bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of Radiotherapy for Hemostasis in Tumor-Related Bleeding
Authors: Deloughery Emma P , Wilson Byron , Grossberg Aaron
Published: December 2023

Introduction: Hemorrhage is a common complication of malignancy. When undergoing invasion and angiogenesis, malignancies can produce highly vascular lesions with friable and disorganized vessels that are prone to bleeding (Hughes and Radhakrishna, Br J Hosp Med (Lond), 2019). Among patients with advanced cancer, around 10% have bleeding symptoms, which can impact both the quality and quantity of life (Katano and Yamashita, Cureus, 2021). Palliative radiotherapy (RT) has been associated with achieving hemostasis in a variety of bleeding malignancies, including gastric, bladder, lung, and gynecologic cancers. The goal of this study was to better determine the efficacy of radiotherapy in reducing transfusion requirements.

Methods: A retrospective chart review of patients was performed after IRB approval. Patients who received radiation for controlling malignancy-associated hemorrhage were included in this study. The outcome measure was change in red blood cell (RBC) transfusion requirements from the month prior to the month following palliative RT. Data was obtained from the institution's electronic medical record. Change in transfusion requirements was analyzed using Welch's t-test and bleeding recurrence was analyzed using the exact test of goodness-of-fit.

Results: A total of 6002 patients were screened and 30 cases (63.3% female, average age at radiation treatment 62 years) were included in the study with RT treatment dates 2019-2023. Sixteen malignancy types were represented, with pancreatic adenocarcinoma and endometrial adenocarcinoma being the most common (both 4, 13.3%). Median radiation dose was 13 Gy (range 3-30) delivered over a median of 3.5 fractions (range 1-10). Bleeding was not noted to recur in 73.3% of the cases ( P = 0.02). For those patients with recurrent bleeding, median time from RT to recurrent bleeding was 58 days (range 11-544). Transfusion requirements decreased from an average of 2.7 RBC units over one month prior to completion of RT to 1.1 units for the month following completion of RT ( P = 0.03). Median survival after completion of RT was 132 days (range 3-698).

Conclusion: This study showed that radiation therapy resulted in apparent cessation of hemorrhage in over 70% of cases of hemorrhagic malignancies with a significant decrease in RBC transfusion requirements over one month. This suggests that RT is effective in stopping hemorrhage in a variety of malignancies as well as reducing transfusion requirements. More work is needed to test this hypothesis on larger populations, as well as investigation on the mechanism by which RT results in hemostasis.
Clinical Application of the IPSS-M Prognostic Score in Myelodysplastic Syndrome
Authors: Cheng Jian , Liu Jiangnan , Ge Zheng , Zhang Xinyu , Zhang Qiucheng , Chen Bao-An , Ma Jinlong
Published: December 2023

Objectives: Patients with myelodysplastic syndrome (MDS) currently get therapy in accordance with their prognosis scores. The newest MDS risk-stratified score, the IPSS-M, isn't still being extensively used in clinical practice and is based on clinical and molecular data. Comparing the IPSS-M score to the current IPSS-R score will enable us to assess the clinical relevance of the IPSS-M score, especially for low-risk MDS patients.

Methods: In order to determine the IPSS-R and IPSS-M scores, we gathered clinical, cytogenetic, and molecular information from 210 MDS patients who were diagnosed between 2016 and 2023 and followed up until April 2023. Harrell's c index and Kaplan-Meier survival analysis were used to examine the impact of the two scores on overall survival (OS).The lower-risk group included patients with IPSS-R≤3.5 and IPSS-M≤0, whereas the higher-risk group included the remaining patients. Analysis was done on the differences in gene mutations between the two risk groups based on the two scoring standards, as well as the impact of IPSS-M reclassification on the choice of therapeutic treatments.

Results: At least one genetic mutation was identified in 77.1% of patients. The genes ASXL1 (21.4%), TET2 (19.0%), TP53 (14.8%), and DNMT3A (13.3%) have the highest frequency of mutations. According to IPSS-R score, the higher-risk group's TP53 gene mutation rate was significantly higher than that of the lower-risk group; According to IPSS-M score, the higher-risk group had more instances of TP53 and ASXL1 gene mutations than the lower-risk group did, while the lower-risk group had a relatively higher incidence of SF3B1 gene mutations than the higher-risk group did. The difference in survival between IPSS-M groups was more prominent than that between IPSS-R groups under Kaplan-Meier survival analysis, which was used to assess the prognostic prediction power of IPSS-R and IPSS-M. When t 50 months, the Harrell's c index of OS predicted by IPSS-M exceeded that of IPSS-R (IPSS-R vs IPSS-M c-index: 0.710vs0.747, 0.692vs0.707, 0.705vs0.726, 0.752vs0.759, 0.743vs0.773, t=10, 20, 30, 40, 50 months), demonstrating that IPSS-M enhanced the outcome prediction.87 patients (41.4%) were re-stratified by IPSS-M, with 65 (30.9%) being upgraded and 22 (10.5%) being degraded. 64 patients (30.5%) who had changes in their IPSS-M scores qualified for reduced therapy, whereas 48 (22.9%) qualified for intensive treatment, including 32 patients who were reclassified as being in the lower risk category based on their IPSS-R scores.

Conclusions: The research shows that IPSS-M offers a more thorough prognostic evaluation than IPSS-R. Certain patients' treatment modalities may need to be changed as a result of modifying IPSS-M in clinical settings, especially those who were previously classified as low-risk.
HIV-Related Diffuse Large B Cell Lymphoma Influences on T Cell Exhaustion
Authors: Jiang Tingting , Peng Yu , Tang Xinyi , Chen Shuang , Yang Zailin , Liu Yao
Published: December 2023

BACKGROUD

HIV infection leads to T cell dysfunction, which triggers increased incidence of diffuse large B cell lymphoma (DLBCL). It has been shown that PD-1 inhibitors can better restore T cell function and effectively treat HIV-related lymphoma. However, the specific mechanism on the treatment of HIV-related DLBCL patients with PD-1 inhibitors is ambiguous, and related studies on the expression of PD-1 on T cells have not been reported. This study aimed to explore the regulatory role of altered immune function status in the microenvironment of HIV-related DLBCL and to analyze hyper-exhausted T cell subsets.

