high PMN-MDSC (≥0.15%) at day+14 had better outcomes than those with low PMN-MDSC (<0.15%) (95% CI: 1.102-9.706, p=0.030).

Conclusion: Delayed reconstitution of MDSCs at day+14 and day+28 post-allo-HSCT is associated with aGVHD occurrence. MDSCs could serve as potential surrogate markers for predicting aGVHD and CMV reactivation.
Mechanistic Insights into Cronobacter Sakazakii-Induced Neonatal Meningitis Via TLR4-NLRP3-Mediated Pyroptosis Pathway
Authors: Chen Zhenhui , Guo Xiaotong , Yu Lu , Shan Jiamin , Daixuan Zhou , Fan Hongying
Published: December 2024

Background: Cronobacter sakazakii (C. sakazakii) is a Gram-negative pathogen that invades the gastrointestinal tract and spreads hematogenously, leading to bacterial meningitis in premature and low-birth-weight neonates, posing a significant threat to neonatal health. However, the exact mechanisms by which C. sakazakii breaches the blood-brain barrier (BBB) and induces inflammation remain poorly understood. This study aims to elucidate the signaling pathways underlying C. sakazakii-induced neonatal meningitis using in vitro and in vivo models.

Methods: We utilized human brain microvascular endothelial cells (HBMECs), BV2 microglia cells, C57BL/6 neonatal mice, and NLRP3-/- mice to establish models of C. sakazakii-induced meningitis. In vitro assays comprised cell adhesion and invasion experiments, transmembrane resistance measurements, immunofluorescence to assess tight junctions, flow cytometry to evaluate HBMEC cell viability, and Western blot to examine changes in pyroptosis-related proteins in BV2 cells. In vivo experiments involved assessing C. sakazakii penetration through the BBB by cerebrospinal fluid (CSF) plating, immunohistochemistry for Neun protein expression in brain tissue, and Western blot for changes in pyroptosis-related proteins in brain tissue.

Results: Our in vitro findings demonstrated that C. sakazakii adheres to and invades HBMECs, reducing transmembrane resistance and disrupting tight junctions. This bacterial action induced pyroptosis in BV2 cells. In vivo experiments showed that C. sakazakii crosses the BBB, colonizes the CSF, and induces meningitis in neonatal mice. The mechanism proposed involves C. sakazakii-stimulated expression of TLR4 on the cell surface, activation of MyD88, and subsequent nuclear translocation of NF-κB, which induces the expression of NLRP3 inflammasome-related proteins. This leads to the activation of GSDMD, induces pyroptosis, and the subsequent release of the inflammatory cytokine IL-1β, culminating in the development of meningitis.

Conclusion: This study reveals that C. sakazakii disrupts tight junction proteins and breaches the BBB, activating the TLR4-NLRP3-mediated pyroptosis pathway in the brain. This mechanism induces pyroptosis and the release of the inflammatory cytokine IL-1β, ultimately leading to the induction of neonatal meningitis.
Heparin-PEAR1 Interaction Contributes to Platelet Activation By HIT Antibodies
Authors: Buka Richard John , Martin Eleyna , Lamerton Rachel E , Lagonotte Hugo , Rollin Jérôme , Gruel Yves , Calvert Anthony , Poles Anthony , Watson Stephen P , Nicolson Phillip LR , Montague Samantha J
Published: December 2024

Introduction

Heparin is a negatively charged, heavily sulfated polysaccharide that is used in medicine as a highly effective anticoagulant. In about 1% of patients who receive unfractionated heparin, heparin-induced thrombocytopenia (HIT) can occur. This is a disorder characterized by an intensely prothrombotic phenotype and thrombocytopenia that typically occurs 5-10 days after heparin exposure. In HIT, heparin binds to positively charged platelet factor 4 (PF4), exposing neoepitopes on PF4 to which heparin-dependent anti-PF4 antibodies can bind. This results in immune complexes which activate platelets through the low affinity Fc receptor, FcγRIIA. Recently, heparin was shown to activate platelets by binding to platelet endothelial aggregation receptor 1 (PEAR1). We therefore hypothesized that heparin itself may have a role in platelet activation in HIT in cooperation with activation through FcγRIIA.

