bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hetrombopag, an Emerging Iron-Chelating Agent, Alleviates Systemic Iron Overload
Authors: Yufei Zhao , Zhao Xin , Yang Wenrui , Zhang Fengkui 
Published: December 2024

Background: Iron overload is a syndrome in which excessive iron accumulates in the body, leading to tissue damage and functional disorders. This condition is common in patients with refractory anaemia who receive long-term red blood cell transfusions. Hetrombopag (HPAG) is a new generation, oral, small molecule, nonpeptide thrombopoietin receptor agonist that can chelate iron and alleviate iron overload while promoting haematopoiesis. Nevertheless, there is currently a lack of research on the iron-chelating function of HPAG, and its mechanism of regulating iron metabolism in the body is not clear.
Aims: The aim of this study was to clarify the iron-chelating function of HPAG, its effects on haematopoiesis, immune abnormalities, and tissue damage caused by iron overload and explore its potential mechanism of systemic iron metabolism, providing a new theoretical basis for the treatment of haematological diseases with HPAG.
Methods: Iron overload was induced in mice by intraperitoneal injection of iron dextran, and treatment was performed with HPAG, deferasirox (DFX, an iron chelator), or ferrostatin-1 (Fer-1, a ferroptosis inhibitor). The iron-chelating function of HPAG and its effects on haematopoiesis, immune abnormalities, and tissue damage caused by iron overload were clarified in vivo, and the underlying mechanism was explored via transcriptomics and lipidomics.
Results: Iron-overloaded mice treated with HPAG or DFX showed recovery in terms the of weight loss, hepatomegaly, histopathological iron deposition, reduced glutathione/oxidized glutathione (GSH/GSSG) balance and superoxide dismutase (SOD) activity, and increased non-transferrin-bound iron (NTBI) and malondialdehyde (MDA) levels caused by iron overload. Importantly, compared with untreated mice, iron-overloaded mice treated with HPAG, DFX, or Fer-1 presented restored tissue fibrosis and increased numbers of long-term haematopoietic stem cells (LT-HSCs), short-term haematopoietic stem cells (ST-HSCs), and Treg cells and an increased CD4/CD8 ratio. Lipidomic and transcriptomic data from the liver and c-kit+ cells in bone marrow revealed that HPAG induces molecular changes consistent with intracellular iron reduction and lipid peroxidation inhibition, with decreased expression of the HAMP, FTH1, BMP6, and HMOX1 genes. Furthermore, compared with those in DFX-treated mice, immune response-related signalling pathways, especially those related to the inhibition of the response to type I interferon, were significantly enriched in HPAG-treated mice.
Conclusion: HPAG is an emerging iron-chelating agent and a potential inhibitor of ferroptosis that alleviates tissue damage, haematopoietic stem cell injury, and immune abnormalities caused by systemic iron overload and provides an immunoregulatory function.
Venetoclax Plus D-CAG (decitabine, cytarabine, aclarubicin, G-CSF) for Elderly or Unfit Patients with Newly Diagnosed Acute Myeloid Leukemia: A Multicenter, Prospective Study
Authors: Ma Hongbing , Du Yiwen , Li Jianjun , Rao Jin , Guo Yong , Yang Yunfan , Zhang Duanzhong , Wang Jia , Liao Yi , Gong Yuping 
Published: December 2024

Background:
Induction regimens with satisfactory remission rates are limited for patients with acute myeloid leukemia (AML) who are elderly or ineligible for intensive chemotherapy.
Objectives:
This study aims to evaluate the efficacy and safety of venetoclax plus decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (VD-CAG) for newly diagnosed AML patients who are elderly or ineligible for intensive chemotherapy.
Design:
This is a single-arm, multicenter, prospective phase I/II study.
Methods:
The patients(n=40) received 1 cycle of the VD-CAG regimen for induction chemotherapy. The primary endpoint was composite complete remission (CRc) after 1 cycle of induction chemotherapy. The secondary endpoints were measurable residual disease (MRD) by flow cytometry and adverse events.