METHODS

Three patients with DLBCL, two patients with HIV and 11 patients with HIV-related DLBCL who were treated from September 2021 to December 2022 at the Chongqing University Cancer Hospital of were included. Single cell sequencing was used to analyze immune cell and tumor cell related genes in patients'lymph node tissues. InferCNV was used to distinguish normal and malignant B lymphocytes. Gene set enrichment analysis (GSEA) was used to find the expression of exhaustion genes and related signaling pathways in immune cells. And relevant exhausted immune cells were analyzed and validated by flow cytometry.

RESULTS

Compared to the HIV and DLBCL groups, the HIV-related DLBCL group had a higher level of expression of the gene PDCD1, a higher level of expression of CD23(FCER2) in normal B lymphocytes, and a greater difference in malignant B lymphocytes, with a lower percentage of TCF1-positive exhausted T cells and a higher level of CXCL13-positive exhausted T cells (Fig.1-3). Compared with the HIV group, the percentage of follicular helper T cells (T fh) was lower in the HIV-related DLBCL group. The results of the Pseudotime analysis showed two main developing directions of TCF1-positive exhausted T cells (Fig.4). The state2 was primarily the direction of TCF1-positive exhausted T cell development in the HIV group and the HIV-related DLBCL group, and the state3 was primarily the direction of TCF1-positive exhausted T cell development in the DLBCL group and the HIV-related DLBCL group.

CONCLUSION

Patients with HIV-related DLBCL are more at risk of T cell exhaustion. In this study, we found that HIV-related DLBCL induced T cell exhaustion has different states and shows two differentiation directions, and state2 may correlate with HIV-induced T cell exhaustion. T cell exhaustion states may be used for disease status and clinical efficacy assessment of HIV-related DLBCL.
Novel Targeted Agents in Combination with R-ICE (R-ICE-X) Based on Genotyping in Relapsed/Refractory DLBCL
Authors: Shen Yige , Cao Yiwen , Cheng Shu , Xu Pengpeng , Wang Li , Zhao Weili
Published: December 2023

Background: Relapsed/refractory (R/R) DLBCL constitutes 40% of all DLBCL cases. Coventional salvage regimens, such as R-ICE, R-GDP, and R-DHAP, have an overall response rate (ORR) of 60% and a complete response rate (CR) of 30-40%. For patients who have achieved complete metabolic remission as determined by PET-CT evaluation after salvage therapy, undergoing autologous transplantation is crucial in order to achieve durable long-term survival. The outcomes of these R/R DLBCL remain to be improved.

Aims: This prospective study aims to investigate whether adding novel agents to R-ICE (R-ICE-X) based on genetic subtypes could improve clinical efficacy in R/R DLBCL. This trial is registered at clinicaltrials.gov (NCT05348213).

Method:In this study, patients with R/R DLBCL aged 18 -75 years were enrolled. All patients were assigned and stratified by genetic subtype and received different targeted agents combined with R-ICE. The efficacy was evaluated after 3 courses of R-ICE-X (every 21 days). Patients with CR/PR were subsequently treated with autologous hematopoietic stem cell transplantation or 3 courses of R-ICE-X consolidation and lenalidomide maintenance for up to 12 months. See the detail in the figure. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were the 2-year progression-free survival (PFS) rate, 2-year overall survival (OS) rate, and safety evaluation.

Results: At the time of data cut-off, a total of 66 patients were enrolled, with a median age of 61(20-75) years. In the patients with R-ICE-zanubrutinib group (n=28), the ORR was 84.0%, with 15 patients (15/25, 60.0%) achieved CR and 6 patients (6/25, 24.0%) achieved PR. The 1-year PFS rate and OS rate were 68.2% and 90.5%, respectively. In the patients with lenalidomide combined with R-ICE (n=28), 16 patients (16/26, 61.5%) achieved CR, 4 patients (4/26, 15.4%) achieved PR, and the ORR was 76.9%. The 1-year PFS and OS rates were 78.5% and 100.0%, respectively. In the patients with the R-ICE-decitabine group (n=7), the ORR was 66.7%, with 4 patients (4/6, 66.7%) achieving CR. The 1-year PFS rate and OS rate were 50.0% and 60.0%, respectively. The number of other groups needs to be further updated. Among 66 patients, 17 patients had autologous transplantation (ASCT) and 1-year PFS and OS of patients with ASCT were both 87.1%. The number of other groups will be further updated.

Conclusion: Novel targeted agents in combination with R-ICE (R-ICE-X) regimen was well tolerated and efficacy in R/R DLBCL patients, meanwhile, it could be a promising bridging regimen for ASCT. The study is ongoing and further results will be continuously released.
Efficacy of Daratumumab in 34 Patients with Newly Diagnosed Multiple Myeloma in Real World Study
Authors: Li Xiangxin , Wang Lingling , Li Fanglin , Zhou Hai , Liu Na , Yu Shuang , Feng Qi , Li Hao , Wang Luqun
Published: December 2023

Obj ective: To observe the efficacy and safety of daratumumab (Dara) for newly diagnosed multiple myeloma (NDMM) in the real world.