Methods

We assessed activation of healthy donor washed platelets (2 x 108/mL) to the HIT-like monoclonal antibody (mAb) 5B9 and HIT sera in the presence of heparin by light transmission aggregometry. Experiments were performed in the presence or absence of the PEAR1 nanobody, Nb138, which was raised against the heparin-binding domain of PEAR1.

Results

Heparin (0.5 IU/mL) but not the HIT-like mAb 5B9 (20 µg/mL) stimulated slow and sustained aggregation of washed platelets with a second, more rapid phase at ~20 min. The response to heparin was blocked by the PEAR1 nanobody, Nb138 (100 nM). In contrast, the combination of heparin and mAb 5B9 stimulated robust aggregation of washed platelets within 15 min (n=7). In 3/7 donors, the response was blocked by Nb138 and was delayed by over 30 seconds in two others. We then tested the effect of Nb138 on two HIT sera that also induce strong activation of platelets in the presence of heparin. Nb138 delayed aggregation to the first HIT serum in all 7 donors. Nb138 blocked aggregation to the second HIT serum in 4 donors and significantly delayed aggregation in 2 others.

Conclusions

The present results demonstrate that the platelet heparin receptor, PEAR1, potentiates the response to HIT-like mAb and HIT sera and that this is an important variable in diagnostic assays using HIT sera. Further studies are required to establish whether activation of PEAR1 contributes to the pathogenesis of HIT and whether this is due solely to binding of heparin to PEAR1 or to binding of heparin to PEAR1 when present in an immune complex.

Acknowledgements

RJB is supported by a British Heart Foundation Accelerator Award (AA/18/2/34218) and SJM by a British Heart Foundation Project grant (PG/23/11230). SPW holds a BHF Chair (CH03/003).
L-Arginine Reinforces NK Cell-Mediated GVL Effect in Bone Marrow of AML Patients with Early Relapse Post-Allo-HSCT
Authors: Wang Dongyao , Yuan Chuang , Wu Yue , Chen Xingchi , Sun Guangyu , Huang Aijie , Zhu Xiaoyu , Wei Haiming
Published: December 2024

Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow-derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. Using high-resolution mass spectrometry, we demonstrated that the level of L-arginine decreased in the bone marrow and was associated with BMNK cell paucity and dysfunction in these AML patients. In addition, highly expressed arginase-1 in M2 macrophages induced L-arginine deficiency in the bone marrow microenvironment and suppressed mitochondrial oxidative phosphorylation and cytotoxicity of BMNK cells. Additionally, L-arginine deficiency triggered the formation of TFEB-containing transcriptional condensates, and induced liquid-liquid phase separation of TFEB, which resulted in abnormal autophagy and apoptosis of BMNK cells. Furthermore, the supplementation with L-arginine restored NK cell-mediated anti-leukemic responses in the leukemia xenograft mouse model and patient-derived xenografted (PDX) model. Thus, our study reveals a mechanism through which L-arginine deficiency compromises NK cells, highlighting the potential of L-arginine supplementation to improve NK cell-based cancer treatments.
The Influence of Seasonal Variation on Patients with Pulmonary Embolism: A Four-Year Retrospective Analysis
Authors: El-Jabali Aseel , Abdullah Khaled M , Huynh Nam , Johnson Alexa , Mahmood Omar
Published: December 2024

Rationale

The seasonal impact on pulmonary embolism (PE) remains an unexplored topic in prior literature in the United States. In this study, we explore the national inpatient sample (NIS) to determine how seasonal variation may impact such patients. We evaluated clinical outcomes such as all-cause mortality, length of stay, total charges, acute kidney injury, and myocardial infarction to enhance our understanding of its collective impact.

Methods

We analyzed data from the 2016-2019 NIS to identify patients admitted with a principal diagnosis of PE. Patients were stratified based on season. Categorical variables were compared using chi-square tests and continuous variables with independent samples t-testing. To adjust for potential confounding variables, we employed logistic and linear regression models. Confounders were selected through a univariate screen with a p value cutoff of less than 0.1. Additionally, the Charlson comorbidity index was utilized to account for the presence of comorbid conditions to gauge disease severity.

