bluuebunny/crossref_metadata_2025 huggingface dataset:
Nutritional and Immune-Inflammatory Scoring System for Predicting Prognosis in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma
Authors: Peng Yu , Jiang Tingting , Chen Shuang , Tang Xinyi , Zhang Yakun , Ji Dan , Li Liangmei , Ran Longrong , Jun Li , Li Nanjun , Yang Zailin , Liu Yao
Published: December 2024

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, typically associated with poor prognosis. Current prognostic scoring systems, such as the International Prognostic Index (IPI) and the National Comprehensive Cancer Network (NCCN)-IPI, do not account for the impact of patients' nutritional, immune, and inflammatory responses on their prognosis. To develop a prognostic scoring system for DLBCL patients based on easily obtainable or measurable nutritional, immune, and inflammatory indicators to complement and improve the existing NCCN-IPI and IPI systems.

Methods

A retrospective monocentric analysis of 423 patients who were newly diagnosed DLBCL at Chongqing University Cancer Hospital between January 2020 and September 2023. Relevant patient data were collected from the electronic medical record system, including basic patient characteristics and clinical laboratory results. All eligible patients were randomly divided into training set and validation set at a ratio of 7:3. We used the least absolute shrinkage and selection operator (LASSO) Cox regression model to identify nutritional and immune-inflammatory indicators related to patient prognosis. These indicators were then used to develop the prognostic scoring system. Further analysis was conducted to evaluate the clinical characteristics of this prognostic scoring system and compare it with the IPI and NCCN-IPI.

Results

We developed the Nutritional and Immune-Inflammatory Scoring System (NII), which includes Nutritional Risk Screening (NRS2002), Geriatric Nutritional Risk Index (GNRI), Systemic Immune-Inflammation Index (SII), lactic dehydrogenase to albumin ratio (LAR), β2-microglobulin (β2-MG), CD8+ T cells, natural killer (NK) cells, and CD3+ T cells. A high NII (> 6) effectively identifies high-risk DLBCL patients and serves as an independent prognostic factor beyond other clinical characteristics, IPI, and NCCN-IPI (p < 0.05). DLBCL patients with a high NII (> 6) exhibit significantly adverse clinical features, including advanced age, Ann Arbor stage (III/IV), B symptoms, elevated LDH levels, and higher risk groups according to IPI and NCCN-IPI (p < 0.05). Combining NII with IPI or NCCN-IPI significantly improves the assessment of patient prognosis compared to using IPI or NCCN-IPI alone (p < 0.05).

Conclusion

The Nutritional and Immune-Inflammatory Scoring System (NII) is an effective tool for identifying high-risk DLBCL patients. A high NII (> 6) serves as an independent prognostic factor, revealing significantly adverse clinical features that are not captured by IPI and NCCN-IPI alone. Combining NII with IPI or NCCN-IPI significantly improves the accuracy of patient prognosis assessments compared to using IPI or NCCN-IPI alone.
Venetoclax Plus Dexamethasone As First-Line Treatment for t(11; 14) Light-Chain Amyloidosis: Preliminary Result of a Phase II Prospective, Multicenter, Single-Arm Study
Authors: Shen Kaini , Guan Ai , Wu Yu , Sun Chunyan , Zhong Liye , Luo Jun , Li Jian
Published: December 2024

Background: Venetoclax has shown promise in providing rapid and high-quality hematologic responses in relapsed/refractory t(11;14) light-chain (AL) amyloidosis cases and offers the convenience of home treatment. To evaluate the efficacy and safety of venetoclax combined with dexamethasone (Ven-D) as an initial treatment for t(11;14) AL amyloidosis patients, we conducted a phase II prospective, multicenter, single-arm study (NCT05996406). Here, we report the preliminary findings.

Method: The study aimed to enroll 36 patients aged 18 or older with newly diagnosed t(11;14) AL amyloidosis. Participants received 12 cycles (28 days per cycle) of Ven-D, consisting of oral venetoclax at 400 mg qd and oral dexamethasone at 20-40 mg qw for the first six cycles, reduced to 10-20 mg for the remaining cycles. Hematologic and organ responses were evaluated at one month, three months and every three months thereafter while on study treatment. Patients who died before the response assessment were categorized under the no-response group. Treatment discontinuation criteria included drug intolerance, unsatisfactory efficacy at the physician's discretion, or disease progression. The primary endpoint was achieving a complete hematologic response (CR) and very good partial response (VGPR) at three months of treatment initiation.

Results: Between September 8, 2023, and June 25, 2024, 36 patients were enrolled, with a median age of 62 years (range 27-75) and predominantly male (80.6%). The distribution of Mayo 2004 stages was as follows: stage I (16.7%), stage II (50.0%), stage IIIA (19.4%), and stage IIIB (13.9%). Heart, kidney, and liver involvement was observed in 80.6%, 50.0%, and 8.3% of patients. By July 25, 2024, all patients had received a median of 5 treatment cycles (range 1-12). Among evaluable patients (n=29), the CR+VGPR rate at three months was 58.6%, with a CR rate of 27.6%. Considering the best hematologic response at any time, the estimate of the CR+VGPR rate was 62.9%, and the CR rate was 37.1%. At six months, cardiac and renal responses were observed in 35.0% and 90.9% of patients, respectively. There were three deaths due to cardiac events and six patients discontinued treatment due to lack of efficacy. Grade 3-4 hematological adverse events included lymphopenia (5.6%) and neutropenia (2.8%), while non-hematological adverse events included edema (2.8%), infection (2.8%) and liver dysfunction (5.6%).