Methods: The clinical data of 34 patients with NDMM treated with Dara in 3 medical centers in Shandong Province was collected.Treatment options included 15 Dara-Vd, 5 Dara-d, 4 Dara-Rd, 4 Dara-RVd, 3 Dara-ICd, 2 Dara-VCd and 1 Dara-Id. The efficacy was evaluated and the classification of M protein expression, cytogenetics, creatinine clearance and minimal residual disease (MRD) were gathered. NGF MRD-negative was used as the intermediate endpoint of survival prediction to evaluate the related influencing factors.

Results: There were 19 male among the 34 NDMM patients and 21 cases were <65 years. 9 cases completed 2 treatment cycles, 11 completed 4 treatment cycles and 14 completed 6 treatment cycles. The univariate association between efficacy (sCR, CR,VGPR, PR, SD and PD) and the clinical feature showed a statistically significant association between ECOG score and efficacy ( P=0.002).The best response for CR is 38.2% (13/34)) with 0 score, 8.8% (3/34) with 1 score, 5.9% (2/34) with 2 score ,while none with 3 score. As the efficacy was divided into 2 groups (CR and other effects), the CR rate after 2,4, and 6 cycles showed a linear trend (Fisher test P=0.025, linear trend test=7.062, P=0.008). COX multivariate analysis showed the achievement of NGF MRD-negative was associated with increased cycle number, in which 8.8% (3/34) after 2 cycles, 24% (6/25) after 4 cycles and 35.7% (5/14) after 6 cycles, while no association with other factors as gender, ISS stage and cytogenetics. We observed that the incidence of hematological adverse reactions above grade 3 was 20.5%(7/34), mainly neutropenia and thrombocytopenia. Other non-haematological adverse reactions were infection (44.1%) and peripheral edema (41.2%).

Conclusion: Although efficacy was limited in high ECOG scores, Dara based regimen regardless of gender, age, disease stage was a good choice for NDMM in our observation. With the increase of treatment cycles, deep remission was more outstanding with tolerable side effects.
Linking DNA Damage Response to Ferroptosis for Leukemia Stem Cell Eradication
Authors: Malik Bilal , Hassan Nunki , Wang Jenny Y.
Published: December 2023

Relapse in acute myeloid leukemia (AML) is associated with an unfavorable prognosis, primarily due to the poor response to conventional chemotherapy, which has shown disappointing overall outcomes over the past 30 years. The main culprits behind leukemogenesis and therapy resistance are leukemia stem cells (LSCs), characterized by their unique features of self-renewal and evasion from cell death. In our recent work, we have identified a critical self-renewal pathway, RSPO3-LGR4/p-PKAc, which exhibits aberrant activation in relapsed or refractory AML (Salik et al. Cancer Cell, 2020). Blocking this pathway holds the potential to eradicate resistant LSCs and treat relapsed AML effectively.

In this study, our data directly link the self-renewal pathway to ferroptosis resistance through activation of antioxidant defense, which confers protection on AML LSCs against detrimental effects of oxidative stress. We also found that aberrant activation of RSPO3-LGR4/p-PKAc suppressed the DNA damage response (DDR) pathway consequently leading to genomic instability, DNA repair defects, increased stemness and AML aggressiveness. Our whole-genome sequencing and knockout mouse studies showed that deletion of the key DDR gene caused substantial mutations on multiple pathways including DNA damage repair (e.g., Slf1) and self-renewal (e.g., Hox cluster genes), contributing to a more aggressive and therapy-resistant phenotype in AML initiation and progression. Single cell multi-omics sequencing and CRISPR/Cas9 knockout mouse models uncovered essential antioxidant enzymes as downstream targets of DDR pathway inhibition in AML patient-derived LSCs. These antioxidant enzymes induced by DDR pathway inhibition had protective effects against oxidative attack due to the ability to decompose reactive oxygen species (ROS) and detoxify excess iron. ShRNA-mediated stable knockdown of antioxidant enzymes impaired LSCs by increasing accumulation of iron and ROS and sensitized LSCs to ferroptosis (an iron-dependent and ROS-reliant cell death). Our analysis of AML dataset from TCGA (The Cancer Genome Atlas, N Engl J Med 2013) displayed a positive correlation of high expression of antioxidant genes with poor prognosis in a cohort of 172 AML patients (p<0.019), indicating the clinical importance of antioxidant dysregulation in cancer.

Collectively, we report here a functional relationship of DDR pathway inhibition and antioxidant defense mechanism that is regulated by RSPO3-LGR4/p-PKAc self-renewal pathway and contributes to ferroptosis resistance in AML LSCs. Targeting essential pathway components enables LSCs to become sensitive to oxidative damage and ferroptosis and perturbs leukemia progression, presenting a promising new therapeutic approach for relapsed or refractory AML.
Fatal Pulmonary Embolism, Fatal Bleeding and Intracranial Hemorrhage with Systemic and Catheter-Directed Thrombolysis in Intermediate-High and High-Risk Pulmonary Embolism: A Systematic Review with Meta-Analysis
Authors: Patel Anuj Bharatkumar , Mai Vicky , Caiano Lucia , Mercier Mathieu , Carrier Marc , Le Gal Gregoire , Castellucci Lana
Published: December 2023

Background: Thrombolysis, either systemic (ST) or catheter-directed (CDT), may reduce mortality in patients with intermediate-high and high-risk pulmonary embolism (PE), but with an increased risk of major bleeding (MB). Moreover, uncertainties remain for other efficacy and safety outcomes, such as fatal PE, fatal bleeding, and intracranial hemorrhage (ICH).

Aims: To evaluate fatal PE, fatal bleeding and ICH with ST and CDT in patients with intermediate-high and high-risk PE.

Methods: We performed a systematic search in MEDLINE, EMBASE and Cochrane from inception to December 2022. Randomized trials and cohort/observational studies of patients with intermediate-high and high-risk PE were included. We report fatal PE, fatal bleeding and ICH; mortality and MB have been previously reported. Pooled proportions with their 95% confidence interval (CI) were calculated for each treatment group.

