bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of High-Risk Factors and Establishment of an Early Warning Model for Thromboembolism in Lymphoma Patients
Authors: Lin Wenzheng , Pan Lili , Guo Jiangrui , Liu Tingbo , Shen Jianzhen , Li Xiaofan
Published: December 2024

Abstract

Background and Objectives:

Thromboembolism (TE) is a common and serious complication in patients with malignancies, including those with lymphoma, who are at high risk of TE. The incidence of TE in lymphoma patients ranges from 5% to 59.5%. This study aims to investigate the clinical characteristics and high-risk factors of thrombosis in lymphoma patients and to develop a nomogram model for early warning of thromboembolism events.

Materials and Methods:

Clinical data from 790 newly diagnosed lymphoma patients (January 2019 to December 2021) were analyzed, dividing them into thrombus and no thrombus groups. Key clinical features, lab indicators, and lymphoma characteristics were compared. TE risk factors were assessed using multifactor analysis. A nomogram model for predicting lymphoma-related TE was developed using R version 4.3.0, rms, and ggplot packages, and validated with Bootstrap resampling. Model performance was evaluated with ROC and calibration curves.

Results: Clinical Features: TE occurred in 9.75% of patients(77/790), with common sites being upper limb deep veins(58.44%), superficial veins(22.08%), and lower limb deep veins(20.78%).Median age of TE patients was 58 years, with TE occurring a median of 4 months post-diagnosis. Survival Outcomes: TE patients had lower survival rates compared to non-TE patients at 6 months, 1 year, and 2 years.TE complications led to death in 6.50% of TE patients, while disease progression caused 16.88% of deaths.Additionally, 2 patients (2.60%) experienced lower limb functional impairment due to TE, and 1 patient (1.30%) with intracranial TE had cognitive dysfunction. Risk Factor Analysis: Significant risk factors included high ECOG scores, previous venous thromboembolism, coronary artery disease, and central venous catheterization. Prediction Model: The nomogram model showed good predictive accuracy, with ROC AUC values exceeding 0.7 for 0.5, 1, and 2-year predictions.Validation showed consistent predictive performance with an average AUC of 0.705.

Conclusion:

The study identifies key risk factors for TE in lymphoma patients and presents a validated nomogram model for early prediction of TE, which can aid in clinical decision-making and improve patient outcomes.
Incidence, Risk Factors, Microbiology and Outcomes of Bloodstream Infection during Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Pan Ling , Jia Li , Feng Xiaomeng , Jiang Erlie , Feng Sizhou
Published: December 2024

Objectives : Bloodstream infection (BSI) represents a substantial and recurrent complication that often arises during allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite its considerable occurrence, there has been a conspicuous absence of focused research delving into BSI specifically during the conditioning phase before HSCT.

Method: A single-center cohort study, comprising 2395 consecutive patients who underwent allo-HSCT from 2013 to 2023 was conducted. We examined the characteristics of BSI during the conditioning phase, risk factors and its prognosis on patients.

Results: The cumulative incidence of BSI during conditioning was 7.7%, with a median onset on day 8 post-agitation of the conditioning regimen. The most frequently isolated pathogens included Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and coagulase-negative staphylococci. A multivariate analysis identified several variables associated with BSI during conditioning, including neutropenia lasting ≥ 7 days before conditioning, a hematopoietic cell transplantation-comorbidity index ≥ 1, and in vivo T-cell depletion using antithymocyte globulin (ATG). Furthermore, the analysis indicated that BSI caused by carbapenem-resistant Enterobacteriaceae significantly increased the risk of all-cause mortality within 90 days following BSI (odd ratio = 7.492; 95% confidence interval: 1.389, 40.429; P = .019).

