bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-World Study of Glofitamab for the Treatment of Relapse or Refractory Diffuse Large B-Cell Lymphoma in East China
Authors: Tong Jiefeng , Jiang Songfu , Luo Qian , Qian Shanhu , Ouyang Guifang , Lai Yanli , Jiang Huifang , Jiang Yuxia , Zeng Hui , Ye Baodong , Jiang Wei , Qian Wenbin
Published: December 2024

Introduction: Glofitamab is a CD20×CD3 bispecific monoclonal antibody, with demonstrated efficacy and manageable safety for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in clinical studies. In November 2023, glofitamab was approved by the China National Medical Products Administration (NMPA) for the treatment of R/R DLBCL. This study aimed to evaluate the efficacy and safety of glofitamab in the Chinese population in a real-world setting.

Methods: We retrospectively enrolled R/R DLBCL patients who received at least 1 dose of glofitamab in 7 medical centers in east China from November 2023 to June 2024. We reported the objective response rate (ORR) and complete response (CR) rate based on Lugano criteria, and cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS) based on ASTCT consensus 2019.

Results: A total of 28 patients were included. At baseline (initiation of obinutuzumab pretreatment), the median age of patients was 63 years (range, 35-83), with 18 patients (64.3%) aged 60 years or older. 17 (60.7%) patients were male. 26 (92.9%) patients were diagnosed with DLBCL, not otherwise specified (including 2 primary central nervous system lymphoma (PCNSL) patients), 1 with high-grade B-cell lymphoma, and 1 with transformed follicular lymphoma. 10 (35.7%) patients had an ECOG score of 2-4, and 24 patients with Ann-Arbor stages III-IV. The median number of previous therapies was 2.5 (range, 1-6) and 82.1% (n=23) patients received 2 or more lines of previous therapies. 4 (14.3%) patients underwent autologous stem cell transplantation and 6 (21.4%) patients received CAR-T cell therapy. 10 (35.7%) patients had relapsed disease, and 12 (42.9%) were refractory to any prior therapy.

Median follow up was 3 months. Patients received a median of 3 (1-12) cycles of glofitamab treatment and 16 patients were still under treatment atdata cutoff. Of the 24 patients evaluable for response, the ORR and CR rate was 62.5% and 25%, respectively. 2 PCNSL patients all responded. Median PFS and OS were not reached at data cutoff. The most common adverse event was CRS, which occurred in 39.3% of the patients with 2 patients having grade 3 events. No grade 4 CRS appeared. 1 patient developed grade 4 ICANS and was consequently deceased.

Conclusions: This real-word study demonstrated that glofitamab has a consistent efficacy in Chinese R/R DLBCL patients as in previous clinical studies, with a lower incidence of adverse events. The actual CR rate might be higher since most patients were still under treatment.
Clinical Analysis of 15 Cases of Extramedullary Relapse of Acute B-Lymphoblastic Leukemia Post-Transplant Treated with CART Combined with Radiotherapy
Authors: Zheng Ruyue , Yan Hong , Li Biyi , Lin Yuehui , Liu Shuangyou , An Lihong , Deng Biping , Zhang Jun , Tong Chunrong , Wu Tong , Zhao Defeng
Published: December 2024

Background:

Chimeric Antigen Receptor T-cell (CART) therapy has become an important approach for treating acute B-lymphoblastic leukemia (B-ALL) that relapses after hematopoietic stem cell transplantation (HSCT). Radiotherapy may aid in treating leukemia with extramedullary infiltration. Combining CART with radiotherapy might enhance the treatment of extramedullary relapse of B-ALL post-transplant.

Objective:

To investigate whether CART combined with radiotherapy can improve outcomes in treating extramedullary relapse of B-ALL post-transplant.

Methods:

This study included 15 cases of extramedullary relapse of B-ALL post-HSCT treated at Beijing Boren Hospital from August 2017 to October 2023. The median age was 31.5 years (range: 12-71 years), with 7 males (46.7%) and 8 females (53.3%). Nine patients (60%) had concurrent bone marrow relapse before treatment. All patients received CART combined with local radiotherapy targeting sites of extramedullary infiltration. The follow-up period ended on July 1, 2024, with a median follow-up duration of 413 days. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints.

Results:

Among the 15 patients treated with CART combined with local radiotherapy, 11 achieved complete remission in both bone marrow and extramedullary sites, yielding a remission rate of 73.3%. By the end of the follow-up period, 6 patients (54.5%) had relapsed, while 5 remained in continuous remission (45.5%). The median PFS of 1428 days. The 1-year PFS rate is 62.3%, and the 2-year PFS rate is 51.9%. The median OS not yet reached. The 1-year OS rate is 100.0%, and the 2-year OS rate is 83.3%.

Conclusions:

CART is an effective treatment method for post-transplant relapsed acute B-lymphoblastic leukemia.

Combining CART with radiotherapy may help improve the remission rates for post-transplant extramedullary relapsed acute B-lymphoblastic leukemia.
Integration of Gene Mutations in Risk Prognostication for Watch-and-Wait Follicular Lymphoma Patients Initiating First-Line Treatment
Authors: Xu Tianyuan , Wang Nan , Sun Rui , Li Ruichi , Fu Di , Zhao Yan , Xu Pengpeng , Cheng Shu , Wang Li , Tang Wei , Zheng Zhong , Zhao Weili
Published: December 2024

Introduction

Follicular lymphoma (FL) patients with low tumor burden at diagnosis frequently undergo the watch-and-wait (W&W) strategy. The study aimed to facilitate risk assessment in predicting the time to lymphoma treatment (TLT) for W&W patients through an integrated analysis of clinical factors and genetic mutations.

Methods

A retrospective analysis was conducted on 214 FL patients managed with W&W between 2016 and 2023. Among all, 184 patients underwent targeted sequencing. The median follow-up was 30.4 months (IQR 21.4-41.9, range 6.4-95.8). A clinic-genetic model was developed using the multivariate Cox proportional hazards method.