Results: One hundred and fifty-eight studies (87,874 patients) were included. In patients treated with ST, 30-day mortality and MB occurred in 10.4% (95%CI 6.6%-14.8%; I 2=99%) and in 8.0% (95%CI 5.8%-10.5%; I 2=96%), respectively. Fatal PE occurred in 3.9% (95%CI 2.1%-6.3%; I 2=88%), fatal bleeding in 1.7% (95%CI 1.3%-2.3%; I 2=8%) and ICH in 1.6% (95%CI 1.3%-1.9%; I 2=17%). In patients treated with CDT, 30-day mortality and MB occurred in 5.3% (95%CI 3.6%-7.3%; I 2=93%) and in 5.4% (95%CI 3.8%-7.2%; I 2=87%), respectively. Fatal PE occurred in 1.5% (95%CI 1.0%-2.0%; I 2=2%), fatal bleeding in 1.2% (95%CI 0.8%-1.6%; I 2=0%) and ICH in 0.6% (95%CI 0.4%-0.9%; I 2=7%). In patients treated with anticoagulation alone, 30-day mortality and MB occurred in 9.9% (95%CI 7.1%-13.1%; I 2=97%) and in 3.8% (95%CI 2.6%-5.4%; I 2=66%), respectively. Fatal PE occurred in 3.3% (95%CI 1.9%-5.2%; I 2=65%), fatal bleeding in 0.5% (95%CI 0.2%-0.9%; I 2=0%) and ICH in 0.7% (95%CI 0.3%-1.3%; I 2=64%).

Conclusion: In patients with intermediate-high and high-risk PE, fatal PE was non-negligeable in all treatment modalities and must be balanced with equally important fatal bleeding event rates. Additional studies are needed to further assess these efficacy and safety parameters of thrombolytics in patients with intermediate-high and high risk PE.
Zanubrutinib Plus Salvage Chemotherapy in Refractory/Relapsed Diffuse Large B-Cell Lymphoma Patients Non-Candidate for Autologous Stem Cell Transplantation: A Retrospective Study
Authors: He Sha , Sun Jie , Zhong Dani , Rong Chao , Liao Chengcheng , Tan Xiaohong
Published: December 2023

Introduction ：Salvage chemotherapy followed by autologous stem cell transplantation (auto-SCT) is effective for relapsed or refractory DLBCL (R/R DLBCL). However, many patients are unable to undergo auto-SCT due to age, comorbidities, tolerance, economy and other factors. R/R DLBCL has poor clinical outcomes when treated with conventional salvage chemotherapy. Zanubrutinib, a selective Bruton's tyrosine kinase (BTK) inhibitor, has been shown to have modest antitumor activity in R/R DLBCL. Here we aimed to evaluate the efficacy and safety of Zanubrutinib plus salvage chemotherapy in autologous stem cell transplantation-ineligible R/R DLBCL patients.

Methods: We retrospectively reviewed R/R DLBCL patients who were administered with Zanubrutinib 160mg*bid plus BR （Bendamustine 90mg/㎡*d1-2+Rituximab 375mg/㎡*d0）or R2 （Lenalidomide 25mg* d1-21 +Rituximab 375mg/㎡*d0）in our center between January, 2019 and July, 2023.

Results: 49 R/R DLBCL patients were enrolled,including 30 patients in the Zanubrutinib plus BR group(ZBR)and19 patients in the Zanubrutinib plus R2 group(ZR2). Median age at this study was 60 years (range, 33-80). The best overall response rate (ORR) was 57.1% and complete remission rate was 12.2%. The ORR of ZBR group and ZR2 group were 63.2% and 53.3%, respectively. The response rate was lower in elderly, patients with ≥4 line treatment, refractory patients, patients with TP53 mutations, or without MYD88 and CD79A/B mutations. TThere was a positive correlation between the number of treatment cycles and ORR. With a median follow-up of 22 months (range, 6-43), the median progression-free survival (PFS) was 6.0 months, and the overall survival (OS) was 21.0 months. For OS, univariate analysis suggested that the number of treatment cycles was an independent favorable prognostic factor for OS. In multivariate analysis, , relapsed patients had better OS compared with refractory patients, and response after treatment was an independent favorable factor for OS. The most common grade-3/4 adverse events were neutropenia (55.0%), thrombocytopenia (44.9%), and pneumonia (30.1%).

Conclusion: Zanubrutinib combined with BR or R2 showed promising efficacy and acceptable safety in R/R DLBCL patients, which may be a potential treatment option for autologous stem cell transplantation-ineligible R/R DLBCL patients.
Diverse Effects of Cryopreservation-Induced Mitochondrial Dysregulation on Cord Blood Cells
Authors: Huang Yaojin , Liu Mengyao , Xie Xiaowei , Zhang Yawen , Dong Fang , Zhang Yingchi , Cheng Tao
Published: December 2023

Umbilical cord blood transplantation (UCBT) has been performed broadly in clinic by the specific biological and immunological characteristics of umbilical cord blood cells (UCB). UCB-based cell therapy and immune therapy also presents great application potential. UCB was usually cryopreserved for several years before using. Whether and how cryopreservation affects the function of divergent cell populations in UCB still remain to be illuminated.