Conclusion: The combination of Ven-D as an initial treatment for t(11;14) AL amyloidosis demonstrates rapid induction of high hematologic responses with a favorable tolerability profile.
Serum Tsrna Can be Used As a Biomarker of the Activation States of T Cells for Early Detection of GvHD after Allogeneic Stem Cell Transplantation
Authors: Xia Lin , Xu Wei , Tang Shuhan , Yao Han , Zhao Lu , Liu Yuqing , Chen Ting , Tang Jie , Chen Xiaoli , Wang Li , Yang Shijie , Feng Yimei , Zhang Xi
Published: December 2024

Background

Allogeneic hematopoietic cell transplantation is a potentially curative therapy for many malignant and nonmalignant hematologic diseases. However, as a common complication after transplantation, GvHD remains a major cause of morbidity and mortality, limiting the success of a potentially curative transplant. tRNA-derived small non-coding RNA (tsRNA) is a class of newly identified small noncoding RNA (sncRNA), usually ~30 nucleotides (nt) in length. tsRNA was found to be highly enriched in vertebrate serum as remarkably stable forms, suggesting a promising role of serum tsRNAs as diagnostic biomarkers for human diseases and actively involved in starvation, oxidative stress, hypoxia, and other adverse conditions. Here, by employing small non-coding RNA sequencing on serum of patients who underwent HSCT, we presented the landscape of tsRNA profiles and showed the difference in patients with GvHD and non-GvHD, which can be further used as fingerprints for early detection of GvHD after allo-HSCT.

Methods

In this retrospective cohort study, two cohorts were incorporated and serum samples were prospectively collected before drug treatment (-7 day), before stem cell transfusion after drug treatment (-1 day), the 7th day after stem cell transfusion (+7 day), the 14th day after stem cell transfusion (+14 day), and the 28th day after stem cell transfusion (+28 day) if possible, namely 1) the auto-transplantation cohort: 50 serum samples in total, including 10 patients undergoing the auto-transplantation.2) the allogeneic transplantation cohort: 149 serum samples in total, including 35 patients undergoing the auto-transplantation. Serum RNA was extracted and measured by small noncoding RNA sequencing, RT-qPCR, and northern blot.

Results

By employing small RNA sequencing, we found significant differences in tsRNA after hematopoietic stem cell transplantation, especially in GvHD and non-GvHD groups. In the non-GvHD group, tsRNA usually goes through a low (+7d) - high (+14d) - low (+28d) express pattern. However, in the GvHD group, tsRNA still maintains high-level expression at +28d of allo-HSCT, which presents a low (+7d) - high (+14d) - high (+28d) express pattern. Additionally, by simulating T cells in vitro, we found that T cells secrete a large amount of functionally tsRNA into the extracellular space after activation and those tsRNAs can induce cell apoptosis. Taken together, It suggests that tsRNA-mediated epigenetic information may be involved in regulating the occurrence and development of GvHD after allo-HSCT, and can serve as specific diagnostic markers.

Conclusions

The express pattern of serum tsRNA at 14d to 28d after allogeneic stem cell transplantation could represent the activation states of T cells and can be fingerprinted for early detection of GvHD after allo-HSCT.
Efficacy and Safety of Bendamustine, Pomalidomide, Sintilimab in Patients with Recurrent or Refractory Diffuse Large B-Cell Lymphoma: A Retrospective Study
Authors: Yang Haiyan , Zhou Shengsheng , Huang Fengxiang , Li Meiwei , Bao Wenguang , Wang Man , Lan Dong , Peng Zhigang
Published: December 2024

Background:

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Approximately 40% of patients develop recurrent or refractory (R/R) diseases after frontline chemoimmunotherapy. The patients with R/R DLBCL after at least 2 lines of therapy have unsatisfactory outcome and are always encouraged to participate in clinical trials. More effective therapeutic approaches are urgently needed. Here, we conducted a study to evaluate the efficacy and safety of bendamustine in combination with pomalidomide and sintilimab for these R/R DLBCL patients.

Methods:

We retrospectively analyzed the data of R/R DLBCL patients, who had received 2-6 cycles BPD regimen: bendamustine 70mg/m2, d1-2, pomalidomide (POM) 4mg, day 1-14, sintilimab, 200mg, day 2, 21 days/cycle. After 4-6 cycles therapy, patients that achieve PR or CR would continue receive pomalidomide (POM) and sintilimab as maintenance therapy for one year. The primary endpoint was objective response (ORR).

Results:

From May 2022 to July 2024, a total of 13 patients who were not eligible for transplant or CART were included. Key baseline characteristics included: Median age, 62 years (range 45-77), 76.9% IPI score 2-5, 76.9% Ann Arbor stage III-IV, 84.6% non-GCB, 46.2% dual expression, 100% EBER-negative. Patients were heavily pretreated, with a median of 3 (range 2-6) previous lines of systemic therapy. All patients were treated with RCHOP as the first line and platinum-based chemotherapy as a second line. Of these patients, 12 patients had refractory disease or early recurrence, and one experienced relapse＞12 months after the last treatment. Out of the 13 evaluable patients, the disease control rate (DCR) was 92.3%, with an overall response rate (ORR) of 11 cases (84.6%). Among them, stable disease (SD) was observed in 1/13 (7.7%) patients. Complete response (CR) was achieved in 2/13 (15.4%) cases, while partial response (PR) was seen in 9/13 (69.2%) patients. Tumor volume reduction ranged from 40% to 100%. With a median follow-up of 24 months, the median progression-free survival (PFS) was 7 months.

The most common adverse events of any grade were hemocytopenia (50.0%), infection (33.3%), digestive symptoms (16.7%). Grade 3-4 adverse events occurred in 3/13 (23.1%) patients, including neutropenia (15.4%), thrombocytopenia (15.4%), anemia (15.4%), nausea (15.4%), decreased appetite (15.4%), pneumonia (15.4%), herpes virus (7.7%). No treatment-associated death was observed.