Conclusions: Reducing the incidence of BSI during conditioning phase can significantly improve early transplantation outcomes in haematological patients. In patients with prolonged neutropenia, comorbidities, or the inclusion of ATG in the conditioning regimen, particularly among those with multiple risk factors, the likelihood of developing BSI is significantly elevated. Therefore, it is imperative to promptly initiate blood cultures and administer timely and appropriate empiric antibiotic therapy.
TP53 Mutation Heterogeneity Reveals Distinct Prognoses in Mantle Cell Lymphoma
Authors: Liu Shuozi , Zhou Shaowei , Zhang Weilong , Wang Jing , Wang Lingli , Li Chunyuan , Chen Yingtong , Qi Wenxin , Yang Ping , Jing Hongmei
Published: December 2024

Background: Mantle cell lymphoma (MCL) is an uncommon and aggressive type of B-cell non-Hodgkin lymphoma, wherein TP53 mutations play a critical role. This study analyzed the effect of different TP53 mutations on the clinical characteristics and prognosis of patients with MCL.

Methods: TP53 sequencing data and clinical and prognostic information were collected from 215 patients with MCL treated at Peking University Third Hospital between August 2017 and December 2022. Furthermore, descriptive and Cox regression analyses were also performed.

Results: Our findings revealed the association between TP53 mutations and higher Ki67 levels (p = 0.008), elevated combined MCL International Prognostic Index (MIPI-c; p = 0.032), and blastoid/pleomorphic subtypes (p = 0.028). Missense mutations (75.6%; G:C > A:T [48.31%]) were the predominant mutation type, occurring within the DNA-binding domain (DBD; 92.41%) and concentrated in exons 5-8 (82.05%). The extent of the impact on prognosis was dependent on the location of the mutations. G245/R273 mutations were associated with the highest risk. Mutations at zinc-binding motifs and DBD were associated with intermediate risk. Non-DBD and non-TP53 mutations were associated with the lowest risks. Three TP53 mutation groups were defined for further analysis. Notably, these groups exhibited significant differences in OS (p = 0.015) and PFS (p = 0.026).
PET Radiomics Discriminate Among Different Lymphoma Sub-Types
Authors: Chauvie Stephane , Kostakoglu Shields Lale , Guerra Luca , Versari Annibale , Fallanca Federico , Gregianin Michele , Bergesio Fabrizio , Bergalla Enrica , De Maggi Adriano , Sahin Denis , Durmo Rexhep , Vitolo Umberto , Federico Massimo , Gallamini Andrea , Rambaldi Alessandro , Luminari Stefano
Published: December 2024

Despite numerous studies, the predictive role of radiomics extracted from 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (PET/CT) in lymphoma remains uncertain. In several solid cancers radiomics, and in particular the Haralick heterogeneity metrics (HM), have shown the ability to describe the phenotypes of tumors. This study investigates whether HM can differentiate between various lymphoma subtypes.

We conducted an extensive analysis of a large cohorts of patients with diffuse large B-cell lymphoma (DLBCL) from the GOYA (NCT01287741), Hodgkin lymphoma (HL) from the HD0607 (NCT00795613), and follicular lymphoma (FL) from the FOLL12 (NCT02063685) clinical trials in which baseline PET was acquired and analysed per-protocol.

Metabolic tumor volumes (MTVs) were semi-automatically delineated using a fixed SUV threshold of 4, as recommended in 2023 Menton meeting. Only MTVs larger than 50 ml, corresponding to a lesion radius of approximately 2 cm, were included in the analysis. HM were automatically extracted in Cuneo corelab. HM with a correlation coefficient lower than 0.90 and a variance higher than 0.95 were included in the analysis. Different artificial intelligence (AI) models were applied to training and test populations (70-30%).

Data were available for 746 DLBCL, 285 HL, and 276 FL. The total number of lesions analysed were 1,918 for DLBCL, 607 for HL, and for 804 FL. The median MTV were 252, 81, and 90 ml, for DLBCL, HL, and FL, respectively.

Among the AI, Random Forest (RF) showed the highest accuracy, 0.79 (95% CI: 0.76-0.81), on the test dataset. Sensitivity in identifying DLBCL, HL and FL were 0.93, 0.38 and 0.78. Specificity in identifying DLBCL, HL and FL were 0.86, 0.86 and 0.93.