Here, we firstly constructed a single-cell transcriptomic profile of Lineage - CD34 + hematopoietic stem and progenitor cells (HSPCs) and mononuclear cells (MNCs) collected from fresh and cryopreserved UCB with 1, 5, 10 and 19 years. Subpopulations characterized by higher mitochondrial gene expression (Mito high) were identified in all cell populations and found to be increased during cryopreservation. Compared with the fresh group, HSC/MPP cells after cryopreservation showed more active cell cycle and lower expression of HSC/MPP signature genes, especially in the Mito high HSC/MPP cells. Consistently, colony-forming ability as well as long-term hematopoietic reconstitution of HSPCs derived from cryopreserved UCB gradually decreased within 5 years but remained stable thereafter. More importantly, we observed decreased megakaryocyte differentiation ability from cryopreserved HSPCs, which could be partially rescued by antioxidants treatment after cryopreservation. Mechanically, we revealed that the metabolic dysregulation of mitochondria including elevated mitochondrial reactive oxygen species (ROS), reduced adenosine triphosphate (ATP) synthesis and impaired mitochondrial membrane potential of cryopreserved HSPCs led to attenuated hematopoietic reconstitution. Although there was a mild increase of Mito high subpopulations after cryopreservation, the cytokine production levels of T cells and NK cells were comparable to those of fresh samples. Additionally, NK cells exhibited almost same cytotoxic function with the fresh compartments.

Taken together, we elucidated the impact of cryopreservation on UCB HSPCs and provided the strategy for rescuing itsfunctional impairment. The unaffected T and NK cells after cryopreservation also paved the way for UCB-based cell therapy and immune therapy. Our study provides important implements for the quality control of applicable UCB both in hematology and immunotherapy.
Crosstalk between NFAT and NFκB Signaling Regulates NK Cell Immunosurveillance
Authors: Märklin Melanie , Holzmayer Samuel , Mueller Martin R. , Salih Helmut R.
Published: December 2023

One of the major transcriptional regulators in lymphoid cells is NFAT (Nuclear Factor of Activated T Cells), controlling lymphocyte development and activity. The role of NFAT signaling is well defined in T cells, the cytotoxic lymphocytes of the adaptive immunity. However, surprisingly little is known regarding the relevance of this transcription factor family in NK cells as effector cells of the innate immunity. Available data indicate that NFAT activity is dispensable for development of NK cells, whereas effects of the immunosuppressive drugs cyclosporin A and tacrolimus, that inhibit calcineurin and consecutively NFAT, implicate an involvement of the NFAT family in NK cell function. We here employed different genetic mouse models and functional analyses to unravel the role of NFAT1 (NFATc2) and NFAT2 (NFATc1) in NK cell reactivity.

In vitro knockout (KO) of NFAT1 (NFATc2) or NFAT2 (NFATc1) enhanced NK cell degranulation and resulted in increased production of granzyme B and perforin upon stimulation of activating receptors like NK1.1 or Nkp46 or upon co-culture with different leukemia and solid tumor cells. In line, cytotoxicity assays revealed increased lysis of YAC-1 and B16F10 tumor cells by both NFAT1- and NFAT2-deficient NK cells as compared to wildtype (WT) controls. The inhibitory effect of NFAT transcription factors on NK cell effector function could also be confirmed in vivo by employing WT and NFAT KO animals in syngeneic B16F10 melanoma, RMA-S lymphoma and LL/2-luc lung carcinoma models, which revealed a significantly reduced tumor burden in NFAT1 and NFAT2 KO mice. Furthermore, we detected higher numbers of tumor infiltrating NK cells in NFAT KO mice, which suggested improved NK cell migration and homing to the tumor side. Comparative analyses with single NFAT as well as NFAT1+NFAT2 double KO and WT animals further confirmed the inhibitory effect of NFAT1 and NFAT2 and pointed to additive effects of NFAT1 and NFAT2 in NK cell tumor immunosurveillance. Proteomics analysis of NK cells from the different NFAT KO strains revealed altered expression of molecules which are regulating chemokine receptor expression as well as a decreased expression of NFκB inhibitory molecules, like NFKBIB (NFKB inhibitor beta) Commd6 (COMM domain containing 6). NFκB signaling was shown to regulate granzyme B and perforin synthesis and expression. Thus, we suggest that NFAT1 and NFAT2 inhibit NFκB signaling in NK cells, and NFAT1 and NFAT2 KO reinforce NFκB induced granzyme B and perforin expression and thereby increase NK cell cytotoxicity.

Taken together, our results identify NFAT as a negative regulator of NK cell function. In addition, we provide the first evidence for a direct functional involvement of NFAT1 and NFAT2 in NK cell antitumor reactivity by regulation tumor infiltration and cytotoxicity of NK cell.
Adding Hetrombopag to Cyclosporine a to Patients with Newly Diagnosed Transfusion-Dependent Non-Severe Aplastic Anemia-a Prospective Phase 2 Study
Authors: Shen Shupei , Zhang Zhuxin , Zhuang Junling , Hu Qinglin , Chen Miao , Han Bing
Published: December 2023

Abstract

Objective: To investigate the efficacy and safety of adding hetrombopag to cyclosporin A (CsA) in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA).

Methods: This was a single center, prospective phase 2 study. Eligible patients were aged 18 years or older, were diagnosed as TD-NSAA within 6 months and treatment-naïve. Enrolled patients were treated with hetrombopag and CsA. Hetrombopag was started at 10mg/day with possible titration up to 15mg/day, and tapered gradually when the optimal response was achieved. CsA was given at 3-5mg/kg/d for at least 6 months, and tapered after the optimal response was reached. The primary endpoint was the overall response rate (ORR) and safety at 6 months. Patients who had been followed-up for at least 6 months were included in the analysis. A history cohort with compatible baseline characters treated with CsA alone were analyzed as control. The trial was registered with ClinicalTrails.gov NCT05018936.