Results:
The median age of the patients was 64 (55-81) years, and 10 patients (25%) had secondary AML. Our results showed that 1 cycle of VD-CAG had a high overall response rate of 97.5% and CRc of 95%, and all 10 patients with secondary AML achieved CRc. Moreover, the patients who achieved CRc had deep remission, with MRD-negativity of 71.1% and 54.2% by flow cytometry and molecular assessment, respectively. In addition, blood cell recovery was quick, with a median time to absolute neutrophil count ≥ 1.0×109/L and platelet count ≥ 100×109/L at 19 days and 15.5 days, respectively.
Conclusions:
VD-CAG demonstrates high efficacy as an induction treatment for elderly or unfit patients with newly diagnosed AML, and it could be an alternative upfront therapy for this subpopulation, Trials with large-scale subjects are needed for further validation, especially for secondary AML.
All-Trans Retinoic Acid Enhances CS1-BCMA Dual-Target CAR-T Cells in Multiple Myeloma
Authors: Zhang Yinqiang , Zhuolin Wu , Luo Wenjing , Li Chenggong , Mei Heng 
Published: December 2024

Background:CS1-BCMA dual-target chimeric antigen receptor T cell (CAR-T) has exhibited superior efficacy in multiple myeloma (MM). However, there are still obstacles such as target down-regulation and barriers to immune infiltration, which results in refractory or relapse in certain patients. All-trans retinoic acid (ATRA) has been reported to upregulate the expression of CD38 and modulate the tumor microenvironment (TME), but its synergistic effect on CS1-BCMA CAR-T and potential mechanism remains unexplored.
Methods:CS1-BCMA dual-target CAR-T cells were generated by lentiviral transduction of healthy donor T cells. BCMA/CS1 expression was measured by flow cytometry and quantitative real-time PCR after 24 hours coculture of MM cells and ATRA. Tumor lysis of ATRA combined with CS1-BCMA dual-target CAR-T cells was assessed in vitro and in NXG xenograft models. Cancer related fibroblast (CAF) was induced by bone marrow mesenchymal stem cell coculturing with MM cell lines in transwell inserts (0.4um) for 48 hours. Transcriptome sequencing was conducted to reveal the mechanism of ATRA sensibilizing MM cells to CAR-T therapy.
Results: Experiments in vitro demonstrated thatcoculturing MM cell lines with ATRA at concentrations of 10nM-1000nM upregulated BCMA expression (MM.1S: 1.5-fold, P&lt;0.01 at 1000nM by flow cytometry), which was verified in the NXG xenograft model. ARTA synergized CS1-BCMA dual-target CAR-T cells against MM cells both in vitro (MM.1S: P&lt;0.01 at 1000nM for 6-hour coculturing) and in the NXG xenograft model. The addition of CAF to MM cells impaired the cytotoxicity of CAR-T by 27% (P&lt;0.05) but its immunosuppression was reversed by ATRA (P&lt;0.05). Transcriptome sequencing analysis of MM cells showed that ATRA upregulated the arachidonic acid metabolism pathway and down-regulated of the TGF-β pathway..
Conclusion: Our study expands on the hypothesized mechanism that ATRA promotes the cytotoxicity of CS1-BCMA dual-target CAR-T cells by upregulating the expression of BCMA and reversing the immunosuppressive effect of CAF. Sequencing demonstrates that tumor sensitivity is associated with metabolism and TGF-β pathway. Further underlying mechanisms and clinical translation need to be explored.
Split CAR-T Cells Targeting CD312 and TIM-3 for AML to Reduce the Risk of Antigen Escape
Authors: Chai Xiao , Zhang Xiaomei , Zhao Mingfeng , Zhang Rui 
Published: December 2024

Background: Acute myeloid leukemia (AML) is a malignant disorder characterized by the presence of a limited number of leukemia-initiating cells or leukemic stem cells (LSCs), which form a clonal population. Traditional therapies often fail to achieve durable responses due to the disease's intrinsic resistance mechanisms and the presence of leukemic stem cells. CD312 Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising treatment modality. However, its efficacy is limited when targeting a single antigen, leading to antigen escape and subsequent relapse. TIM-3 CAR-T cell therapy may improve the clinical outcomes of patients with AML by eradication of the LSCs present in the minimal residual disease (MRD).