Results

In our analysis, we identified a total of 750,030 hospitalizations (weighted) with a principal diagnosis of PE as shown in Figure 1. The seasonal and monthly admission rates are outlined in Figure 2. There was a statistically significant difference in all-cause mortality (odds ratio [OR]: 1.09, p-value=0.046) during winter compared to summer. There was a statistically significant increase in acute myocardial infarction injury (odds ratio [OR]: 1.06, p-value=0.034), acute kidney injury (odds ratio [OR]: 1.05, p-value=0.044), and total charges prior to deduction (adjusted coefficient: $2,186, p-value<0.001) during fall compared to spring. There was a statistically significant increase in length of stay (adjusted coefficient: 0.11 Days, p-value=0.002) and sepsis (odds ratio [OR]: 1.15, p-value=0.032) during winter compared to spring.

Conclusions

Compared to patients admitted during spring or summer, patients with PE admitted during the winter or fall were associated with a longer length of stay and higher total charges in addition to increased risk of all-cause mortality, acute myocardial infarction, acute kidney injury, and sepsis. These findings could be explained by several reasons including increased incidence of infections in winter leading to critical illness, colder temperatures increasing blood viscosity, abnormal coagulation due to platelet and coagulation factor dysfunction, and reduced mobility during winter increasing risk of venous thromboembolism. Literature reflects correlations between winter and increased cardiovascular complications which increases risk for pulmonary embolisms.
Entirely Venetoclax-Based Nonintensive Treatment Regimen for Newly Diagnosed NPM1-Mutated Acute Myeloid Leukemia in the ELN Favorable-Risk Group
Authors: Dou Xueqing , Chen Suning , Wu Depei
Published: December 2024

The NPM1 mutation is one of the most common mutation types in acute myeloid leukemia (AML) and has shown a good response to venetoclax-based treatment. However, there are currently no prospective clinical trials for a nonintensive treatment regimen that is entirely venetoclax-based in NPM1-mutated AML. We conducted a single-arm, multicenter clinical study of venetoclax in combination with hypomethylating agents (decitabine or azacitidine) for the treatment of newly diagnosed NPM1-mutated AML in the ELN favorable risk group.

A total of 14 patients, including 9 males and 5 females, have been enrolled from 4 medical centers. The median age is 57 years (range, 30-76), and 12 patients were fit, while 2 were unfit. All the patients were diagnosed as AML according to the WHO 2022 criteria, while 11 cases were diagnosed with AML, 1 case with MDS-EB1, and 2 cases with CMML according to ELN 2022 diagnostic criteria. Twelve (85.7%) had NPM1 type A transcripts, 1 (7.1%) had type B, and 1 (7.1%) had a rare type. None of the patients had high-risk karyotypes, but 6 (42.9%) patients had recurrent MDS-related changes (MRCs).

The median follow-up time was 3.0 months (range, 0.5-25.0), with a median of 3 (range, 0-11) treatment cycles completed. All 12 patients who completed at least 1 treatment cycle achieved a CR/CRi rate of 100% after just 1 cycle. Of these patients, 9 (75%) achieved bone marrow (BM) molecular MRD-negative remission after a maximum of 4 treatment cycles. The median number of cycles to achieve molecular negativity was 2 (range, 1-4), with a median time to molecular negativity of 2 months (range, 1-7).

One patient experienced molecular relapse and had to withdraw from the cohort after 10 treatment cycles, while another patient had to discontinue due to severe infection. In general, NPM1-mutated patients in a favorable risk group who received a venetoclax-based nonintensive treatment regimen were able to achieve early BM molecular remission, though longer-term relapse outcomes remain to be seen.
Prior ASCT Has a Negative Impact on Outcomes in Relapsed/Refractory Multiple Myeloma Patients after BCMA CAR-T Therapy
Authors: Jin Chunxiang , Chen Rongrong , Fu Shan , Chang Alex H. , Huang He , Hu Yongxian
Published: December 2024

Background

Despite the promising efficacy of BCMA CAR-T cell therapy in relapsed or refractory multiple myeloma (R/RMM), some patients relapse after initially responding to the treatment. Analyzing risk factors and proposing refined CAR-T cell therapy strategies is crucial to improving the prognosis of these patients.