Result: Between Oct 2021 to Oct 2022, 28 patients were enrolled, comprising 13 men and 15 women, median age 46(range: 18-81). The ORR was 68.2% at 6 months. The most frequently reported adverse events were gastrointestinal discomfort grade 1 or 2. No grade 3 or 4 treatment-emergent adverse events were reported. There were 30 patients enrolled in the history control cohort with compatible baseline characters including age, sex ratio, complete blood cell count (P>0.05). After a median follow-up of 15 (range: 9-22) vs 16 (range:9-24) months(P>0.05), the ORR at 3, 6 months and the end of follow-up were 57.1% vs 16.7% (P=0.001), 68.2% vs 30.0% (P=0.006) and 90.9% vs 46.6%(P<0.001) in hetrombopag plus CsA group and CsA alone group, respectively. The complete response rate (CRR) at 3, 6 months and the end of follow-up were 10.7% vs 0% (P=0.068), 22.7% vs 10.0% (P=0.217) and 36.4% vs 16.6% (P=0.109) in both groups, respectively. Adverse effects were reported in 13 (46.4%) patients in hetrombopag plus CsA group and 15 (50%) patients of CsA alone group (P>0.05). 1 (3.6%) vs 8 (26.6%) patient relapsed (P=0.038) at 6 month in both groups. Clone evolution were noticed in no patients in hetrombopag plus CsA group and 2 (6.7%) patients in CsA alone group at 12 and15 months, respectively (P=0.225).

Conclusion: Adding hetrombopag to CsA can improve the ORR for newly diagnosed TD-NSAA, with good tolerance and lower relapse rate.

Keywords: Transfusion-dependent aplastic anemia, Hetrombopag, Cyclosporin A, efficacy, relapse.
Targeting the Oncofetal Transcription Factor Protein SALL4 in Cancer By a Non-IMiD Degrader
Authors: Vu Kim Anh L. , Kumari Kalpana , Liu Bee Hui , Gao Chong , Li Feng , Tang Jing Ping , Maddalo Danilo , Tian Xi , Liu Miao , Bassal Mahmoud Adel , Moein Shiva , Iakovleva Viktoriia , Tan Justin L. , Stein Alicia J. , Zhou Qiling , Fischer Patrick D. , Sigua Logan H. , Qi Jun , Arthanari Haribabu , Tenen Daniel G. , Chai Li
Published: December 2023

Sal-like protein 4 (SALL4) is a C2H2 zinc finger transcription factor (TF) with two naturally occurring isoforms; SALL4A and SALL4B. It is typically detected in fetal tissues and silenced in most normal adult tissues. It is therefore intriguing that SALL4 is aberrantly re-expressed in about one-third of almost all primary human malignancies, presumably by demethylation dependent mechanisms. Direct evidence of the causative role of SALL4 in cancer has been demonstrated in SALL4 transgenic mice, which developed myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and/or liver tumors. Loss-of-function studies by SALL4 knock-down using shRNA showed cell growth inhibition and death in leukemias and solid tumors in culture and in in vivo xenotransplants.

TF's, such as SALL4, which are critical for cancer development and survival, have historically been viewed as “undruggable”. However, rather than blocking activity, an alternative approach to target TFs is to induce protein degradation. Immunomodulatory imide drugs (IMiDs), including thalidomide, lenalidomide and pomalidomide, are used in treating patients with multiple myeloma (MM), MDS with 5q deletion, mantle cell lymphoma (MCL), and other hematological malignancies. Recently, several groups have reported that IMiDs can degrade SALL4 in a proteasome-dependent manner. To that end, we sought to investigate whether IMiDS could be utilized to treat SALL4-positive/expressing cancers.

Initially, our studies observed that IMiDs had no effect on SALL4-positive cancer cells. Additional investigations thereafter demonstrated that IMiDs could only degrade SALL4A. These findings suggested that SALL4B may not be affected by IMiDs, and may be essential for SALL4-mediated cancer cell survival. Further investigation revealed that SALL4B knockdown led to an increase in apoptosis and inhibition of cancer cell growth. Moreover, through high-throughput screening, we identified a new non-IMiD SALL4 degrader that targets SALL4B via proteasomal degradation and which exhibited potent anti-cancer activity, inhibiting cancer cell proliferation in culture and in vivotumor growth by 70%.

Our observation therefore suggest that protein degraders could possess isoform specific effects. Additionally, our results exemplify the importance of delineating drug action and oncogenesis at the isoform level to develop more effective cancer therapeutics.
Patterns of CS1 Expression on Natural Killer Cells and Correlated Factors in Plasma Cell Dyscrasias
Authors: Li Chunrui , Wang Di , Li Chunhui , Xu Yanjie , Mao Xia , Que Yimei , Li Zhe , Yu Qiuxia , An Ning , Long Xiaolu
Published: December 2023

Abstract

BackgroundCS1 is overexpressed on myeloma cells, making it a promising target for immunotherapy in plasma cell dyscrasias (PCDs). However, monoclonal antibody (mAb) targeting CS1 showed limited efficacy when used alone. In addition, few clinical data of anti-CS1 chimeric antigen receptor T cell (CAR-T) have been published to date, suggesting that there may be some barriers to CS1-targeted immunotherapy. From previous studies, CS1 is expressed on some normal lymphocytes and plays an immunomodulatory role, and NK cells in particular play an important role in CS1-mediated immunity against MM. However, there are few studies on CS1 expression by NK cells in patients with plasma cell disease. Therefore, we investigated the expression of CS1 on NK cells, normal lymphocytes, and plasma cells in plasma cell dyscrasias and examined factors related to the CS1 expression level of NK cells and its relationship to survival.

Methods Between January 2018 and September 2019, a retrospective analysis was performed in 236 patients with multiple myeloma (MM) and 30 patients with other PCDs, including systemic light chain amyloidosis (AL), monoclonal gammopathy of undetermined significance (MGUS), POEMS syndrome, and monoclonal gammopathy of renal significance (MGRS). CS1 expression levels in NK cells, lymphocytes, and monoclonal plasma cells were assessed in patients with plasma cell dyscrasias. Membrane-bound CS1 of these three cell types was measured by multiparameter flow cytometry. Associations of CS1 expression with clinical and laboratory features were determined by univariate and multivariate analyses. Correlations between CS1 expression and survival were computed using the Cox proportional hazards regression and by plotting Kaplan-Meier survival plots.