Radiomics has the potential to classify different lymphoma subtypes, when calculated on lesions large enough to mitigate the technical limitations of PET scanners. The discrimination is particularly high for DLBCL and FL. We anticipate that PET images acquired using new digital PET technology with dedicated reconstruction algorithms could further enhance the classification of lymphoma subtypes, thereby paving the way for their use also in patients prognosis definition.
Cardiotoxicity Among Lymphoma Patients Undergoing Chemotherapy: 5 Years Follow up
Authors: Al Gahtani Farjah Hassan , Alsadhan Ghada , Almazyad Leena , Alomairini Mona , Aldahash Nora , Alsadhan Munira , Alrefaei Rand , Alquwayz Sarah , Alotaibi Ghazi S , Aleem Aamer , Sewaralthahab Sarah
Published: December 2024

Background: Cardiotoxicity afflicts 10-20% of cancer survivors thus compromising long term survival. Based on ASCO guidelines cancer patients (pts) are considered at increased risk of developing cardiotoxicity (CT) if they receive high dose (HD) anthracyclines (A) or HD radiation therapy (RT) or low dose (LD) A + LD RT, or LD A with ≥ 2 cardiovascular (CV) risk factors (RF) or age ≥ 60 years (y) at diagnosis, or compromised cardiac function before or during treatment. Objectives: The aim of the study is to find the incidence and RF of cardiotoxicity in lymphoma patients post chemotherapy. Methodology: Retrospective study of lymphoma pateins seen in oncology clinic from 2015-2022 within 5years of lymphoma therapy. Chart review included demographics, dose of antheracycline and RT dosing, imaging, Cardiovascualr risk and treatment details. Results: A total of 410 lymphoma patients were included in the study. The age range of the patients was from 4 to 93 years, with a mean age of 46.9 ± 22.1 years. Among the patients, 239 (58.3%) were male, 349 (85.1%) were Saudi, 205 (50%) were married, and 141 (34.4%) were single. Following chemotherapy, 22 patients (5.37%) met the criteria for cardiotoxicity, while the majority, 388 patients (94.63%), did not exhibit cardiotoxicity. The incidence of cardiotoxicity was higher among older patients, with 11.3% of those aged 60 years or older affected, compared to 1.7% of patients under 30 years of age, a statistically significant difference (P=0.040). Other demographic factors did not show a significant association with cardiotoxicity. Additionally, 11.8% of patients who required ICU admission developed cardiotoxicity, compared to 4.5% of those who did not require ICU admission (P=0.043). Smoking status was also associated with cardiotoxicity, with 10.3% of smokers affected compared to 5% of non-smokers (P=0.049). Diabetic patients had a higher incidence of cardiotoxicity at 11.5%, in contrast to 3.7% of non-diabetic patients (P=0.012). Other risk factors did not show a significant association with cardiotoxicity in the study population. Conclusion: This study highlights the significant risk of cardiotoxicity in lymphoma patients undergoing chemotherapy, with an overall incidence of 5.37%. Older age, ICU admission, smoking, and diabetes were identified as significant risk factors for developing cardiotoxicity. These findings underscore the importance of vigilant cardiac monitoring and management, particularly for high-risk groups, to mitigate the long-term adverse effects of chemotherapy in lymphoma patients. Further prospective studies are warranted to confirm these associations and to explore potential preventive strategies.
Long-Term Outcomes of Bronchus-Associated Lymphoid Tissue Lymphoma Based on Lung Involvement Status: A Single-Center Real-World Data Analysis in Korea
Authors: Kim Changgon , Kim Seok Jin , Kim Won Seog , Yoon SangEun
Published: December 2024

BackgroundThe occurrence of primary lymphoma in the lung is exceedingly uncommon, with the majority of these cases representing marginal zone lymphoma originating from bronchus-associated lymphoid tissue (BALT). BALT lymphoma (BALToma) is a rare and indolent type of lymphoma. Given the limited number of cases and the necessity for prolonged observation, treatment options based on lung disease status remain uncertain.