Objective: In this study, we aim to evaluate the efficacy of modified split CD312/TIM-3 CAR-T cell against AML tumor cells with varying levels of antigen expression through in vitro experiments and immunodeficient mouse models, particularly focusing on their ability to eradicate LSCs and reduce the risk of relapse following CAR-T cell infusion.
Methods: The expression levels of CD312 and TIM-3 were assessed in AML cell lines and primary blasts by flow cytometry. Subsequently, split CD312/TIM-3 CAR-T cell were developed. The cytotoxicity of CD312 CAR-T cell and split CD312/TIM-3 CAR-T cell were evaluated in vitro against AML cell lines, primary blasts. Additionally, the activation rates and cytotoxicity of split CD312/TIM-3 CAR-T cell against CD34+CD38- LSCs and normal monocyte were assessed in a coexisting milieu consisting of CAR-T cells, primary blasts, and CD64-positive monocyte. Then, the cellular characteristics and functionality were compared through in vitro experiments. Ultimately, the efficacy and safety of CD312 CAR-T cell and split CD312/TIM-3 CAR-T cell were evaluated in vivo.
Results: Split CD312/TIM-3 CAR-T cell demonstrated significantly enhanced cytotoxicity against AML cell lines, primary blasts and CD34+CD38- LSCs compared to CD312 CAR-T cell. Meanwhile, split CD312/TIM-3 CAR-T cell revealed a remarkable cytotoxicity against CD34+CD38- LSCs and remained unaffected by monocyte influence derived from healthy donors PBMCs in a coexisting milieu consisting of CAR-T cells, LSCs and CD64-positive monocyte. In a relapsed AML animal transplantation model, split CD312/TIM-3 CAR-T exhibited remarkable anti-AML activity, leading to prolonged survival of the treated animals. Importantly, the split CAR-T cells could be safely eliminated in emergency situations through a natural safety switch mechanism, ensuring that hematopoietic stem cells remained unaffected.
Conclusion
The split CAR-T cells targeting CD312 and TIM-3 exhibit potential as a promising and secure therapeutic approach for patients with refractory and relapsed AML, particularly focusing on their ability to eradicate LSCs and reduce the risk of relapse following CAR-T cell infusion.
Ribosome Profiling Sequencing Reveals LPIN1 As a Potential Therapeutic Target for Acute Myeloid Leukemia with FLT3 -ITD Mutation
Authors: Yuang Gao , Zhang Qianyu , Lv Zhichun , Liu Shuhong , Sun Yide , Gao Huiying , Zhao Xiongwei , Li Xin , Xue Yang , Li Hao , Li Changyan , Ning Hongmei 
Published: December 2024

Internal tandem duplication mutations of FLT3 (FLT3-ITD) are the most frequent genetic alteration in adult acute myeloid leukemia (AML) and confer poor prognosis. The use of FLT3 inhibitors has improved outcome among FLT3-ITD mutant patients, but clinical efficacy is transient and limited, largely due to the emergence of drug resistance which can occur through activation of alternative signaling pathways or metabolic degradation of the inhibitors within the tumor microenvironment. Therefore, it is urgent to explore new intervention targets and develop novel therapeutic strategies for FLT3-ITD mutant AML.
In this study, we use ribosome profiling sequencing from 13 healthy donors and 35 AML patients (including 17 FLT3-ITD mutant AML cases and 18 non-FLT3-ITD mutant AML cases) to identify differentially expressed genes.In FLT3-ITD mutant AML patients, 143 up-regulated genes were obtained, which are mainly involved in cell adhesion, embryonic skeletal cell formation, coping with hypoxia, and T-cell activation etc. 538 down-regulated genes are mainly associated with signal transduction, cell differentiation etc. Among these up-regulated genes, we validated the abnormally elevated expression of LPIN1 in FLT3-ITD mutant AML patients using RT-PCR. LPIN1 has been previously reported to be a divalent magnesium ion-dependent phosphatidic acid phosphatase and play a key role in lipid metabolism. Analysis of clinical data from public databases indicated that high LPIN1 expression is positively correlated with poor prognosis in FLT3-ITD mutant AML patients.