Results When subgroups of MM and other PCDs were compared, there were no significant differences in CS1 expression in lymphocytes and NK cells alone. MM Patients had significantly higher CS1 expression levels in monoclonal plasma cells than other PCDs patients. In both MM and other PCDs patients, CS1 expression was significantly higher on monoclonal plasma cells than on NK cells and lymphocytes. There was a significant correlation between CS1 expression of monoclonal plasma cells (r = 0.60; P < 0.001) and that of NK cells (r = 0.79; P < 0.001) on univariate and multivariate analysis(Figure 1). Factors such as cytogenetic abnormalities, disease progression, or survival were not associated with CS1 expression level on NK cells. Neither CS1 expression level of monoclonal plasma cells nor that of NK cells was an independent predictor of patient survival.

Conclusion We demonstrated that CS1 expression level in NK cells is consistent in plasma cell dyscrasias. CS1 expression in NK cells positively correlates with that in clonal plasma cells. This positive correlation may have implications for the development of immunotherapy targeting CS1.
The Diagnostic Value of Circulating Blasts in Patients with Myeloproliferative Neoplasms in Accelerated or Blast Phase
Authors: Yacoub Abdulraheem , Philipose Shirene
Published: December 2023

Introduction: Myeloproliferative neoplasms (MPNs) are progressive cancers with variable propensity to transform to accelerated phase and blast phase (APBP), an acute leukemia-equivalent state. MPN in APBP is associated with very poor prognosis with shortened survival and is notorious for poor response to therapy. The only curative therapy is allogeneic stem cell transplant.

Blast phase is defined by 20% blasts or higher in the bone marrow biopsy (BMBx) or peripheral blood (PB), while accelerated phase is defined by blast percentage 10% or higher. The diagnosis, and response to therapy often requires serial BMBx and PB testing. There is recognition of excessive circulating PB blasts in MPNs that occasionally exceeds blast count in BMBs, especially in fibrotic bone marrow. The aim of this study is to investigate the correlation between PB and BMBx blasts, and if PB testing might be a more convenient and lest costly marker for diagnosis and response assessment of MPN in APBP.

Methods: This is a cross sectional study, based on single institution retrospective chart review. Subjects included all available subjects over the age of 18, diagnosed with APBP MPN between January 1, 2017, to July 1, 2022. We collected serial blast percentages in simultaneously collected BMBx and PB samples, assessed by the same hematopathologist. We also collected baseline disease characteristics upon transformation to APBP. This is reported descriptively, and statistically analyzed for significance using a paired t-test.

Results: 15 subjects and 54 paired BP and BMBx blast assessments were identified. Median age was 59 (range 30 -71) and median duration since MPN diagnosis was 48 months (1-420). Median OS of the cohort since APBP diagnosis was 10 months. BMBx fibrosis was Grade II-III in 13/15 patients. Cytogenetic and mutation profiles, and therapies delivered are listed on Table 1. Based on evaluation of the results, there was no statistical correlation between blasts in the PB and BMBx both prior to therapy, and during therapy (detailed biostatistical analysis will be provided during ASH presentation)

Conclusions: Patients with APBP MPN undergo frequent diagnostic testing, including a bone marrow biopsy, to evaluate the percentage of blasts in the bone marrow. Quantification of blast count in peripheral blood should not be as a standalone diagnostic lab test for APBP MPN. BMBx remains essential for this diagnosis, response assessment, as well as cytogenetic and molecular profiling. The outcomes on APBP remain poor despite utilization of modern targeted therapeutics.
Real World Data of Extended Venous Thromboembolism Prophylaxis with Low Dose Apixaban Following Cancer Associated Thrombosis
Authors: Lalezari Shadan , Carmiel Rivka , Budnik Ivan , Kenet Gili , Levy-Mendelovich Sarina
Published: December 2023

Introduction:

Cancer-associated thrombosis (CAT) is a leading cause of morbidity and mortality among patients with malignancies. Direct oral anticoagulants (DOACS) are frequently used to manage CAT. Bleeding risk is higher in cancer patients influencing the risk/benefit balance of treatment. Unlike in other cases of venous thromboembolism (VTE), there are no guidelines for dose reduction and extended prophylaxis after the initial period of full-dose treatment for cancer patients. We aimed to provide efficacy and safety data on patients with CAT that received extended VTE prophylaxis with a reduced dose of apixaban for the prevention of VTE recurrence.

Aim:

To investigate the clinical outcomes of patients with CAT treated with low-dose apixaban after initial treatment with full-dose anticoagulation.

Methods:

Data of all cancer patients over the age of 18 years from Sheba medical center that were diagnosed with VTE during the years 2012-2022, and treated with low-dose apixaban were retrieved using the MD Clone platform. All demographic, laboratory, and clinical data were collected from computerized medical files and statistically analyzed. The study was approved by the local IRB committee.

Results:

One hundred and seventeen patients with CAT, treated by a reduced dose of apixaban after initial full dose treatment for at least 6 months, were followed at our center. Table 1 summarizes the demographic and clinical characteristics of our cohort.

At the time of diagnosis with CAT the median age of patients was 72 (IQR 62-78).70.1% were female and 29.9% were male. 54.7% of patients had metastatic disease. After initial treatment with full-dose anticoagulation, patients were switched to low-dose apixaban for a median of 31 months (IQR 21-44 months). Twenty-one patients (18%) had a minor bleed and four patients (3.4%) had a major bleed while treated with low-dose apixaban. During this period 7 patients (6%) had a recurrent VTE. Two-thirds of the patients died. Mortality was attributed to thrombosis in one (0.9%) patient and major bleeding in two patients (1.7%).