Methods This retrospective study aimed to investigate the characteristics and survival outcomes of patients with marginal zone lymphoma (MZL) involving the lung at Samsung Medical Center diagnosed between 2003 and 2019. The disease status was classified as unilateral lung disease, bilateral lung disease, or lung disease with other site involvement. The treatment methods were classified into four categories: observation and waiting, surgical intervention, chemotherapy, and a combination of surgery and chemotherapy, followed by radiotherapy. Progression-free survival (PFS) and overall survival (OS) were subsequently compared using Kaplan-Meier survival analysis.

Results A total of 40 patients were analyzed, and the median OS was not reached, with a median PFS of 156 months. The 10-year OS rate was 89.1%, and the 10-year PFS rate was 55.1%. Of the 40 patients, 14 had unilateral stage 1 disease and 26 had stage 4 disease. Of these, 12 patients exhibited bilateral lung disease, while 14 patients demonstrated involvement of other sites. In patients with unilateral lung disease, the median PFS for those who underwent surgery was not reached and was significantly improved compared to those who did not undergo surgery, with a median PFS of 37.4 months (p-value = 0.00465). In patients with bilateral lung disease, the median PFS was not reached in the chemotherapy group, in comparison to 26.3 months in the non-chemotherapy group. This represents a significant increase (p-value = 0.00684). In a multivariate analysis based on clinical information, significant decreases in PFS were observed in patients with involvement of other sites, those with air-bronchogram presentation on CT scan compared to patch or nodular lesions, and those aged 70 years or older. No factors were identified that significantly increased OS.

Conclusion In patients with BALToma, the tailoring of treatment strategies based on the disease status of the lung may result in an increased PFS. Surgery plays a pivotal role in the treatment of this condition, particularly in cases of unilateral lung disease, whereas chemotherapy is an effective treatment for bilateral lung disease.
Preliminary Results from a Phase II Study of Chidamide in Combination with CHOP in Previously Untreated Peripheral T-Cell Lymphoma with T Follicular Helper Phenotype (SWIFT study)
Authors: Cai Qingqing , Xia Yi , Zeng Dongfeng , Li Xi , Fang Xiaojie , Nie Man , Tian Xiaopeng , Li Lirong , Liu Yingxian
Published: December 2024

Background: Peripheral T-Cell Lymphoma with T-follicular helper phenotype (PTCL-TFH), which mainly includes angioimmunoblastic T-cell lymphoma (AITL), is characterized by recurrent mutations affecting epigenetic regulators. Chidamide is an oral, subtype-selective histone deacetylase (HDAC) inhibitor that targets HDAC subtypes 1, 2, 3, and 10. It has been approved for relapsed or refractory (R/R) PTCL, advanced breast cancer, R/R adult T-cell leukemia-lymphoma, and previously untreated diffuse large B-cell lymphoma with double expression of MYC and BCL2. Single-agent chidamide has shown safety and efficacy in R/R PTCL-TFH. This study aimed to assess the efficacy and safety of chidamide in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in previously untreated PTCL-TFH.

Methods: This multicenter, open-label, single-arm phase II study was conducted in China (NCT05572983). Previously untreated PTCL-TFH patients received chidamide combined with CHOP for up to 6 cycles in the induction therapy phase. Patients achieving complete response (CR) received chidamide 20 mg biweekly as maintenance therapy. The primary endpoint was CR rate at the end of treatment, with secondary endpoints including overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety profiles.

Results: Between May 2023 and May 2024, 17 previously untreated PTCL-TFH patients were enrolled in this study. The median age was 62 years (range: 38-73); 80% were male, and all had AITL subtype. Among the 14 evaluable patients, the ORR was 85.7%, with a CR rate of 71.4%. Follow-up is ongoing for PFS results. A total of 17 patients were included in the safety analysis. Common grade 3 or 4 adverse events (AE) included neutropenia (64.7%), leukopenia (52.9%), and thrombocytopenia (23.5%), respectively. The majority of AEs were reversible and clinically manageable.