Conclusions：

These data supported that bendamustine in combination with pomalidomide and sintilimab had promising anti-tumor activity and manageable safety profile in R/R DLBCL. Currently, a phase II, prospective study is ongoing to further investigate the efficacy and safety of this regimen (ChiCTR 2400084099).
Adsl, As a Hub for Amino Acid Metabolism and Glucose Metabolism, Promotes the Development of Multiple Myeloma
Authors: Zhong Ling , Xiao Jialing , Luo Ji , Wu Yajie , Yi Qing , Gong Bo
Published: December 2024

Multiple myeloma (MM) is the second most common hematological malignancy, with its global incidence on the rise. Despite significant improvements in the survival rate of MM patients, there is still considerable variation in prognosis, with some patients experiencing rapid progression and short survival periods. Therefore, identifying specific markers for highly malignant plasma cell subgroups with poor prognosis is crucial.

To address this, we conducted single-cell transcriptome sequencing across the entire disease progression spectrum, including MGUS, MGRS, SMM, and MM. We identified highly malignant plasma cell subgroups (clusters 5 and 17) based on copy number variations and malignant plasma cell subgroup (MPCS) scores. Using a malignant metabolic pathway scoring method (MPAS), we discovered that abnormalities in the alanine, aspartate, and glutamate metabolic pathways significantly impacted the poor prognosis of patients in these subgroups. Notably, within these pathways, adenylosuccinase (Adsl) was significantly overexpressed. Data from the GEO (GSE6477) and MMRF databases revealed that Adsl was significantly associated with poor clinical stages (R-ISS) and survival prognosis of patients. Knockdown of Adsl significantly promoted apoptosis and reduced the proliferation index, as evidenced by TUNEL, cell cycle assay and expression levels of classic apoptotic proteins (cleaved Caspase-3 and cleaved PARP). Further research showed that Adsl knockdown led to a significant reduction in AMP production, which was the main downstream product of Adsl. This reduction inhibited AMP from directly binding to the γ subunit of AMPK, thereby inhibiting phosphorylation at the Thr172 site and suppressing AMPK pathway activation. Mitochondrial fission factor (MFF), a core member of the mitochondrial fission process, is a phosphorylation substrate of AMPK at Ser172. After Adsl knockdown, MFF Ser172 phosphorylation was significantly reduced, leading to decreased mitochondrial fission. Reduced mitochondrial fission weakened glycolysis, enhanced oxidative phosphorylation, and increased ROS production. Consequently, increased ROS inhibited myeloma cell proliferation and promoted apoptosis.

In summary, Adsl acts as a bridge linking amino acid metabolism and glucose metabolism and serves as a specific marker for highly malignant plasma cell subgroups. This finding provides a novel therapeutic target for improving the prognosis of MM patients.
Clinical Analysis of Sequential CAR-T Therapy Combined with Demethylating Agents and Personalized Targeted Drugs in 18 Elderly Patients with Relapsed/Refractory Acute B-Lymphoblastic Leukemia
Authors: Li Biyi , Yan Hong , Zheng Ruyue , Liu Shuangyou , Lin Yuehui , An Lihong , Deng Biping , Zheng Qinlong , Tong Chunrong , Wu Tong , Zhao Defeng
Published: December 2024

Background: CAR-T therapy is a crucial method for treating relapsed/refractory acute B-lymphoblastic leukemia (ALL). Elderly patients often have poor treatment tolerance and limited treatment options.

Objective: To observe the efficacy of sequential CAR-T therapy combined with demethylating agents and personalized targeted drugs in elderly patients with relapsed/refractory acute B-lymphoblastic leukemia (B-ALL).

Methods: This study included data from 18 patients treated at Beijing Boren Hospital between June 2018 and March 2023, with follow-up until June 20, 2024. All patients were over 50 years old, diagnosed with relapsed/refractory acute B-ALL. All patients relapsed after chemotherapy or allo-HSCT and received two different antigen-targeted sequential CAR-T therapies, followed by maintenance therapy with BCL2 inhibitors, demethylating agents, and specific targeted drugs. The cohort consisted of 5 males and 13 females, with an age range of 53 to 74 years (median age: 60.5 years). Four patients (22.2%) were Ph+, one patient (5.56%) had undergone allo-HSCT before CAR-T therapy, and four patients (22.2%) underwent allo-HSCT after CAR-T therapy.

Results: All 18 elderly patients achieved MRD-negative remission by flow cytometry after the first CAR-T therapy and then received a second sequential CAR-T therapy targeting different antigens. One-year continuous remission was achieved in 12 patients (66.7%), and two-year continuous remission in 6 patients (33.3%). Progression-free survival (PFS) after sequential CAR-T therapy ranged from 2 months to 39 months (as of June 20, 2024). The two-year event-free survival (EFS) rate was 65.81% (95% CI: 39.06%~83.01%), and the three-year EFS rate was 29.25% (95% CI: 7.7%~55.34%), with a median EFS of 849 days. The two-year overall survival (OS) rate was 79.91% (95% CI: 49.31%~93.13%), and the three-year OS rate was 59.94% (95% CI: 27.34%~81.7%), with the median OS not reached. During the first CAR-T therapy, the probability of CRS was 66.7%, with 11 patients (61.1%) experiencing grade 1 CRS, 1 patient (5.6%) experiencing grade 2 CRS, and no patients experiencing grade 3 or higher CRS or ICANS. Only one patient experienced grade 1 CRS during the second CAR-T therapy.