In FLT3-ITD mutant AML cell lines, both shRNA-mediated knockdown of LPIN1 expression and pharmacological inhibition of LPIN1 activity suppressed cell proliferation and increased apoptosis, indicating that LPIN1 plays an important role in the growth and survival of FLT3-ITD mutant AML cells. The combination of the LPIN1 inhibitor Propranolol with the FLT3 inhibitor Quizartinib significantly reduced the cell proliferation of both FLT3-ITD AML cell lines and primary FLT3-ITD mutant AML patient samples. Furthermore, the combination of Propranolol with Quizartinib eradicated leukemic cells and prolonged survival in a xenograft FLT3-ITD mutant AML model.
In summary, our study demonstrates that LPIN1 plays a pivotal role in FLT3-ITD mutant AML pathogenesis and chemotherapy resistance. LPIN1 inhibition synergizes with FLT3 inhibitor to eliminate FLT3-ITD AML cells in vitro and in vivo, providing a new therapeutic target for FLT3-ITD mutant AML.
Impact of Ultra Rapid Molecular Profiling on Treatment Delays and Healthcare Utilization of Patients Hospitalized for Acute Leukemia
Authors: Dhawale Tejaswini , Nardi Valentina , Wang Charlotte , Bard Adam , Essigmann Natalia , Leonard Daniel , Graubert Timothy Aaron , Fathi Amir T. 
Published: December 2024

Background
Molecular testing is fundamental to treatment decisions in patients with acute leukemia. The impact of rapid molecular profiling on the timing of treatment initiation and healthcare utilization in patients hospitalized for suspected acute leukemia has not been described.
Methods
We conducted a retrospective chart review of patients hospitalized and treated for suspected acute leukemia at Massachusetts General Hospital between September 2023 and April 2024. We conducted a detailed workflow analysis comparing the time to obtaining molecular profiling results from admission [“time to results” or TTR] between routine (legacy) methods (i.e., RT-PCT, karyotype, FISH, targeted DNA and RNA sequencing) and an ultra-rapid genomic profiling test (Thermo Fisher Genexus Oncomine Myeloid Panel, or “Genexus”) which was run in parallel. We used linear regression models to evaluate the impact of TTR on time to treatment initiation from admission [TTTI] and hospital length of stay [LOS].
Results
Of the 111 patients who had ultra-rapid genomic profiling conducted during the study period, 57 (51.4%) were adult patients who were hospitalized for diagnostic workup and treatment of suspected acute leukemia. The most common leukemia subtypes were acute myeloid leukemia (n=39/57, 68.4%), B-lymphoblastic leukemia (n=9/57, 15.8%), and acute promyelocytic leukemia (n=4/57, 7.0%). The mean TTTI was 5.2 days (range 1-17) and mean LOS was 30.9 days (range 3-86). Genexus had a mean TTR of 3.1 days (range 1-8), whereas legacy methods had a mean TTR of 5.4 days (range 3-10). Longer TTR was associated with longer TTTI (b=0.95; SE=0.20; P=&lt;0.001) and longer LOS (b=4.08; SE=1.30; P=&lt;0.003).
Conclusions
Ultra-rapid molecular profiling reduces the time to obtaining actionable genetic sequencing results for patients hospitalized for suspected acute leukemia by 2 days compared to legacy methods. Delays in obtaining molecular profiling of these patients is associated with treatment initiation delays and longer hospital length of stay, underscoring the importance of expanded access to ultra-rapid molecular profiling for acute leukemia. Further work is needed to elucidate the full economic impact of ultra-rapid molecular profiling on overall healthcare utilization.