Results

The clinic-genetic model incorporated two clinical factors (bone marrow involvement and elevated β2-MG) and three gene mutations (KMT2D, EP300, and TP53). Each factor was assigned one point based on its relative importance, as indicated by the z-Wald values from the Cox model. The total score for each patient was calculated as the sum of these points. Since this model includes two clinical factors overlapping with those in PRIMA-PI, along with three additional gene mutations, we termed it m3-PRIMA-PI. Patients were stratified into three risk groups based on their scores: low (score 0-1, n=127, 69.0%), intermediate (score 2, n=40, 21.7%), and high (score 3-5, n=17, 9.2%). The probabilities of treatment initiation at one year were 11.0% (95% CI, 5.2%-16.5%), 26.0% (95% CI, 10.7%-38.7%), and 54.3% (95% CI, 22.3%-73.1%); and at two years were 29.4% (95% CI, 20.2%-37.5%), 49.8% (95% CI, 31.1%-63.4%), and 93.5% (95% CI, 56.7%-99.0%), respectively. The predictive performance for TLT was superior with m3-PRIMA-PI, achieving a C-index of 0.66 (95% CI, 0.63-0.69), compared to established indexes like FLIPI (C-index 0.59, 95% CI 0.56-0.62) and FLIPI2 (C-index 0.59, 95% CI 0.55-0.61).

Conclusion

Integration of genetic mutations with clinical risk factors presents a promising tool for risk stratification in W&W FL patients.
UHRF1 Is a Promising Therapy Target in Aggressive Mantle Cell Lymphoma
Authors: Yang Yuan , Yang Ping , Zhang Weilong , Wang Jing , Chen Yingtong , Li Chunyuan , Jing Hongmei
Published: December 2024

Backgrounds: Therapy resistance and recurrent relapses continue to be significant challenge in the management of mantle cell lymphoma (MCL), which cannot be explained by genetic alone. Discovering drugs that can successfully correct epigenetic changes is a promising strategy to address the inadequate therapeutic response in MCL. Epigenetic regulator ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is aberrantly expressed in many human diseases and correlated with disease progression, but its function in MCL remains unclear.

Methods: Through integrative analyses of the gene-expression profile and clinical parameters, UHRF1 was screened as a potential epigenetic therapy target in MCL patients. The pro-tumor function of UHRF1 was demonstrated by in vitro and in vivo experiment. The anti-tumor effect and safety of CM272, a functional inhibitor of UHRF1, was assessed in MCL xenograft animal model.

Results: UHRF1 was highly expressed and positively correlated with Ki67 expression in MCL tissues samples. UHRF1-high expression predicted poor prognosis in MCL patients. Knockdown of UHRF1 inhibited MCL cell proliferation, migration and invasion whereas induced MCL cell apoptosis and cell cycle arrest. Administration of mice with CM272 significantly inhibited MCL progression and no obvious treatment-related side effects in liver and renal.

Conclusion: Our study demonstrated that UHRF1 signaling involved in MCL tumorigenesis and progression, and provides a novel insight for therapeutic interventions in MCL by targeting UHRF1.
The Parous Female Donor Is Not Inferior to Young Male Donor for Haploidentical Peripheral Blood Stem Cell Transplantation with Low-Dose ATG Plus Low-Dose Ptcy-Based Regimen for Gvhd Prophylaxis
Authors: Cao Jingjing , Huang Chongmei , Li Xingying , Cai Yu , Zhou Kun , Yang Jun , Xu Xiaowei , Qiu Huiying , Niu Jiahua , Zhang Ying , Xia Xinxin , Wei Yu , Shen Chang , Tong Yin , Dong Baoxia , Wan Liping , Song Xianmin
Published: December 2024

The haploidentical donor is diverse and an optimal donor is critical for the survival of patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Under anti-thymocyte (ATG) or post-transplant cyclophosphamide (PTCy) alone-based graft-versus-host disease (GVHD) prophylaxis for haplo-HSCT, young male donor is always preferred due to a lower non-relapse mortality (NRM) and better survival, while mother or collateral relative donor is usually the last resort. The combination regimens of anti-thymocyte (ATG) and post-transplant cyclophosphamide (PTCy) in haplo-HSCT were more and more utilized due to their promising efficiencies for graft-versus-host disease (GVHD) prophylaxis, however, the impact of different donors on patient outcomes under the combination regimens remains to be unclear. Therefore, we performed a retrospective study for patients undergoing haplo-HSCT with a low-dose ATG plus low-dose PCTy-based regimen for GVHD prophylaxis at our center. The study enrolled 262 patients, whose donors were categorized into the young male donor group (age <30 years, n=74), non-parous female donor group (n=25), older male donor group (age ≥30 years, n=117), and parous female donor group (n=46). For the whole cohort, the cumulative incidences (CIs) of grade Ⅱ-Ⅳ acute GVHD (aGVHD) at 180 days and moderate-to-severe chronic GVHD at 2 years after transplantation were 11.45% (95% CI, 7.95%-15.65%) and 19.04% (95% CI, 14.38%-24.22%). In multivariate analysis, the parous female donor had a strong trend to increase the risk of grade Ⅱ-Ⅳ aGVHD (HR, 3.32, 95% CI, 0.99-11.10; P=0.051) and significantly decreased the risk of relapse (HR, 0.14, 95% CI, 0.03-0.63; P=0.010). In the parous female donor group, the 2-year OS, and RFS were relatively higher with both of 73.37% (95% CI, 61.49%-87.54%). The results suggested that the parous female donors could reduce the risk of relapse and might improve survival under the combination regimen for GVHD prophylaxis.
Association between Lipid Profile and Molecular Signature of Monocytes in Patients with Lower-Risk MDS
Authors: Kotsianidis Ioannis , Tasis Athanasios , Rimpa Christina Maria , Kymparidou Chrysa , Hatzikirou Haralampos , Mitroulis Ioannis
Published: December 2024

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with accelerated atherosclerosis and a 40% increased risk of cardiovascular disease (CVD), linked to increased innate immune cell activation (Jaiswal et al., 2017). Monocytes are critical players in CVD, due to their infiltration in atherosclerotic plaques and their differentiation to foam cells, whereas dyslipidemia is linked to long-term inflammatory activity of monocytes (Mitroulis et al., 2023). Herein, we sought to investigate whether lipid profile is associated with the molecular signature of peripheral monocytes in patients with lower-risk MDS (LR-MDS; i.e., IPSS-R <3.5).