Conclusion: CAR-T therapy in elderly patients with relapsed/refractory B-ALL shows high remission rates, minimal side effects, and high safety, effectively prolonging disease-free survival and overall survival.For elderly patients with relapsed/refractory B-ALL, sequential CAR-T therapy combined with BCL2 inhibitors and demethylating agents (decitabine or azacitidine) as part of maintenance therapy can effectively extend remission duration, providing a new treatment option for these patients.
Clinical Analysis of CAR-T Cell Therapy in Patients with Relapsed Acute B-Lymphoblastic Leukemia after Second Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yan Hong , Li Biyi , Zheng Ruyue , Lin Yuehui , An Lihong , Deng Biping , Tong Chunrong , Wu Tong , Zhao Defeng
Published: December 2024

**Background:** Patients with relapsed acute B-lymphoblastic leukemia (B-ALL) after a second allogeneic hematopoietic stem cell transplantation (allo-HSCT) have limited treatment options and low remission rates. This study explores the efficacy of CAR-T cell immunotherapy in these patients.

**Objective:** To observe the efficacy of CAR-T therapy in patients with relapsed B-ALL after a second allo-HSCT and to evaluate the effect of maintenance therapy with demethylating agents and targeted drugs in patients who achieve remission after CAR-T therapy.

**Methods:** The study included eight patients treated at Beijing Boren Hospital from February 2021 to July 2024. Follow-up continued until July 16, 2024. All patients had relapsed after a second allo-HSCT and received CAR-T therapy. Patients who achieved remission after CAR-T therapy received sequential CAR-T treatment and maintenance therapy with targeted drugs.

The cohort consisted of four males and four females, aged between 5 and 58 years, with a median age of 29 years. Two patients did not respond to CAR-T therapy, while the remaining six achieved varying degrees of remission. The shortest remission duration was 1.3 months, and the longest was 20 months (as of July 16, 2024), with a median remission duration of 9.5 months.

**Results:** Among the eight patients, six achieved minimal residual disease (MRD)-negative remission (75%) after CAR-T therapy, while two did not respond (25%). The overall survival (OS) ranged from 1.3 months to 20 months (as of July 16, 2024). Among the six patients who achieved remission, one received two different CAR-T treatments, one received four different CAR-T treatments, and the remaining four received one CAR-T treatment each. During the first CAR-T treatment, all patients experienced cytokine release syndrome (CRS) with a 100% incidence rate. Five patients had grade 1 CRS (62.5%), and one patient had grade 3 CRS (37.5%). No patients experienced grade 3 or higher CRS or ICANS (immune effector cell-associated neurotoxicity syndrome).

**Conclusion:** CAR-T therapy shows a significant remission rate, minimal side effects, and high safety in patients with relapsed B-ALL after a second allo-HSCT, effectively prolonging disease-free survival.Combining CAR-T therapy with BCL2 inhibitors and demethylating agents may improve patient outcomes and extend survival, providing a new treatment approach for patients with relapsed/refractory B-ALL after a second allo-HSCT.
Wogonin Induces Apoptosis of Acute Myeloid Leukemia Cells through PI3K/Akt Pathway and Synergies with Venetoclax
Authors: Jiang Xia , Li Youhong , Jiang Lei , Pei Renzhi , Jin Jie , Lu Ying
Published: December 2024

Background:Acute myeloid leukemia (AML) is a highly aggressive and heterogeneous hematological malignancy. Although 80% of patients with AML achieve complete remission after receiving standard chemotherapy, most relapse or die from treatment-related complications, and the overall prognosis remains less than 30%. Wogonin is a kind of natural flavonoid with anti-inflammatory, anti-tumor and other biological activities which could kill tumor cells by inducing cell cycle arrest. Venetoclax is a highly selective BCL-2 inhibitor that is currently approved for the treatment of chronic lymphocytic leukemia. Although venetoclax combined with demethylated drugs or low-dose cytarabine has become a first-line treatment option in elderly AML patients who were unable to tolerate high-intensity chemotherapy, resistance remained unavoidable, suggesting the need for more venetoclax-based combination regimenes. However, it was unclear whether Wogonin could promote the anti-AML effects of venetoclax.

Objective: To explore whether Wogonin combined with venetoclax has synergistic effect in the treatment of acute myeloid leukemia and the potential synergistic mechanism.

Methods: After treatment with Wogonin alone or combined with venetoclax, the viability of AML cell lines and primary AML cells was detected by cell proliferation assay, and the combined index of the two drugs was calculated by Compusyn software to evaluate the synergy effect. Apoptosis and cell cycle changes were detected by flow cytometry. The enrichment of differentially expressed genes and related signaling pathways in different drug treatment groups were analyzed by RNA sequencing. The expression levels of apoptosis-related proteins, BCL-2 family proteins, and the activation levels of PI3K/Akt signal related molecules were detected by western blot.

Results: In AML cell lines and patient-derived primary tumor cells, Wogonin combined with venetoclax significantly inhibited cell viability, and the inhibitory effect on AML was stronger than that of the two drugs alone. Flow cytometry detected that Wogonin promoted apoptosis of AML cells in a dose-dependent manner and blocked the cells in the G0/G1 phase. Western blot verified that Wogonin promoted the cleavage of apoptotic proteins such as caspase3 and PARP, affected the expression of BCL-2 family proteins, such as down-regulating MCL-1 and BCL-xL, inactivating the PI3K/Akt/GSK3β signaling pathway, and further inducing the death of AML cells.