The “Walk through the Clinic Door” Effect: Differences in Survival and Toxicity Based on Site of CAR T Administration in a Default Outpatient CAR T Program
Authors: Hunter Bradley D. , Hoda Daanish , Asch Julie , Sharma Prashant 
Published: December 2024

Introduction:
Due to the potential of long-term PFS, CAR T-cell therapy is frequently given to patients with suboptimal performance status (PS). Differences in outcomes regarding PS of 2 or greater have been demonstrated in real world analyses of CAR T outcomes. However, it is unknown if patients who require hospitalization at the time of CAR T-cell infusion due to non-CAR T comorbidities have differential outcomes compared to patients who would otherwise be able to “walk into clinic.” To date, many patients are infused with CAR T as inpatients due to monitoring needs, not necessarily due to medical status. The Intermountain Health CAR T-cell program's default infusion setting is outpatient for all commercial CAR T-cell products, thus allowing for a more accurate evaluation of the association between true inpatient status and CAR T-cell therapy related outcomes.
Methods:
Patients were identified from scheduling and billing records. Patient's oncology notes for CAR-T 30-day, 100-day and 1 year follow up visits were reviewed to evaluate setting of CAR-T infusion, treatment response and toxicity. Survival was determined by any death record within the IH EMR and the patient's last known visit date. Two proportion pooled z-tests were calculated to compare OS rates between inpatient and outpatient groups.
Results:
There were 125 patients included in this analysis. 5 patients received CAR T for ALL, 98 patients received CAR T for B-cell lymphoma, and 22 patients received CAR T for multiple myeloma. 27/125 patients (22%) received CAR T-cell therapy in the inpatient setting, and 98/125 (78%) were infused at as outpatients. Overall survival (OS) was significantly inferior for patients who received CAR T-cell therapy as inpatients vs outpatients, with 30 -day OS of 81% vs 97% (p=0.02), 90- day OS of 56% vs 92% (p&lt;0.01), and 1 year OS of 30% vs 77% (p&lt;0.01). 1 year CR rates were 19% in inpatients vs 48% in outpatients. Among lymphoma patients, 7/21 (33%) of those who received inpatient CAR T were alive at 1 year, vs 59/77 (77%) of outpatients (p&lt;0.01). For multiple myeloma patients, 1 year OS for those who received inpatient infusion was 25% (1/4 patients), vs 72% (13/18) for outpatients (p=0.02). Grade 3+ CRS in inpatients was 30% for inpatients vs 2% in outpatients (p,0.01). Grade 3+ ICANS was 26% in inpatients vs 10% in outpatients (p=0.04).
Conclusion:
Patients who require inpatient CAR T-cell administration due to performance status experienced significantly inferior OS and rates of CR at 1 year compared to patients who received CAR T-cell therapy in the outpatient setting. Rates of high-grade CRS and ICANS were significantly increased in patients who required inpatient CAR T administration. There appears to be a “walk through the clinic door” effect that may better capture CAR T-cell treatment risk for both outcomes and toxicity.
Combination of Mitoxantrone Hydrochloride Liposome with Gemcitabine, Cisplatin and Dexamethasone in Patients with Relapsed or Refractory Peripheral T Cell Lymphoma: A Phase I Study
Authors: Wei Chong , Zhou Shengyu , Xu Shuangnian , Jing Hongmei , Liu Hui , Zhang Wei , Zhou Daobin 
Published: December 2024

Background : Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature aggressive T-cell non-Hodgkin's lymphomas characterized by poor prognosis, highlighting the urgent need for novel therapeutic strategies. The combination of gemcitabine, cisplatin and dexamethasone (GDP) is recommended as the second-line treatment regimen according to lymphoma guidelines. Mitoxantrone hydrochloride liposome (Lipo-MIT) is a nano-drug that has been approved as the first treatment option for relapsed/refractory (r/r) PTCL, and has shown certain efficacy and safety in a pivotal phase Ⅱ study. This study aims to investigate the safety and efficacy of combining Lipo-MIT with GDP regimen (MGDP) in patients (pts) with r/r PTCL (NCT05441761).