Methods

From July 30, 2018, to September 27, 2023, 141 R/RMM patients who were receiving BCMA CAR-T therapy were enrolled. Logistic regression, Cox regression and competing risk analyses were employed to identify risk factors associated with the prognosis. Flow cytometry was conducted to measure the proportion of CAR-T cells within the total T cell population, monitoring the post-infusion dynamics of CAR-T cells.

Results

During the median follow-up of 20.2 months, the objective response rate (ORR) was 94.8%, with 50.7% of patients achieving a complete response (CR). The median progression free survival (PFS) was 15.2 months (95% CI: 7.6-22.8). Prior autologous stem cell transplantation (ASCT) was associated with lower CR rate (RR, 0.352 [95% CI: 0.149-0.830]; P = 0.017). Among 68 CR cases, patients with extramedullary disease (HR, 2.381 [95% CI: 1.108-5.116]; P = 0.026), and prior treatment with ASCT (HR, 3.622 [95% CI: 1.420-9.237]; P = 0.007) had higher cumulative incidences of relapse (CIR). Extramedullary disease (HR, 2.095 [95% CI: 1.310-3.349]; P = 0.002) and prior ASCT (HR, 2.272 [95% CI: 1.314-3.929]; P = 0.003) were identified as risk factors for poor PFS. Extramedullary disease (HR, 2.033 [95% CI: 1.104-3.744]; P = 0.023) was significantly associated with shortened overall survival (OS).

Further investigation into potential mechanisms revealed that, among the 136 patients with expansion peak data, the peak of CAR-T cell expansion was significantly lower in the ASCT group compared to the non-ASCT group (74.8% vs. 89.8% , P < 0.001).

Conclusions

Our study found that prior ASCT and extramedullary disease serve as adverse prognostic factors in R/RMM patients undergoing BCMA CAR-T cell therapy. Research on the adverse effects of prior ASCT revealed it impaired the peak expansion of CAR-T cells in vivo. Moving forward, we will conduct an in-depth study on the mechanisms by which extramedullary disease affects CAR-T cell therapy outcomes in the near future.
Outpatient Maintenance Therapy of Venetoclax Combined with Azacitidine in Patients with Acute Myeloid Leukemia– a Real-World Retrospective Study
Authors: Nie Zi-Yuan , Ren Jinhai , Zhan Ying , Zhang Xiaolei , Li Jinao , Guo Xiaoling
Published: December 2024

Objective: With the increasing use of venetoclax in patients with acute myeloid leukemia (AML), several social issues have also emerged. Hence, we have proactively explored home treatment and outpatient follow-up management for AML patients undergoing venetoclax-based therapy. This approach aims to maintain treatment efficacy while facilitating patients' reintegration into society and reducing the burden of frequent hospitalizations.

Methods: A retrospective analysis was conducted on clinical data from AML patients who received venetoclax combined with azacitidine maintenance therapy at the outpatient department of Hebei Medical University Second Hospital from July 2021 to May 2024.We retrospectively studied the effectiveness and safety of this regimen.