To do so, peripheral blood samples were collected from 11 patients with LR-MDS (MDS with low blasts n=9, MDS with SF3B1 n=2). RNA sequencing performed in isolated monocytes. Differential expression analysis was performed utilizing the edgeR Bioconductor R package. Statistically significant differentially expressed genes (DEGs) were identified based on a FDR threshold of <0.1 and a logFC threshold of >0.58. Gene set enrichment analysis (GSEA) was performed, using well-annotated Hallmark gene sets from the Molecular Signatures Database (MSigDB) as input.

Principal Component Analysis (PCA) demonstrated a clear segregation of samples into two distinct subgroups (Subgroup_1 and _2). Differential expression analysis identified 483 DEGs upregulated in Subgroup_1 and 1035 DEGs upregulated in Subgroup_2. Pathway enrichment analysis revealed an enrichment of genes associated with oxidative phosphorylation (OXPHOS) and TNF-α signaling in Subgroup_1. Of note, Subgroup_1 exhibited an upregulation of the cholesterol homeostasis pathway, which was in line with the significant increase in total and non-HDL cholesterol and triglycerides in this group. Moreover, unsupervised clustering based on the expression levels of genes involved in inflammasome-related signatures (Basiorka et al., 2016), led to clear separation of the two groups, with Subgroup_1 displaying significantly higher expression levels of the inflammasome-related genes NRLP3 and PYCARD.

Herein, we show that lower lipid levels in LR-MDS patients is associated with a suppressed inflammatory signature in peripheral monocytes and a down-regulation in the expression of genes related to inflammasome. Considering the link between CVD and CHIP, our findings show that early administration of lipid-lowering regimens can be beneficial in patients with LR-MDS, suppressing the inflammatory potential of monocytes, a critical cell population in CVD.

Acknowledgements: Supported by the UAE-NIH Collaborative Research grant AJF-NIH-25-KU
Exploring Prognostic Factors of Venetoclax Combined with Azacitidine in Unfit AML Based on Real-World Data from a Chinese Population
Authors: Zheng Boyue , JIyi FU , Wu Jiafei , Yu Wang , Wang Jun , Jiang Chuanyan , Huan Wang , Haiqing Yang , Yang Xi , Zheng Hong , Hui Li
Published: December 2024

Background: Venetoclax combined with azacitidine (VA) has become the standard first-line treatment for elderly unfit acute myeloid leukemia (AML) patients. In the era of targeted therapy, it is essential to explore new prognostic factors.

Objective: To investigate the factors influencing overall survival (OS) in newly diagnosed unfit AML (ND unfit AML) patients induced with VA, and in unfit AML patients who achieved composite complete remission (cCR unfit AML) and received VA maintenance therapy.

Methods: We retrospectively analyzed the clinical data of 112 ND unfit AML at Sichuan Provincial People's Hospital from January 2022 to May 2024. We observed treatment efficacy and survival outcomes, and utilized the COX regression model for statistical analysis to identify influencing factors.

Results: The median age of the included patients was 68 years (range: 43-86), with 57 male patients (51%). Eleven patients (10%) had secondary AML, and 81 patients (72%) had an ECOG score of 0-1. According to ELN-2022 cytogenetic risk stratification, 21 patients (19%) were low-risk, 44 patients (39%) were intermediate-risk, and 47 patients (42%) were high-risk. The cCR rate in ND unfit AML patients was 79% (including 24% CR and 55% CRi), with an MRD negativity rate of 47%. Seven patients (6%) received allogeneic transplantation after remission. The median follow-up was 16.2 months (95% CI: 14.7-17.7), and the median OS was 12.9 months (95% CI: 8.0-17.8). Patients who achieved cCR had a significantly longer median OS compared to incomplete remission (IR) (42.4 months vs. 2.0 months, p<0.0001). There was no significant difference in survival curves among different ELN risk stratifications (NR vs. 12.1 months vs. 11.2 months, p = 0.3150). Among cCR unfit AML patients, those with MRD negativity had significantly better OS compared to those without MRD negativity (NR vs. 8.7 months, p<0.0001). COX regression analysis indicated that IR, MRD positivity, t(8;21)(q22;q22)/AML1-ETO positivity, U2AF1 mutation, and post-treatment ECOG (＞1) were independent adverse prognostic factors in ND unfit AML patients. For cCR unfit AML patients, MRD positivity, U2AF1 mutation, and post-treatment ECOG (＞1) were independent adverse prognostic factors.