Methods: Pts with r/r PTCL were recruited in this prospective, multicenter, open-label phase I study with a 3+3 dose-escalation design. Lipo-MIT was administered at three dose levels (DL1: 12 mg/m2, DL2: 16 mg/m2, DL3: 20 mg/m2, d1). Gemcitabine was given at 1000 mg/m2, cisplatin at 75 mg/m2, and dexamethasone at 40 mg on day 1 of each cycle (Q3W), and up to 6 cycles of therapy were planned. The primary endpoint is to explore the recommended phase II dose (RP2D) of Lipo-MIT. Secondary endpoints were to assess the tolerability (i.e. dose-limiting toxicity (DLT)), complete response (CR) rate, objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety.
Results: At data cut-off on 17 July 2024, 9 eligible pts (DL1: n=3, DL2: n=3, DL3: n=3) were enrolled including 3 with angioimmunoblastic T-cell lymphoma (AITL), 5 with PTCL-NOS and 1 with ALK positive anaplastic large cell lymphoma (ALCL). Among them, 6 cases (66.7%) were refractory pts. The median age of all pts is 46 (range, 31-70) years, and 4 pts (44.4%) were IPI score 3-5. 8 pts (88.9%) had advanced stage III or IV (Ann Arbor stage). No DLT occurred in this phase I study. And the RP2D was 20 mg/m2 for Lipo-MIT. The CR rate and ORR were 33.3% (3/9, 95% CI 7.5%-70.1%) and 55.6% (5/9, 95% CI 21.2%-86.3%), respectively. Besides, in refractory pts, the CR rate was 33.3% (2/6) and ORR rate was 66.7% (4/6). With a median follow-up of 5.1 (range, 0.03-20.2) months currently, the median PFS and OS will be reported after long-term follow-up. The common grade 3/4 Treatment-related adverse events (TRAEs) were mainly hematological toxicity, including neutropenia (66.7%), leucopenia (44.4%), anaemia (33.3%) and thrombocytopenia (11.1%). Overall, safety in all pts was tolerable during this study.
Conclusions: Lipo-MIT plus GDP (MGDP) regimen proves an promising efficacy in r/r PTCL pts with manageable safety profiles. A phase II, multi-center, single-arm study is ongoing to confirm and validate the findings from this study.
Safety, Efficacy, and Pharmacokinetics of Unecritinib (TQ-B3101) in Pediatric Patients with Relapsed/Refractory Anaplastic Lymphoma Kinase Positive Anaplastic Large Cell Lymphoma: A Phase I Study
Authors: Lu Suying , Huang Junting , Cai Ruiqing , Gao Yan , Zhu Jia , Wang Juan , Que Yi , Zhen Zi-Jun , Sun Feifei , Huang Huiqiang , Zhang Yizhuo 
Published: December 2024

Background
Over several decades, despite multiple treatment strategies for pediatric patients with anaplastic large-cell lymphoma (ALCL), approximately 30% of pediatric patients with ALCL experience relapse. This study investigated the safety and efficacy of unecritinib (TQ-B3101), a novel inhibitor of ROS1, ALK, and c-MET kinases, for the first time, in pediatric patients with relapsed/refractory (R/R) ALK+ ALCL.
Methods
This was an open-label, single-arm, phase I study. Eligible patients were aged 10-18 years. A 3+3 design was employed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). The dose levels investigated were 200, 250, and 300 mg twice daily (BID). The primary end points were safety and drug pharmacokinetics. Secondary endpoints included the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Results
Nine patients were screened, enrolled, and evaluated for toxicity and responses. No dose-limiting toxicities occurred, and the MTD was not reached. The most frequently reported treatment-related adverse events were neutropenia, leukopenia, vomiting, and nausea, predominantly of grade 1 or 2. Most of the administered unecritinib was hydrolyzed by carboxylesterase in the body to form unecritinib M, with Tmax of approximately 3 h. The ORR was 100%, with six complete and three partial responses. The median PFS and OS have not been reached, with all patients still alive. Six patients who underwent targeted gene panel sequencing had alterations in other genes, including TP53, MYC, KMT2D, and MYCL1, indicating poor prognosis.
Conclusion
Unecritinib showed a good safety profile and promising efficacy in pediatric patients with R/R ALK+ ALCL. The RP2D of unecritinib is 300 mg BID for pediatric patients older than 10 years.