Results: A total of 31 patients were included, with 17 males (54.8%) and 14 females (45.2%), and a median age of 61 years (range 21-85). Among the patients receiving outpatient VA maintenance therapy, the median follow-up was 11.9 months (range 2-35.1 ), and the median treatment period was 6 (range 2-24) cycles. The best overall response rate (ORR) was 92.6% (25/27). Of the 25 patients achieving the best response of CR/CRi, 3 patients experienced progression during outpatient VA treatment, and 5 patients had relapse, resulting in an overall relapse rate of 25.9% (7/27). A total of 26 patients were tested for minimal residual disease (MRD) during treatment, and the optimal MRD negative rate was 65.4% (17/26). The median relapse-free survival (RFS) for MRD-positive patients was 8.7 months, while it was not reached for MRD-negative patients. The most common adverse events (AE) was hematologic, and the most common non-hematologic AE was pulmonary infection. Among the 31 patients, 245 cycles of chemotherapy were administered, with grade 4 thrombocytopenia occurring in 4/19 patients (21%), neutropenia in 11/13 patients (85%), and anemia in 9/19 patients (47%). Compared to inpatient treatment, where thrombocytopenia (85%), neutropenia (100%), and anemia (100%) were more common, these rates were significantly reduced during outpatient treatment. The infection rate during inpatient treatment was 70%, while the average infection rate during outpatient VA maintenance therapy was 7%, a statistically significant difference (P < 0.05). The need for inpatient care due to infection was only 11 times.

Conclusions: Real-world data from our center indicate that venetoclax combined with azactidine is feasible for outpatient maintenance therapy. Patients who achieve MRD negativity can attain longer RFS and overall survival (OS), and both hematological and non-hematological toxicities are significantly reduced compared to inpatient treatment. Importantly, outpatient treatment of AML is more convenient and practical, allowing for broader implementation across various centers.
Prediction of Thrombosis in Polycythemia Vera：Development and Validation of a Globally Applicable “ANA Model”
Authors: Meng Qing , Zheng Yueyue , Liu Xiaohan , Liu Zhenyi , Jiang Xinwen , Ji Qingli , Hu Dongmei , Zhou Minran , Chunyan Chen , Ma Sai
Published: December 2024

Background:

Avoiding or reducing the occurrence of thrombus is still the focus of clinical management in patients with polycythemia vera. Although the conventional stratification system of thrombosis has improved clinical diagnosis and treatment, it still needs to be further improved.

Objectives:

The aim of this study is to develop a prediction model of thrombosis for polycythemia vera that is globally applicable with inexpensive and readily available predictors.

Methods:

We collected clinical information of 213 newly diagnosed patients with polycythemia vera from Qilu Hospital of Shandong University,then we randomly divided them into a training cohort and a validation cohort.Multivariable Cox regression analyses were conducted for the identification of thrombotic risk factors and model development.

Results:

We investigated data from 213 patients with polycythemia vera who were diagnosed according to the 2016 World Health Organization (WHO) criteria to identify covariates associated with thrombosis.Multivariable analyses indicated that age ≥60 years (hazard ratio [HR] 2.48, 95% CI 1.00-6.15, P=0.049),neutrophil count >8×10^9/L (HR 4.43, 95% CI 1.44-13.60, P=0.009),arterial thrombosis at or prior to diagnosis (HR 2.93, 95% CI 1.11-7.76, P =0.03) were independent risk factors of thrombosis. After assigning coefficient-weighted scores to those risk factor, a new thrombosis prediction model named “ANA model(age,neutrophil count,arterial thrombosis history-ANA)” was developed, classifying patients into low-risk and high-risk groups according to the final total score.Patients in the 2 groups had notably different thrombosis-free survival rates both in training cohort (P < .001) and validation cohort (P < .001). The ANA model outperformed the conventional model in discrimination power (C-statistic: 0.786 [95% CI 0.729-0.843] vs 0.759 [95% CI 0.718-0.800]).Moreover, the DCA curve of ANA model showed better net benefits compared to the conventional model especially when the threshold is between 12 .5%-50%, encouragingly, the incidence of thrombosis after polycythemia vera diagnosis is within this threshold range.

Conclusion:

This retrospective study confirmed the risk factors affecting thrombosis-free survival in PV.And the ANA model shows excellent accuracy and utility for thrombosis prediction in WHO-defined polycythemia vera.
Favorable Outcomes with Bridging Radiation Therapy Prior to Anti-CD19 Chimeric Antigen Receptor T-Cell CART in B Cell Lymphoma, a Report from Saudi Arabia
Authors: Hejab Amal , Alsuhaibani Khalid , Ahmed Syed Osman , Khafaga Yasser , Alshabanah Mohamed , Alahmari Ali , Hanbali Amr , Rasheed Walid , Alshaibani Alfadel , Chaudhri Naeem A. , Saad Ayman , Alotaibi Shaykhah , Alkhaldi Hanan , Alamer Abdullah , Alfayez Mansour , Alhayli Saud , Samarkandi Hadeel H , Elhassan Tusneem Ahmed M , Syed Farhatullah , Shaheen Marwan , Alfraih Feras Abdulaziz , Alotaibi Ahmad S. , Alsharif Fahad , Almohareb Fahad , Alzahrani Hazza A. , Aljurf Mahmoud , Elfakih Riad , Albabtain Abdulwahab
Published: December 2024