Conclusion: Wogonin combined with venetoclax has a synergistic anti-AML effect, providing scientific basis for preclinical and clinical trials, and a potential combination strategy for the clinical treatment of AML.
Bone Marrow Impairment in Patients with Adenosine Deaminase 2 Deficiency
Authors: Miano Maurizio , Lupia Michela , Schena Francesca , Caorsi Roberta , Barzaghi Federica , Giarratana Mariacarla , Corcione Anna , Terranova Paola , Aiuti Alessandro , Mortellaro Alessandra , Cafaro Alessia , Palmisani Elena , Cangemi Giuliana , Barco Sebastiano , Dell'Orso Gianluca , Arcuri Luca , Grossi Alice , Traggiai Elisabetta , Ceccherini Isabella , Gattorno Marco , Dufour Carlo
Published: December 2024

Introduction

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory syndrome caused by biallelic mutations in the ADA2 gene characterized by early-onset inflammatory vasculopathy, strokes and immunodeficiency. Haematologic manifestations include lymphopenia, and bone marrow failure (BMF) mainly pure red cell aplasia. The diagnosis of DADA2 is confirmed by decreased enzymatic activity of ADA2 and genetic testing. TNFα inhibitors control inflammatory symptoms whereas hematopoietic stem cell transplant may be needed to treat refractory cytopenia.

Objectives

The aim of this study is to characterize the mechanisms of bone marrow damage in DADA2 patients.

Methods

Bone marrow(BM) samples from DADA2 patients and healthy donors (HD) were analyzed for different in-vitro assays to test in vitro potential therapeutic agents. In-vitro colony forming unit assay were performed from fresh bone marrow mononuclear cells (BMMNCs) in presence of anti-TNFα, human recombinant ADA2 or Eltrombopag. After 14 days CFU colonies were scored. Pro-inflammatory cytokines in the BM plasma were also measured by flow cytometry bead array.

Results

Fourteen patients (median age 17yo) were studied. Eight /14 (57%) showed reduced erythroid (CFU-E 0.5, normal range 27-81/2 × 104) and myeloid (CFU-GM 3.5, normal range 33-100/2 ×104) progenitor cell growth; The addition of anti-TNFα and eltrombopag 1 ug/ml, had a statistically significant stimulatory effect on the growth of myeloid progenitors (p=0.01 and p= 0.05, respectively). The addition of ADA2 (1 ug/ml and 10 ug/ml) had a stimulatory effect on myeloid progenitors, although not statistically significant. TNFα marrow plasma levels were higher in 4/9 patients (44 %) compared to 1/6 (17%) of healthy controls (p=0,002). No differences were noted in marrow plasma IFNγ levels.

Conclusion

Our study shows that the bone marrow of DADA2 patients is characterized by an inflammatory milieu and by a reduced growth of marrow progenitor cells, partially rescued in vitro by anti-TNFα and Eltrombopag.

Further studies are needed to better understand the mechanisms of BM damage and to develop novel potential therapeutic approaches.
Daratumumab Overcome Platelet Transfusion Refractoriness in Patients with Aplastic Anemia: A Pilot Trail
Authors: Gao Zhen , Pan Hong , Huang Jinbo , Zhao Xin , Zhang Lele , Li Weiwang , Li Jianping , Nie Neng , Zhao Jingyu , Li Liyun , Xu Jing , Yu Xiao , Kuang Zhexiang , Ge Meili , Fang Liwei , Shi Jun
Published: December 2024

Introduction

Platelet transfusion refractoriness (PTR) represents a significant clinical challenge, markedly elevating the risk of hemorrhagic mortality in some patients with transfusion-dependent aplastic anemia. There is an urgent need for effective therapeutic strategies to enhance platelet transfusion responsiveness, beyond the administration of repeated platelet transfusions.

Methods

We conducted a single-arm, single-center, prospective pilot study involving patients with aplastic anemia who exhibited platelet transfusion refractoriness, as evidenced by a decrease in the corrected count increment (CCI) on at least two occasions (1-hour CCI < 7500 or 24-hour CCI < 4500 post-transfusion). Daratumumab was administered intravenously at a dose of 8 mg per kilogram of body weight once weekly for four consecutive weeks. The primary endpoints were adverse events and overall response rate (ORR), defined as the percentage of patients achieving at least two effective platelet transfusions, followed by a 12-week follow-up.

Results

A total of 10 patients were recruited with 8 reaching the 12-week primary endpoint. Within this subset, one patient was administered daratumumab monotherapy, six received a combination therapy with cyclosporine, and one was treated with a regimen including tacrolimus and danazol. The median baseline platelet count was 2.5×109 per liter (range, 1 to 13). The ORR at 12 weeks was 87.5% (7 out of 8 patients), with a median time to response of 3 weeks (range, 1 to 6). The most frequently observed adverse events were grade 1-2 electrolyte imbalances (75%) and grade 1 general symptoms (62.5%), such as fatigue, headache, and insomnia. Throughout the study, a total of 38 transfusions were administered, with transfusion reactions occurring in 4 cases (10.5%). The infection rate during the 12-week follow-up period was 50% (4 out of 8 participants), with infections classified as severity grade 2-3. Importantly, no fatalities were reported during the study period.

Conclusion

Anti-CD38 targeted therapy demonstrates promising preliminary efficacy in addressing platelet transfusion refractoriness, while exhibiting mild and tolerable adverse reactions in patients with aplastic anemia. (Funded by the National Clinical Research Center for Blood Diseases Fund for Clinical Research; ClinicalTrial.gov ID: NCT05832216).

Keywords: Aplastic anemia, Platelet transfusion refractoriness, CD38 monoclonal antibodies
A Comprehensive Stratification Integrated the Clinical, Pathological, and Molecular Biological Features to Distinguish High-Risk Mantle Cell Lymphoma
Authors: Yang Ping , Li Chunyuan , Liu Shuozi , Yang Yuan , Zhang Weilong , Wang Jing , Chen Yingtong , Jing Hongmei
Published: December 2024

Background The heterogeneity of the clinical course, biology and genomics manifestations has observed in MCL patient. The unified consensus information on high-risk MCL definition is sparse and unclear. A more refined risk stratification are imperative needed for MCL patients. In our study, we aimed to define the generalized high-risk group who had more than one factors including MIPI, aggressive pathological features, TP53 alterations and complex karyotypes.