Conclusion: The VA regimen is effective in treating unfit AML patients. Patient OS is influenced by treatment response, performance status, and cytogenetic factors.
Evaluation of Obexelimab in Patients with Warm Autoimmune Hemolytic Anemia: Preliminary Results from an Open Label Phase 2 Study
Authors: Fattizzo Bruno , Evans Gillian , Wells Audrey , Poma Allen , Quinn Shauna , Zhang Dale , Yamashita Mason , Fischer Tanya Z.
Published: December 2024

Introduction. Warm autoimmune hemolytic anemia (wAIHA) is a rare, serious autoimmune disorder characterized by the binding of autoantibodies to red blood cells (RBCs) at core body temperature (37°C), leading to hemolysis and signs/symptoms of anemia, including severe fatigue, dyspnea, pallor, and jaundice. There are currently no FDA-approved treatments for wAIHA, and anemia is typically managed with corticosteroids. Relapse is common and long-term steroid use carries significant risk of side effects and other complications. There is a need for new, safe and effective therapies. Obexelimab is a bifunctional, non-depleting humanized monoclonal antibody that binds CD19 and FcγRIIb to inhibit B-lineage cell activity. Obexelimab is an investigational product and not approved for any indication. Here we report on the safety and efficacy of obexelimab in an open-label Phase 2 study in patients with wAIHA (NCT05786573).

Methods. The ongoing, multicenter, open-label study will evaluate the safety, tolerability, pharmacokinetics (PK)/pharmacodynamic (PD), and efficacy (including improvement in hemoglobin (Hgb)) of obexelimab in patients with wAIHA. The study is expected to enroll 14 patients with primary or secondary wAIHA due to autoimmune disorders. Eligible patients are 18 years of age or older, have been clinically diagnosed with wAIHA for at least 3 months with documentation of a positive direct antiglobulin test and have failed at least 1 previous wAIHA therapy. Patients must have at least one sign/symptom of anemia with a hemoglobin level of ≥ 7 to < 10 g/dL on Day 1. Eligible patients self-administer obexelimab via weekly subcutaneous (SC) injections.

Results. Six patients have been enrolled to date. The median age at the time of enrollment was 70.5 years. Other demographics include: 5/6 (83.3%) of patients were female; 5/6 (83.3%) were white; 1/6 (16.7%) was Asian. All patients had a diagnosis of primary wAIHA, and the median disease duration was approximately 3 years. Median Hgb at baseline was 9.50 g/dL, and 4 patients were on background therapy (including glucocorticoids, EPO, mycophenolate) at the time they entered the study.

All 6 patients have been on study for a minimum of 10 weeks (range 10 - 24 weeks). Hemoglobin improvement from baseline have been observed in 3 of the 6 patients.

Four out of 6 patients (67%) experienced a total of 18 treatment emergent adverse events (TEAEs). 3 TEAEs were considered related, and all these were grade 1. There was one serious and not related event of cholecystitis. There were no discontinuations due to adverse events.

Conclusions. Data from the ongoing study suggests that obexelimab administered SC is well-tolerated and may provide improvement in Hgb and other biomarkers of anemia in patients with primary wAIHA, who have failed at least one prior therapy.
Inpatient Outcomes of Spontaneous Bacterial Peritonitis in Patients with Sickle Cell Disease
Authors: Dave Prashil , Uddin Anwar , Uddin Rahat , Ahad Afgal , Shastri Dipsa , Mahmoud Yasmin , Winer Andrew
Published: December 2024

Introduction: Spontaneous bacterial peritonitis (SBP) is a severe complication that can occur in patients with sickle cell disease (SCD), particularly those experiencing splenic dysfunction and portal hypertension. This condition is characterized by infection of the peritoneal cavity without an obvious source, often leading to significant morbidity and mortality. Using the nationwide database, this study evaluated inpatient outcomes associated with SBP in SCD patients.

Methods: The Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) was used to identify adult patients with SCD during 2016 - 2020 using ICD-10-CM codes (D57). ICD-10-CM codes were used to identify patients who had SBP. The primary outcomes were in-hospital mortality, length of stay (LOS), and hospital costs. The secondary outcomes included renal cancer, pancreatic cancer, acute liver failure, liver cirrhosis, hepatic steatosis, and hepatitis B and C. The association between spontaneous bacterial peritonitis and SCD was evaluated using survey-based multivariate logistic regression models for in-hospital mortality and secondary outcomes, Poisson regression for LOS, and a generalized linear model with gamma distribution and log link for hospitalization cost. Models were adjusted for age, sex, race and ethnicity, primary payer, Charlson comorbidity index, hospital bed size, hospital region, and hospital teaching status.

Results: A total of 899,610 SCD patients were identified as required hospitalization between 2016 and 2020 in the United States, and 320 (0.04%) of them had SBP. Inpatient mortality and length of stay were significantly higher in SCD patients with SBP compared to those without SBP (inpatient mortality: 11% vs 0.6%, adjusted OR: 5.27, 95% CI: 2.30 - 12.00, P < 0.001; length of stay: 11.5 vs 5.1 days, p = 0.033). SCD patients with SBP had an increased cost of hospitalization ($36,769 ± 12,018 vs $11,818 ± 105, P < 0.045). SCD patients with SBP had increased odds of having liver cirrhosis and acute liver failure (55% vs 1.1%, 17% vs 0.3%, respectively, p < 0.001).

Conclusion: This analysis shows thatwhile the incidence of SBP in this population is low, it is associated with significantly higher inpatient mortality, prolonged hospital stays, increased hospitalization costs, and elevated rates of hepatic complications. Further research is essential to explore the gastrointestinal complications arising from hepatic and splenic dysfunction in this cohort and identify any preventative strategies to mitigate these risks.
DDX3X Mutation Endow R-Loop-Dependent Lymphomagenesis
Authors: Xiong Jie , Cheng Shu , Cai Hua-man , Qiu Yu-Ran , Zhao Wei Li
Published: December 2024