Objective:

To analyze the outcomes of B cell Lymphoma patients who received bridging Radiation therapy (XRT) prior to anti-CD19 CART axicabtagene ciloleucel (Axi-cel).

Methods:

Retrospective review of patients with relapsed/refractory B cell lymphoma who received anti-CD19 CART axicabtagene ciloleucel (Axi-cel), since its launch in King Faisal specialist Hospital and Research Center from February 2023 until April 2024. We analyzed the outcomes of patient who did vs did not receive bridging XRT pre- CAR-T lymphodepletion and infusion.

Results:

Fifty patients received Axi-cel in our institution during the study period, of whom, 13 patients received bridging XRT. The median follow up was 7.6 months or 228.5 days (25-475). The baseline characteristics were similar between the XRT & no XRT group. Median age was 53.5 years (17-78), 30 patients (60%) were males, ECOG was 1 or less in 43 pts (86%). CART was used as a third line or beyond in 9 patients (69%) in the XRT group, vs in 22 patients (59.5%) in the no XRT group.

The ORR & CR by day +90 were both 77% in the XRT group (10 of 13 pts). In the no XRT group, day +90 ORR was 51.4% (19 pts of 37) & CR was 43.2% (16 of 37 pts). At 12 months, the estimated PFS in the XRT group was 76%, vs. 47% in no XRT group (P=0.051). At 12 months, the estimated overall survival (OS) in the XRT group was 88.9%, vs. 72.1 % in the no XRT group (p= 0.299).

The median radiation dose was 28 Gy (range 9-30). The median number of fractions was 10 fractions (range 4-17). The most frequent radiation site was the mediastinum, n=5 (38.5%), of whom, 3 patients had Primary mediastinal B Lymphoma.

In the XRT group, all 13 patients (100%) experienced Cytokine Release syndrome CRS and all were grade I/II. In the no XRT group, 33 patients (89%) had CRS with 2 pts (6%) being grade III/IV CRS. Immune effector cells associated neurotoxicity syndrome ICANS occurred in 7 patients (54%) of the XRT group and in 12 patients in the no XRT group (32.4%). Grade III/IV ICANS was reported in 3 pts (43%) vs 8 pts (66.7%) in the XRT vs no XRT groups, respectively.

Conclusion:

Bridging Radiation therapy prior to anti-CD19 CART Axi-cel appears to be a promising strategy to improve outcomes. Further studies are needed to understand the interaction of XRT with CART, perhaps at the molecular level, with the potential benefit of avoiding further systemic therapy to preserve the fitness of T-cell prior to CAR-T infusion.
A Prospective Clinical Study of Zanubrutinib Combined with R-CHOP Regimen in the Treatment of Newly Diagnosed Double Expression Diffuse Large B-Cell Lymphoma
Authors: Wu Yingying , Zhang Ao , Zhang Liling , Cui Guohui , Liu Fang , Chen Zhichao , Chen Zhipeng , Zhang Lu , Liu Lin , He Wenjuan , Hu Yu , Xia Linghui , Fang Jun
Published: December 2024

Objective

To explore the efficacy and safety of Zanubrutinib combined with the R-CHOP regimen (ZR-CHOP) in the treatment of newly diagnosed diffuse large B-cell lymphoma with MYC/BCL2 double expression (DE-DLBCL).