Conclusions:

Low-dose apixaban may be a safe and appropriate option for extended treatment of cancer patients with VTE, with low rates of recurrence and major bleeding.
The Efficacy and Safety of Decitabine Combined with Fludarabine and Cyclophosphamide As Conditioning Regimen in Second CD19 CAR-T Infusion
Authors: Ye Shiguang , Zhou Lili , Lu Yan , Luo Xiu , Li Shaoguang , Li Ping , Liang Aibin
Published: December 2023

Background

Chimeric antigen receptor (CAR) T therapy is widely accept for the first line treatment of refractory/relapsed diffuse large B cell lymphoma(DLBCL). However, insufficient remission and short duration of response are the barrier of current CART therapy. More and more patients meet the failure of CD19 CART therapy. Pre-CART condition treatment is an important factor in durable responses. Decitabine, the hypomethylating agent, has been found that it can reduce T cell exhaustion, enhance T cell cytotoxicity and overcome tumor immune escape in the tumor microenvironment. We initiated this study to evaluate the efficacy and safety of decitabine combined with fludarabine and cyclophosphamide as conditioning regimen in 2nd CD19 CART therapy.

Methods

Patients are enrolled in the clinical trail (NCT02537977), inclusion and exclusion criteria are described. Pre-CART conditioning regimen is decitabine 10mg/m2 D-7~-3, fludarabine 25mg/m2 D-5~-3 and cyclophosphamide 300mg/m2 D-5~-3. The dose of second CD19 CART infusion is 5*10^6/kg. Primary outcome is the safety and secondary outcome is the efficacy.

Results

6 patients are enrolled in this trail and all patients are failure of CD19 CART. The media age is 57 year old and median line of treatment is 4. 4 patients(67%) are female. 5 patients(83%) have TP53 mutation/deletion and double expression, 4 patients(67%) have IPI ≥3.4 patients(67%) got complete remission(CR) after the first CD19 CART therapy and 2 patients(33%) got partial remission(PR). The median time of relapse/progression after first CD19 CART is 9 months.

The objective response rate is 50%, 2 patients(33%) got CR and 1 patient(17%) got PR. With median 13 months followup, the 3 patients(50%) maintain remission more than 1 year and are still under follow up. 2 patients(33%) got stable disease for 3 months and undergo salvage therapy. 1 patient(17%) had no response in 1 month and died due to disease progression. Of all 6 patients, only 1 patient(17%) received 2nd CART infusion in 3 months after 1st infusion and had detecable CART cell in peripheral blood.

2 patients(33%) got grade 1-2 cytokines release syndrome(CRS). No sever CRS and Immune effector cell-associated neurotoxicity syndrome(ICANS) were observed. Grade 3-4 adverse events are hematologic toxicity.

Conclusion

Decitabine combined with fludarabine and cyclophosphamide maybe an alternative conditioning regimen in CD19 CART therapy in high risk DLBCL patients. More patients are needed for further study and the trail is undergoing.
Selinexor, Ixazomib, Pomalidomide and Dexamethasone in Functionally High-Risk Multiple Myeloma: Results from the Myeloma Developing Regimens Using Genomics (MyDRUG) Sub-Protocol Y3
Authors: Richter Joshua , Zonder Jeffrey A. , Nathwani Nitya , Bianchi Giada , Hofmeister Craig C. , Vij Ravi , Pianko Matthew , Kaur Gurbakhash , Hultcrantz Malin , Wozniak Katie , Martillo Mercedes , Cho Hearn Jay , Kumar Shaji Kunnathu
Published: December 2023

Background: Multiple myeloma (MM) is characterized by somatic mutations involving cancer-associated genes. The MyDRUG trial was initiated to explore the efficacy of specific molecularly-targeted therapies in combination with a standard triplet combination in MM.

Methods: MyDRUG (NCT03732703) is a genomically-guided umbrella trial for patients with functional high-risk MM, defined as early relapse following primary therapy (3 years for transplant with maintenance, 18 months without), with specific genetic abnormalities. Patients with no actionable mutation or mutations with allelic burden below 30% were randomly assigned to one of the “non-actionable” arms. Here we present the data for the Y3 arm which combines selinexor (60mg po days 1,8,15), ixazomib (4mg po days 1,8,15), pomalidomide (3mg po days 1-21) and dexamethasone (40mg po weekly) (Seli-IPD), given on a 28-day cycle. The primary objective of the Y3 sub-protocol was to evaluate the overall response rate (ORR) according to the International Myeloma Working Group consensus criteria. Secondary objectives included assessment of adverse events (AEs).

Results: 17 patients were enrolled into the Y3 arm. The average age was 62 (51-79), 65% were male with a median of 29 months since initial diagnosis and a median of 2 prior lines of therapy. The ORR (> PR) was 52.9% with a clinical benefit rate (> MR) of 58.8%. The median progression free survival was 10.2 months ( 95% CI: 3.9; 12.9) with a median overall survival which has not yet been reached; with all 17 patients still alive at the current data cutoff. No dose-limiting toxicities were seen. Eight patients (47.1%) experienced a serious AE with 2 patients (11.8%) experiencing an AE leading to treatment discontinuation. Two patients (11.8%) required dose reductions. The most common non-hematologic AEs were fatigue, nausea and constipation; all of which were grade 1 and 2.

Conclusions: In this platform study of patients with relapsed, functionally high-risk MM, patients who received Seli-IPd exhibited significant efficacy and a manageable AE profile. Furthermore, this provides an all-oral option for patients wishing to minimize their office visits and parenteral therapy administrations.