RNA helicase DDX3X is generally implicated in inflammasome activation and anti-viral responses. We characterized the common features of scattered DDX3X mutation using molecular dynamic simulation and full-length crystallization, and extended the vital role of DDX3X as a pan-cancer mutation in Epstein-Barr virus (EBV) lytic gene-driven manner. DDX3X mutation was significantly related to impaired STING/IRF-7/IFN-α/β-mediated innate immunity, overexpression of EBV lytic gene BNLF2b, and increased formation of RNA-DNA hybrids R-loops. In Ddx3x449_450ET>DP conditional knock-in transgenic mice, BNLF2b overexpression induced R-loop accumulation, genomic instability, and abnormal proliferation of CD3-/CD19-/NK1.1+ cells, thereby promoting malignant progression. DNA-damaging agent etoposide enhanced γ-H2AX co-localizing with R-loops, heightened genomic instability beyond cellular tolerance, eventually triggering synthetic lethality in DDX3XmutBNLF2b+ tumors. These findings provide better understanding on functional interaction of DDX3X mutation with EBV to provoke R-loop-dependent oncogenesis, shedding new lights on pathogenic mechanism of EBV and future therapeutic approaches targeting R-loops in diseases involving RNA helicase alterations.
Transcriptional Profiling of Plasma Cells in AL Amyloidosis and Multiple Myeloma: A Single-Cell RNA Sequencing Approach
Authors: Kim Ka Young , Park Sung-Soo , Kim Na Yung , Lim Ji-Young , Lee Jung Yeon , Yun Sujin , Chung Yeun-Jun , Jung Seung-Hyun , Yoon Jae-Ho , Kim Hee-Je , Min Chang-Ki
Published: December 2024

Background

AL amyloidosis, characterized by the deposition of amyloid fibrils derived from monoclonal light chains, often results in multi-organ dysfunction. Timely diagnosis is crucial for effective management. The gold standard for AL amyloidosis diagnosis involves the demonstration of amyloid deposits by biopsy, usually in affected organs. Despite their potential co-occurrence between multiple myeloma (MM) and AL amyloidosis, distinguishing AL amyloidosis within the context of MM poses diagnostic challenges.

Method

By single-cell RNA sequencing (scRNA-seq), we investigated bone marrow aspirates of 8 treatment-naïve AL amyloidosis, 18 treatment-naïve MM. Publicly available scRNA-seq data of BM-MNCs from 23 healthy donors were used as normal control.

Results

Utilizing single-cell RNA sequencing, we identified 37 distinct subtypes of plasma cells, with the majority being MM-specific and showing patient-specific independence. In contrast, control and AL groups exhibited a more convergent pattern, comprising 1-2 plasma cell subsets. We discovered gene expression differences among plasma cells in control, AL, and MM groups. Through comparative analysis of up-regulated and down-regulated genes, we identified 2,342 potential candidates specific to AL amyloidosis, of which 1,598 were up-regulated and 744 were down-regulated. Focusing on tier-1 genes with possible driver mutations and confirming gene nature related to protein metabolism disorders, we selected 54 genes unique to AL amyloidosis compared to MM or healthy controls. To develop a transcriptional biomarker panel for AL amyloidosis, we further refined the selection to 31 genes that facilitated panel construction, including two housekeeping genes and 14 genes with the highest statistical significance for panel development QC. Ultimately, we assembled a transcriptome panel consisting of 47 genes, specific to the diagnosis of AL amyloidosis.

Conclusion

This panel has the potential to aid in the identification of patients with asymptomatic plasma cell dyscrasia who should undergo amyloidosis tissue testing. However, its validation status necessitates further assessment in a validation cohort.
5-y Follow-up of Combination of Ibrutinib, Obinutuzumab and Venetoclax for Patients with Newly Diagnosed Mantle Cell Lymphoma, the Oasis Trial
Authors: Tessoulin Benoit , Morschhauser Franck , Chiron David , Bouabdallah Krimo , Cartron Guillaume , Rossi Cedric , Milin Caroline , Fouillet Ludovic , Herbaux Charles , Tchernonog Emmanuelle , McCulloch Rory , Gastinne Thomas , Callanan Mary B. , Le Gouill Steven
Published: December 2024

Background:

Targeted therapies (such as Ibrutinib and Venetoclax) have improved Mantle Cell Lymphoma (MCL) patients' outcomes. OAsIs trial has evaluated the efficacy and toxicity of the Ibrutinib Obinutuzumab plus venetoclax combination in both R/R and untreated MCL patients (NCT02558816, Le Gouill et al. Blood 2021). In the present work, we updated the outcome of patients enrolled in OASIS trial, especially for patients with newly diagnosed MCL.

Methods:

The OASIS trial was a 3 arms multicenter prospective phase 1/2 trial. Arm A (n=9) enrolled R/R patients who were treated with Obinutuzumab (Obi, 1000mg) and Ibrutinib (Ibru, 560mg). Patients in Arm B (R/R; n=24) and C (newly diagnosed MCL; n=15) were treated with Obi+Ibru+Venetoclax (Ven, 400mg). Patients' characteristics have been described in the original manuscript.

Results:

In R/R cohorts A (n=9) and B (n=24), overall response rates were 89% and 71%, respectively. Median Follow-ups were 72 and 58 m, the 6-y PFS were 53% and 40%, respectively. No safety signals appeared during long term FU. Patients who progressed were treated with Bendamustine-containing regimen (6 out of 10) and one patient received Odronextamab and anti-CD22xCD3 bispecific antibodies.

For Cohort C (n=15), all patients presented with a medium or high-risk MIPI, the median follow-up was 61 m (48-68m). The overall response rate was 93%, with 87% of CR. Median PFS and DOR were not reached, the estimated 60m-PFS and DOR were 80%. Two patients prematurely discontinued, one early PD (after 4m) and one for Adverse Event (neuropathy after 9m). The early PD patient harbored no adverse event, especially no TP53 alteration. One patient with TP53 mutation is still experiencing disease control. One patient experienced atrial fibrillation and one patient had acute cardiac failure. Regarding infections, one patient died of a progressive multifocal leukoencephalopathy (PML) after the completion of treatment. Two patients prematurely discontinued the treatment, one patient had a PD at C4 and has subsequently been treated with R-CHOP, one patient relapsed after treatment completion and has been treated with Glofitamab. In all, 2 patients progressed and 1 died in arm C (PML), hence, the 5-y OS is 93%.