Methods This retrospective study analyzed data for adult patients diagnosed with MCL from January 2000 to October 2022 at 19 comprehensive hospitals in China with the total of 1017 patients. 861 patients with complete medical records and follow-up data were included in the analysis. Among of them,150 patients belonged to the narrow definition of high-risk group by MIPI score, 284 patients were the generalized high-risk group by comprehensive factors(Figure 1).

Result According to the narrow definition of high-risk stratification, the median PFS was 46.0 and 21.0 months, and the 5-year PFS was 39.3% and 15.6% in low-risk group(n=659) and high-risk group(n=150), respectively. The median OS was 106 and 47.0 months, the 5-year OS was 72.3% and 46.1%((all p<0.05). According to generalized high-risk stratification, the median PFS was 51.0 and 23.0 months in the low-risk group (n=562) and high-risk group(n=283), and the 5-year PFS was 42.8% and 17.9%, respectively. The median OS was 118.0 and 57.0 months, with the 5-year OS of 78.3 % and 49.2%, respectively (all p<0.05, Figure 2). Furtherly, prognostic analysis in the generalized high-risk grouprevealed that high-risk group according to MIPI score and patients with TP53 alterations were independent prognostic factors for PFS.TP53 alterations combined with other high-risk genes, elevated β-2 microglobulin levels, and the presence of B symptoms were independent prognostic factors for OS in this study.

Conclusions Our study indicated that the generalized high-risk group that integrated the clinical, pathological, and molecular biological features had a good predictive value in the prognosis of MCL. It is a simple and feasible method to distinguish high-risk mantle cell lymphoma and provide better treatment decisions for clinical practice.
Gut Microbial Metabolite Butyrate Alleviates the Susceptibility to Septic DIC By Suppressing Caspase-11/ Gsdmd-Dependent Macrophage Pyroptosis
Authors: Li Yingying , Wu Zhong , Jiang Huiwen , Chen Zhaozhao , Xu Min , Shu Jinhui , Wang Jingming , Xie Qinying , Deng Jun , Hu Yu , Luo Lili , Mei Heng
Published: December 2024

Introduction: Disseminated intravascular coagulation (DIC), a prevalent complication of sepsis, is a significant contributor to multiple organ dysfunction syndrome (MODS) and mortality in septic patients. The intestine has been considered as the motor of MODS in sepsis. We identified a disparate predisposition to DIC in septic mice, which we categorized into two groups-DIC-resistant (Res) and DIC-sensitive (Sen) mice. However, the mechanism behind this phenomenon remains unclear.

Methods: Cecal ligation and puncture (CLP) was used to induce septic DIC. Feces were collected before CLP to detect intestinal flora composition by 16S rRNA and short-chain fatty acids by targeted metabolome. Fecal microbiota transplantation was performed to study the role of gut microbiota and its metabolites in susceptibility to septic DIC.Macrophage pyroptosis were comprehensively assessed by morphology, levels of IL-1β and lactate dehydrogenase (LDH) in plasma and supernatants. The Western blotting was used to confirmed pyroptosis at the molecular level.

Results: The Sen mice were more likely to develop DIC and multiple organ failure than Res mice. The relative abundance of butyric-producing bacteria, Firmicutes and the concentration of butyrate in Res mice were significantly higher compared to the Sen mice. Intriguingly, the susceptibility to septic DIC could be transmitted via the intestinal microbiota. Meanwhile, butyrate can effectively reduce the mortality of DIC, concurrently alleviating coagulopathy and mitigating MODS. Mechanistically, the proportion of peritoneal macrophage pyroptosis, plasma levels of IL-1β and LDH in Sen mice were statistically higher than that in Res mice, and butyrate could reduce these indicators and downregulate the expression of histone deacetylase 3 (HDAC3). For LPS-transfected bone marrow derived macrophages (BMDMs), sodium butyrate (NaB), HDAC3 inhibitor, caspase-11 inhibitor, and GSDMD inhibitor could improve the changes of morphology, which was manifested by diminished cellular antennae, augmented swelling, and the presence of distinct pyroptosis vesicles. In addition, the release of IL-1β was significantly reduced by NaB and inhibitors above, compared to LPS-transfected BMDMs. Under LPS-transfected condition, NaB could impeded HDAC3 expression compared to the control and HDAC3 inhibitor groups. Moreover, NaB and HDAC3 inhibitor effectively inhibited the cleavage of caspase-11 and GSDMD.

Conclusion: Butyrate, a metabolite of enteric Firmicutes, exerts a suppressive influence on the activation of the caspase-11/GSDMD pathway in macrophages by modulating the activity of HDAC3, subsequently impeding the onset and progression of DIC in sepsis, providing a novel theoretical basis for targeted intervention in sepsis and DIC.
Association between Venetoclax Plasma Concentrations and Treatment Response of Acute Myeloid Leukemia
Authors: Yang Yufei , Zhao Lei , Yang Jinjun , Li Xuefeng , Wu Yu
Published: December 2024

Background:

Venetoclax (VEN) as a BCL-2 inhibitor, has shown promising results in treating adult acute myeloid leukemia (AML). However, studies on the relationship between VEN plasma concentrations and clinical efficacy and prognosis are still insufficient. According to the importance of plasma concentrations in clinical treatment, this study aims to analyze the impact of VEN plasma concentrations on the efficacy and prognosis of AML treatment.