Methods

This is a prospective single-arm clinical study. Patients aged 18-80 years with newly diagnosed DE-DLBCL were enrolled and treated with 6 cycles of ZR-CHOP plus 2 cycles of rituximab. The immunohistochemical criteria for DE-DLBCL are MYC expression of 40% or higher, and BCL2 expression of 50% or higher. High-grade B-cell lymphoma with MYC and BCL2 rearrangements was excluded. Treatment response was evaluated using PET/CT after 4 cycles and 6 cycles.

Results

From April 15, 2022, to July 25, 2024, 15 patients were enrolled in the study. The median age was 56 years (range 35-70), and 13 patients (86.7%) were female. At diagnosis, 9 patients (60.0%) were in Ann Arbor stage III-IV, 5 patients (33.3%) had an ECOG score of 2 or higher, and 5 patients (33.3%) had an IPI score of 3 or higher. Additionally, 6 patients (40.0%) presented with B symptoms, 5 patients (33.3%) had extra nodal involvement, and 10 patients (66.7%) had the non-GCB subtype. All 15 patients (100%) completed 4 cycles of treatment, and 13 patients (86.67%) completed 6 cycles of treatment. The overall response rate (ORR) was 100.0%, with 13 patients (86.67%) achieving complete response (CR) and 2 patients (13.33%) achieving partial response (PR). As of the follow-up date on July 25, 2024, the median follow-up duration was 15.8 months (range 4.0-27.8). The 1-year estimated PFS and overall survival (OS) rates were both 92.3%, while the 2-year estimated PFS and OS rates were 69.2% and 92.3% respectively. One patient relapsed after 18.9 months of induced remission, and one patient died from accident. Common adverse events of grade 3-4 included anemia (46.7%), leukopenia (40.0%), neutropenia (46.7%), thrombocytopenia (33.3%), and pulmonary infection (26.7%, all are grade 3). Febrile neutropenia, atrial fibrillation and severe bleeding were not observed.

Conclusion

Zanubrutinib combined with R-CHOP regimen demonstrates a significant efficacy and good safety in the treatment of newly diagnosed DE-DLBCL, warranting further exploration.
Outcome in Patients with Multiple Myeloma Receiving Salvage Therapy after Exposure to BCMA-Targeted CAR-T Therapy
Authors: Jiang Yiwen , Gao Wen , Zhu Honghu , Chen Wenming
Published: December 2024

Novel immunotherapies such as B-cell maturation antigen (BCMA) targeted directed chimeric antigen receptor T-cell (CAR T) therapy has shown favorable responses in patients with relapsed/refractory multiple myeloma (R/RMM). Despite their remarkable efficacy, disease progression still occurs in some patients with limited treatment options.

To investigate optimal strategies of subsequent therapies. We retrospectively performed a comprehensive analysis of the clinical characteristics, post-CAR T treatments, and outcomes of 31 patients from our center who experienced disease progression following BCMA-directed CAR T cell therapy.

A total of 48 patients with R/RMM were treated with BCMA-directed CAR-T in our study. 31 patients suffered progressive disease (PD) with 5 (range 2~9) prior lines of therapy and received subsequent salvage therapies, including one patient who lacked of following treatment details after relapse post BCMA-directed CAR T therapy but had available survival data. There was a median time of 41.5 months (7.7- 175.8 months) between the time of MM diagnosis and CAR-T infusion.

The median overall survival from relapse after BCMA CAR-T for the cohort of 31 patients was 19.5 months (95% confidence interval [CI], 15.7-NE months). Among them, 13 (42%) patients suffered death, although receiving antimyeloma treatment after PD. The overall response rate (ORR) and the median progression-free survival (PFS) for first line salvage therapy after BCMA CAR-T relapse was 46.7% and 5.5 months (95% CI 3.9-27.5 months). Carfilzomib-containing therapy is the most commonly used first line salvage treatment, with the highest ORR of 72.7%, demonstrating a median PFS that was not reached (95% CI 2.03months-NE) and no patients suffered death. Overall, a total of 78 salvage treatment lines were used among the 30 patients at any time post-CAR T relapse with an ORR of 39.4%.

This analysis indicates that Carfilzomib-containing therapy after previous BCMA-targeted treatments offers clinical benefit with higher objective response rates in patients who have few other options.