Conclusion:

The Ibrutinib-Venetoclax-Obinutuzumab triplet is associated with a highl and sustained disease control in newly diagnosed (5y-PFS of 80%) patients presenting with high risk-profiles. The anti-CD20+Ibrutinib vs anti-CD20+Ibrutinib+Venetoclax combinations are currently under investigation in OASIS-II trial (NCT04802590) for untreated patients with MCL and may represent a bona-fide alternative to Chemo-based treatments.
Comparison of Alternative Mayo Staging Classification Systems USED in LIGHT-Chain Amyloidosis
Authors: Laires Pedro A , Thompson Jeffrey , Catini Julia , Manwani Richa , Zhang Yu , Yang Feifei
Published: December 2024

Background: Light chain amyloidosis (AL), a rare, life-threatening disorder, is characterized by deposition of abnormal amyloid fibrils in various organs, notably the heart. Morbidity and mortality in AL patients are closely linked to the magnitude of heart involvement. The Mayo staging system is widely used for stratifying the severity and prognosis of patients with AL. The initial approach, developed in 2004 (Mayo 2004), was later revised into two separate approaches (Mayo 2004 European, Mayo 2012). Currently, no consensus exists on which staging system to use, with clinical trials utilizing either European Modification Mayo 2004 or Mayo 2012 as part of their patient inclusion criteria.

Objectives: This study aimed to characterize the most severe AL patients using different Mayo staging systems and to determine the agreement between European Modification Mayo 2004 and Mayo 2012.

Methods: A cross-sectional analysis (July 1, 2017 - June 30, 2023) was conducted using an anonymized dataset from the TriNetX Dataworks comprising about 95 million patients from 57 USA healthcare organizations. Adults diagnosed with AL between January 1, 2018, and December 31, 2022, with ≥2 records for AL (ICD-10-CM code E85.81) ≥30 days apart were included. Characteristics of interest, including organ involvement (i.e. cardiac, renal, hepatic), the Charlson Comorbidity Index (CCI) and lab values required for staging (NT-proBNP, cTNT, and dFLC) were captured ±180 days from AL diagnosis (ICD-10 E85.81). All patients with available data were staged according to the classification systems under comparison.

Results: Among 525 AL patients, 54.3% (n=285) and 54.1% (n=284) were classified as severe AL according to European Modification Mayo 2004 (stages IIIa: 29.9%; IIIb: 24.4%) and Mayo 2012 (stages III: 41.9%; IV: 12.2%), respectively. Most severe AL patients were predominantly male (65.6%/70.3%) with a mean age of 67.4/67.5 years, and mean CCI of 4/3 in stage IIIb (European Modification Mayo 2004) or stage IV (Mayo 2012), respectively. Renal involvement was observed in 76.6% / 56.2% and liver involvement in 8.6% / 4.7% of stage IIIb/IV patients. The overall agreement for all stages between the two systems was 46.8% (246 out of 525 patients), indicating low concordance.

Conclusion: Our findings reveal a notable lack of agreement among the AL Mayo staging systems. Given developments in the standard-of-care for AL since their inception, it is crucial to re-evaluate the prognostic value of these staging systems in the context of contemporary and upcoming treatments.
The Causality between Immune Thrombocytopenia and Thrombosis : A Bidirectional Two-Sample Mendelian Randomization Study
Authors: Zhao Yajing , Han Shouqing , Liu Xinguang , Guo Li
Published: December 2024

Background: Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease characterized by low platelet count and bleeding manifestations. However, observational studies have shown that ITP patients have a significantly higher incidence of arterial and venous thromboembolism compared with the normal population, despite the low platelet counts. Treatments options, complications, and inflammatory status of ITP patients are considered to contribute the thromboembolism formation. This study aimed at investigating the causal associations of ITP with arterial and venous thromboembolism.

Methods: A bidirectional two-sample Mendelian randomization (MR) analysis was designed by using summary-level data from large genome-wide association studies performed in European individuals. Inverse variance weighting with multiplicative random effect method was used to obtain the primary causal estimates, and weighted median, weighted mode, and MR egger regression were replenished as sensitivity analyses to test the robustness of the results. We also collected data from 302 ITP patient hospitalized in Qilu Hospital during October 2016 to September 2018 to observe the incidence of thrombotic events.

Results: Among the 302 ITP patients included in our retrospective study, 49 patients (16.2%) presented with coronary atherosclerosis, 12 patients with cerebral infarction, and 2 patients with deep venous thrombosis. In the MR analysis, we found no significant causal effects of ITP on coronary atherosclerosis (odds ratio [OR]: 1.000034, P = 0.74), arterial thrombosis (OR: 1.030618, P = 0.07), ischemic stroke (OR: 0.9999557, P = 0.07), myocardial infarction (OR: 0.9999557, P = 0.77), and venous thromboembolism (OR:1.0011961, P = 0. 82) including deep venous thrombosis (OR: 0.9998565, P = 0.02), pulmonary embolism (OR: 0.999987, P = 0.69), and portal venous thrombosis (OR:0.997588, P = 0.96). In the other direction, there were also no significant causal effects of thrombotic events on ITP.

Conclusion: This MR analysis demonstrated no significant causal associations of ITP with arterial or venous thromboembolism in both directions. Although the previous observational studies indicated a positive association between ITP and thromboembolism, the external effects may be dominant. Further investigations are still needed for the underlying pathogenesis of thrombosis in ITP.
Clinical Observation of Daratumumab Based Immunochemotherapy in the Treatment of Light Chain Amyloidosis
Authors: Du Jun , Gu Xiao-Ran , Liu Jia , Lu Guang , Zhong Lu
Published: December 2024

Purpose: Systemic light chain (AL) amyloidosis arises from the aberrant folding of monoclonal immunoglobulin light chains, resulting in the formation of amyloid proteins. These proteins are subsequently deposited in various tissues and organs, instigating structural damage, organ impairment, and relentless disease progression. Daratumumab, a fully human IgG1κ monoclonal antibody engineered to target CD38, serves as both a depleting agent for plasma cells and an immunomodulator. In 2021, daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone (D-VCd regimen) became the first formally licensed treatment for AL amyloidosis. Our study, an observational investigation involving five patients diagnosed with AL amyloidosis, aims to demonstrate the efficacy and safety of daratumumab based treatment.