Method:

This retrospective study included AML patients treated with VEN who were assessed for efficacy and at least one measurement of VEN plasma concentrations at West China Hospital from November 2021 to June 2024.

Results:

A total of 92 AML patients treated with VEN were included, encompassing both newly diagnosed and relapsed/refractory patients. In these patients, overall response rates (ORR), including CR, CRh, CRi, and PR, were 52.2%. Patients with response had higher VEN plasma concentrations compared with those no response (Wilcoxon, 2387.0 ng/ml vs. 1733.5 ng/ml, P=0.043) and had a significantly better overall survival (691d vs. 257d, P=0.014). There was a certain correlation between VEN plasma concentrations and efficacy (P=0.043). The optimal cut-off for VEN plasma concentrations was 2250 ng/ml and patients with higher VEN plasma concentrations (N=38) showed better response than lower concentrations (N=54) (chi-square, 65.8% vs. 42.6%, P=0.047). But there was no significant difference in survival on either side of 2250 ng/ml (358d vs. 268d, P=0.725).

Conclusion:

VEN plasma concentrations were associated with clinical response, suggesting that VEN plasma concentrations above 2250 ng/ml might achieve beneficial clinical outcomes. However, higher concentrations do not mean longer survival, which may be related to adverse reactions caused by high concentrations.
Identification of the Saga Complex As a Key Regulator of Hematopoiesis
Authors: Haney Michael , Shankar Archana , Olender Leonid , Hsu Ian , Miyauchi Masashi , Meaker Grace , Kaito Satoshi , Rizq Ola , Khoo Hwei Minn , Bozhilov Yavor , Palovics Robert , Igarashi Kyomi , Bhadury Joydeep , Munson Christy , Mack Paul K. , Tan Tze-Kai , Rehwinkel Jan , Iwama Atsushi , Wyss-Coray Tony , Nakauchi Hiromitsu , Wilkinson Adam
Published: December 2024

The hematopoietic system declines with age, and its dysfunction is associated with many diseases, ranging from infections to cancers. However, the processes that sustain lifelong hematopoiesis remain incompletely understood. To identify genetic regulators of hematopoiesis, we developed an in vivo hematopoietic stem cell (HSC)-based large-scale CRISPR knockout screening platform. Targeting ~2000 genes with this platform, we identified SAGA complex members Tada2b and Taf5l as key regulators of hematopoiesis. Genetic perturbation of Tada2b or Taf5l in murine HSCs led to significant HSC expansion ex vivo, strongly inhibited hematopoiesis in vivo, led to a buildup of immature hematopoietic cells in the bone marrow, and was associated with upregulation of interferon pathway genes. These results were validated in an ex vivo human HSC culture as well, and loss of these SAGA complex components enhanced the cell outgrowth and drives interferon pathway gene expression in an in vivo human myelodysplastic syndrome model, suggesting that loss of SAGA complex activity could contribute to hematological disease progression in humans. Altogether, this study offers a new platform to screen genetic regulators of hematopoiesis and identifies novel regulators of hematopoiesis.
Comparing Estimated Glomerular Filtration (eGFR) Equations in Patients with Transfusion-Dependent Thalassemia
Authors: Ogunsanya Olubunmi , Kirpalani Amrit , Zavitz Jennifer , Geerlinks Ashley , Tole Soumitra
Published: December 2024

Renal dysfunction is a well-described complication in children with transfusion-dependent thalassemia (TDT), and is linked to chronic anemia, hypoxia, hemolysis as well as nephrotoxicity from free iron and chelating agents. Nuclear medicine-based (DTPA) measurement of glomerular filtration rate (nmGFR) remains the gold standard test of renal function but is expensive, invasive and unsuitable for routine screening. Creatinine is the most used biomarker for renal function but is less accurate in children and those with low muscle mass. Cystatin C has been widely adopted as a more accurate marker but can be affected by iron chelation therapy. While early detection of renal dysfunction is important to guide management, there remain limited data on the most reliable method to estimate eGFR in children with TDT.

We designed a single-center retrospective cohort study to explore the correlation between nmGFR and eGFR equations based on creatinine, cystatin C, or both. Patients with TDT aged 0-17 years who had a nmDTPA study and serum cystatin C between 2013-2023 were included. Cystatin C measurements taken on the same day or up to 7 days from their DTPA scan were used. Eight eGFR calculations were performed (Schwartz, Schwartz-Lyon, Cr CKID U25, Filler, CysC Zapatelli, CysC CKID U25, Cr-CysC Zapatelli, Cr-CysC CKID U25). The Pearson correlation (rho) was used to measure the correlation of each eGFR equation versus the nmGFR. Mean bias (95% confidence intervals, CI) was calculated using the Bland-Altman method assuming constant variance.

Eleven children (55% female) with TDT (73% β0/β0 or β0/β+, 9% E0/β0, 18% non-deletional alpha thalassemia) with median age of 13 years were included. Nine (82%) children were receiving deferasirox for iron chelation, one (9%) was receiving deferoxamine and one (9%) was being phlebotomized having undergone a hematopoietic stem cell transplant. Two (18%) children were concurrently receiving hydroxyurea.

The mean nmGFR was 94.1+/-20.9 mL/min/1.73 m2, 72.3% had a normal nmGFR > 90 mL/min/1.73 m2. The Cr-CysC CKID U25 equation showed the strongest correlation to nmGFR (rho=0.84, p=0.002) with the lowest risk of bias (-3.01, 95% CI -28.5-25.1). The Cr CKID U25 and CysC CKID U25 equations showed moderate correlations [(rho=0.61, p=0.045) and (rho=0.64, p=0.047)] but showed significant bias [(-21.8, 95% CI -58.1-14.6) and (19.2, 95% CI -10.3 - 48.7)]. The Schwartz, Schwartz-Lyon, Filler, CysC Zapatelli, Cr-CysC Zapatelli equations did not correlate well with the nmGFR.