Methods: This clinical observation encompasses five patients, with four undergoing renal biopsies and one undergoing a fat biopsy. All patients were diagnosed with confirmed and symptomatic AL amyloidosis and received treatment with the D-VCd regimen at our institution between August 2021 and August 2023. The treatment protocol involved administering daratumumab at a dose of 16 mg/kg, bortezomib 1.3 mg/m2, cyclophosphamide 300 mg/m2 (500 mg maximum weekly dose), and dexamethasone 20 mg intravenously. Treatment was initially administered once weekly for weeks 1 to 8, followed by every 2 weeks from weeks 9 to 24 (for all patients), and subsequently extended to every 4 weeks for up to 12 months (only for Pt 3 and Pt 4).

Results: The case series comprises five male individuals with a median age of 66 years (range, 43-73 years). Among these individuals, four patients achieved a hematologic very good partial response (VGPR), two of whom achieved a complete response (CR). The mean difference of serum free light chain (dFLC) value changed from 384.2 mg/L (range, 81.1-926.1) to 95.72 mg/L (range, 0.73-447). Conversely, one patient exhibited no discernible improvement following six months of therapy, prompting the discontinuation of daratumumab. Four patients showed cardiac and renal responses after six cycles of treatment. Remarkably, after 6 cycles of treatment, according to common terminology criteria for adverse events, (CTCAE) assessment, no patients experienced adverse reactions of grade 3 or above.

Conclusions: This study presents our clinical observation of daratumumab based immunochemotherapy for AL amyloidosis, unveiling its safety and efficacy. Notably, 80% (4/5) of patients exhibited hematologic response following six cycles of treatment, devoid of any discernible side effects. Simultaneously, an equivalent proportion of patients 80% (4/5) showcased cardiac and renal responses, underscoring the treatment's effectiveness in preserving organ function and extending patient survival.
VA Combined with Mbucy Conditioning Regimen Followed By Allo-HSCT Can Improve Survival of High-Risk AML Patients: A Prospective, Single-Center, Single-Arm Clinical Trial
Authors: Cui Wei , Chen Xiaoqian , Cui Qingya , Li Zheng , Chen Sifan , Li Mengyun , Li Xuekai , Chen Juan , Yu Yan , Wu Depei , Tang Xiaowen
Published: December 2024

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for high-risk acute myeloid leukemia (AML). And relapse remains a leading cause of death post transplantation due to poor survival for high risk AML patients. Therefore, how to optimal conditioning regimens to reduce the relapse rate and improve overall survival(OS) post transplant are necessary.The combination of venetoclax and azacitidine(VA) disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia.Therefore, we evaluate the safety and efficacy of VA regimen followed by modified BuCy (VA-mBuCy) as conditioning regimen for high-risk AML.

Methods: This prospective, single-center, single-arm clinical trial enrolled patients diagnosed with high-risk AML (reference 2022-AML-ELN guideline) in the First Affiliated Hospital of Soochow University (NCT05823714). All patients received the VA regimen, comprising venetoclax 200mg from day 1 to day 7 and azacytidine 75mg/m2 from day 1 to 7, followed by the mBuCy conditioning regimen(Me-CCNU 250 mg/m2/d on day -10, cytarabine 2 g/m2 every 12 h on days -9 to -8, busulfan 0.8 mg/kg every 6 h on days -7 to -5, and cyclophosphamide 1.8 g/m2/d on days -4 to -3).

Result s: From Jan 2022 to Mar 2024, a total of 20 patients were enrolled, with a median age of 47 years (range: 16 to 62 years) at the time of transplantation. All patients achieved morphological complete remission(CR).16 of the 20 patients (80%) did not achieve molecular MRD-negative CR prior to transplantation, including 5 patients with KMT2A rearrangement, 2 patients with TP53 mutations, 2 patients with Mutated NPM1 with FLT3-ITD,1 patient with CBFB-MYH11 transcript,1 patient with NUP98-HOXCB transcript,1 patient with extramedullary disease. The median time for neutropenia and thrombocytopenia recovery were 12(10-15)and 13 (10-36) days. Among the 20 patients, 4 patients developes grade Ⅰ-Ⅱacute graft-versus-host disease (GVHD) and 2 patients developed mild chronic GVHD. There were no cases of veno-occlusive disease and hemorrhagic cystitis. The incidence rates for active CMV and EBV infections were 30% (6 out of 20) and 20% (4 out of 20), respectively. However, bloodstream infections (10 out of the 20 cases) occurred frequently,which responded to antibiotics soon.There were no transplantation-related mortality. The median follow-up time was 16.5 months (3-30 months). One-year overall survival (OS) rate and leukemia-free survival (LFS) rate was 94.4% and 62.6% respectively. Two-year OS rate and LFS rate was 79.3% and 46.4% respectively.