Most commonly used eGFR calculations poorly estimate renal function in children with transfusion-dependent thalassemia. The Cr-CysC CKID U25 equation showed strong correlation with the nmGFR and may represent a better biomarker for renal dysfunction in this population. A large prospective cohort study is needed to confirm and validate these findings.
Investigating the Role of Neutrophil Extracellular Traps (NETs) in Multiple Myeloma Pathogenesis and Disease Evolution
Authors: Dowling Paul , Dunphy Katie , Bazou Despina , Miettinen Juho J. , Heckman Caroline A. , O'Gorman Peter
Published: December 2024

Neutrophils implement a variety of mechanisms to fight infection and neutralize pathogens, including phagocytosis and degranulation, as well as the more recently characterized release of neutrophil extracellular traps (NETs) termed NETosis. NETs are web-like DNA structures combined with histones and antimicrobial proteins that are released from stimulated neutrophils. Stimulated neutrophils migrate and accumulate at the site of infection and eliminate microbes by phagocytosis, reactive oxygen species (ROS) production, and cytoplasmic granule release. The landscape of NETs in cancer is quickly changing as current basic and clinical research is providing evidence substantiating the role of neutrophils in cancer progression and therapeutic resistance. Several studies support the functional role of NETs in cancer therapeutic resistance, involving T-cell exhaustion, drug detoxification, angiogenesis, epithelial-to-mesenchymal transition, and extracellular matrix remodeling mechanisms. Previously, our group performed a mass spectrometry-based label-free quantitative proteomics analysis of bone marrow mononuclear cells (BMNCs) and blood plasma from multiple myeloma (MM) patients with and without extramedullary spread (soft tissue plasmacytomas) (PMID: 37568580). Pathway analysis identified neutrophil extracellular trap formation associated proteins (including proto-oncogene tyrosine-protein kinase Src (SRC) and spleen tyrosine kinase (SYK)), as significantly increased in patients with extramedullary myeloma (EMM). To assess NET formation in EMM based on a secreted/shed protein signature, plasma concentrations of the main NETosis markers, neutrophil elastase (ELA2), myeloperoxidase (MPO), citrullinated histone H3 (CitH3), and circulating nucleosomes, were evaluated using enzyme-linked immunosorbent assays (ELISAs). Plasma levels of ELA2 were significantly increased in EMM patients compared to MM (no evidence of extramedullary spread), while MPO plasma levels showed a trend towards increased concentrations in EMM patients. Building upon the hypothesis that NETs could play a role in the establishment of resistance/aggressive disease, future clinical applications could involve both monitoring and pharmacological targeting of NETs to predict and improve response to therapy.
Real-World Experience of Blinatumomab for 8 Years Regarding Predictive Factors Including Lymphocyte Kinetics for Response and Survival Outcome in Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia
Authors: Lee Seonghan , Yoon Jae-Ho , Kwag Daehun , Min Gi-June , Park Sung-Soo , Park Silvia , Lee Sung-Eun , Cho Byung-Sik , Eom Ki-Seong , Kim Yoo-Jin , Kim Hee-Je , Min Chang-Ki , Cho Seok-Goo , Lee Seok
Published: December 2024

Background: Blinatumomab became available in Korea since 2016 and has proved its efficiency for remission and safe bridging role to allo-HCT in patients with R/R BCP-ALL. This T-cell engager system has changed the paradigm of ALL treatment in terms of safe chemotherapy-free approach and need for understanding T-cell immunology.

Aim: Here, we report our long-term experience of blinatumomab regarding well-known traditional factors and lymphocyte kinetics during blinatumomab treatment.

Methods: We analyzed 152 adult patients (median age 59.5 years, range 18-79) with R/R BCP-ALL treated with blinatumomab between 2016 and 2023 (110 Ph-negative, 42 Ph-positive). Ph-negative BCP-ALL could be treated with blinatumomab from first line salvage while Ph-positive BCP-ALL after Dasatinib failure, thus at least from second line salvage. The standard protocol consisted of pre-phase dexamethasone, first cycle blinatumomab 28 days (9mcg during initial 7 days followed by 28mcg for 21 days) was followed by 2-week resting period and second or more cycle of 28mcg blinatumomab for 28 days. For post-remission therapy, allo-HCT was conducted as early as possible.

Results: After first cycle, CR was achieved in 98 (64.5%) and best response was in 104 (68.4%) patients after median 2 cycles, and 74 responders (48.7%) subsequently proceeded to allo-HCT. After median follow-up of 45.2 months, 4-year OS and CIR was 25.7% and 61.0% in entire cohort, and 37.0% and 47.9% after allo-HCT. We observed higher relapse rate with short CR duration, PB blast prior to blinatumomab, and later-line salvage were related with poor response to blinatumomab and old age and early relapse for poor OS even after allo-HCT. Regarding absolute lymphocyte count (ALC), ALC at first day of blinatumomab was not significantly associated with CR rate (OR=1.00, P=0.0523), OS (ALC≥500: 21.8% vs. ALC<500 36.6; P=0.160), as well as CIR (ALC≥500: 50.2% vs. ALC<500 55.7; P=0.819). However, we observed ALC decrement>2000/mcL at 2-weeks after blinatumomab was predictive for poor response (OR 2.88, P=0.011), and that ALC<250/mcL and decrement>2000/mcL at 2-weeks after blinatumomab was associated with poor survival (Figure).

Conclusions: Our data shows that blinatumomab can be effective even in patients with low ALC at first day of blinatumomab, and that lesser decrease in ALC predicts higher CR in adult patients with R/R ALL.