Conclusion: In conclusion, our results suggest that VA-mBuCy conditioning regimen followed by allo-HSCT represented a valid regimen, able to provide better OS of high-risk AML patients, especially with MRD-positive status.
High Efficacy of Adding G-CSF to Venetoclax Plus Azacitidine As Front-Line Treatment in Previously Untreated Acute Myeloid Leukaemia:a Pilot Study
Authors: Shi Ting , Jian Yuan , Zhang Yanru , Liu Nian , Geng Chuanying , Wang Guorong , Zhang Zhiyao , Huang Lefu , Zhang Jiajia , Zhou Yalan , Zhou Huixing , Tang Ran , Li Wenjing , Jiang Xingran , Zhao Fengyi , Gao Wen , Huang Zhongxia , Chen Wenming , Li Xin , Leng Yun , Wu Yin , Zhu Honghu
Published: December 2024

Background: Venetoclax plus azacitidine (VA regimen) is recommended for treatment-naive patients with acute myeloid leukaemia (AML) who are unfit for intensive chemotherapy. However, the composite complete remission rate after one cycle of VA regimen is only 43.4%, which need to be improved. Regimens containing granulocyte colony-stimulating factor (G-CSF), such as FLAG,CLAG, CAG and HAG have been used in clinical practice for many years and has shown certain efficacy. We presumed that venetoclax plus azacitidine in combination with G-CSF (referred to as the VAG regimen) could have a better composite complete remission rate while maintaining an acceptable safety profile.

Methods: All patients received induction with venetoclax (100mg d1, 200mg d2, 400 mg d3-14, orally), azacitidine (100 mg/d, d1-7, subcutaneously); and G-CSF (5ug/kg/d, d1-7, subcutaneously) in 28-day cycles. The dose of venetoclax was adjusted based on concomitant moderate or strong CYP3A inhibitors. Efficacy was evaluated by bone marrow morphology and flow cytometry on day 28 of cycle 1. The primary and secondary end point were composite complete remission, MRD and safety, respectively.

Results: A total of 37 patients with AML were enrolled between January 1, 2023, and March 31, 2024, with a median age of 68 years (range, 53 to 87). Seventeen patients (46%) had adverse risk, 10 patients (27%) had intermediate risk, 9 patients (24%) had favorable risk, and 1 patient (3%) was not available. All patients completed at least 1 cycle of treatment (range: 1-8). Three patients were lost to follow-up after one cycle and two patients died during induction. The composite complete remission rate was 63% (20/32), and 14 patients (70%) were MRD negative by flow cytometry. The composite complete remission rates for the favorable-risk group, intermediate-risk group, and adverse-risk group were as follows: 89%(8/9), 33% (3/9) and 64%(9/14). Haematological adverse events of all grades occurred in most patients. The most common non-haematological adverse events of any grade included fatigue (51%, 19/37), constipation (43%, 16/37), febrile neutropenia (30%, 11/37), and pneumonia (20%, 7/37). All adverse events could be managed and improved through dose adjustments and supportive treatment.

Conclusion:The VAG regimen achieved high rates of complete remission and MRD negativity in unfit patients with newly diagnosed AML. This combined regimen has an acceptable safety profile, with low incidence of infection. A phase 2 study of VAG regimen has completed and a phase 3 trial comparing VAG vs VA regimen is undergoing currently by us.
Mondoa Promotes Resistance to Asparaginase Treatment in B-ALL By Inducing Asparagine Synthesis
Authors: Madeira Alissia Fernandes , Brückner Christian , Segner Constantin , Kolesnikova Alisa , Sipol Alexandra , Wolf Elmar , Rad Roland , Sorensen Poul H. , Hauer Julia , Ruland Jürgen Maximilian , Burdach Stefan
Published: December 2024

Background: Cancer cells often exhibit rapid proliferation and uncontrolled division, employing adaptations to metabolic stress to maintain homeostasis and survival. MondoA (Myc-associated factor X-like protein X-interacting protein [MLXIP]), a member of the MYC interactome, is a metabolic sensor playing an important role in cancer cell adaption to stress. Our previous work demonstrated that increased MondoA expression correlates with poor outcomes in subgroups of pediatric common acute lymphoblastic leukemia (ALL; B-precursor ALL [B-ALL]) by inducing resistance to metabolic stress (Sipol et al. BLOOD 2022).

Methods: We explored the role of MondoA in resistance to L-Asparaginase (ASNase) treatment, a major non-genotoxic therapeutic principle in pediatric B-ALL, which depletes Asparagine (Asn) in the bloodstream. Utilizing CRISPR/Cas9 technology, we generated MondoA knock-out B-ALL NALM6 cell line (MKO) to study the effects on cellular metabolism and resistance mechanisms. We tested the effect of ASNase on cell viability and performed multi-omics analyses to evaluate changes in metabolic pathways and MYC binding sites in both MKO and control cells.

Results: Our study demonstrates that MondoA induces resistance to ASNase treatment in B-ALL cell lines. In our experiments, MKO cells exhibited a 92% loss of viability upon ASNase treatment, compared to an 84% loss in control cells (N = 4). Mechanistically, MondoA knock-out resulted in a redistribution of MYC binding to promoter regions, significantly affecting the epigenome, transcriptome, and proteome of the cells. Proteomic analysis revealed reduced expression of electron transport chain (ETC) complexes and key tricarboxylic acid (TCA) cycle enzymes, resulting in lower aspartate (Asp) production, a substrate for Asparagine Synthetase (ASNS). Alpha-ketoglutarate supplementation rescued MKO cells, likely by enhancing Asp production through the TCA cycle; this effect was not observed in control cells. Additionally, we discovered that ASNase resistance partially depends on sufficient glutamine (Gln) levels, another substrate for Asn de novo synthesis. Multi-omics coherence analysis of ASNS-promoter MYC binding, transcriptome, and proteome revealed downregulation of ASNS in MKO cells. These data are supported by our previous transcriptome analysis results of MondoA knock-down in other B-ALL cell lines, Reh and 697, which showed downregulation of ASNS transcripts upon silencing MondoA expression.

Conclusion: Our findings suggest a pivotal role of MondoA in ASNase therapy-resistant B-ALL and highlight its potential as a therapeutic target to improve treatment outcomes in pediatric B-ALL by enhancing sensitivity to ASNase asparaginase therapy.

Key words: B-ALL, MondoA, L-Asparaginase resistance.