Conclusions: This study demonstrated that chidamide plus CHOP is safe, well tolerated, and effective in previously untreated PTCL-TFH patients. Further randomized controlled studies are warranted to assess this promising combination.
Effect Analysis of 33 Patients with Corticosteroids Resistant Grade III/IV Acute Liver Graft-Versus-Host Disease Treated with Sequential Low-Dose Cyclophosphamide and Anti-Thymocyte Globulin Following Plasma Exchange
Authors: Wang Juan , Zu Yingling , Gui Ruirui , Li Zhen , Zhang Wenli , Xin Xiangke , Zhang Yanli , Lu Wenyi , Fu Yuewen , Zhou Keshu , Zhou Jian
Published: December 2024

Background

Acute graft-versus-host disease (aGVHD) represents a significant complication and leading cause of mortality in allo-HSCT. The response rate to corticosteroids is approximately 50%, with poor long-term survival observed in individuals with steroid-resistant (SR) aGVHD. Plasma exchange stands as the primary treatment for patients experiencing acute liver failure. Cyclophosphamide and anti-thymocyte globulin (ATG) function to inhibit lymphocyte activity in vivo. Currently, there are no clinical studies validating the efficacy of plasma exchange followed by low-dose cyclophosphamide and ATG for the treatment of liver Grade III/IV SR aGVHD.

Methods

A retrospective analysis was performed on 33 hematological patients who developed liver grade III/IV aGVHD after allo-HSCT in Henan Cancer Hospital from October 2020 to March 2024 and were treated with sequential low-dose cyclophosphamide and anti-thymocyte globulin after plasma exchange. Cyclophosphamide dose: 400 mg/ time for adults and children weighing ≥35 kg, 200mg/ time for children weighing < 35 kg, immediately after the end of plasma exchange. Anti-thymocyte globulin dose: adults and children weighing ≥35 kg 50mg/ time, children weighing < 35 kg 25mg/ time, immediately after the end of cyclophosphamide. Efficacy was evaluated 28 days after the first plasmapheresis.

Results

Among the 33 patients, 19 were males (57.6%) and 14 were females (42.4%). The median age was 29 (5-57) years.There were 9 cases (27.3%) of typical aGVHD and 24 cases (72.7%) of delayed aGVHD. There were 27 patients (81.8%) with grade III liver aGVHD and 6 patients (18.2%) with grade IV liver aGVHD. 15 patients (45.5%) achieved complete response (CR), 9 patients (27.3%) achieved partial response (PR), and 9 patients (27.3%) achieved no response (NR). The overall response rate (ORR) was 72.7% (24/33). After a median follow-up of 100 (6-1344) days, the overall survival (OS) rate of the 33 patients at 6 months after treatment was 42.8% (95%CI 25.4%-60.2%), and the OS rate at 1 year after treatment was 35.9% (95%CI 18.8%-53.0%). The OS rates of CR group, PR group and NR group at 6 months after treatment were 69.2% (95% CI 36.1%-86.3%) ,44.4% and 0, respectively. One year after treatment, the OS rates were 52.7% (95%CI 25.1%-80.3%), 44.4% (95%CI 11.9%-76.9%), 0, respectively, and the difference was statistically significant among the three groups (χ2 = 4.474, P < 0.001).

Conclusions

Sequential low-dose cyclophosphamide and anti-thymocyte globulin after plasma exchange may be an effective treatment for patients with corticosteroids resistant liver grade III/IV aGVHD.
Dynamic Changes of Genetic Mutations in AML Patients from Diagnosis to Complete Remission and Relapse
Authors: Yan Xin , Song Chunhua , Ge Zheng
Published: December 2024

Background

Acute myeloid leukemia(AML)is an aggressive hematopoietic malignancy and accumulation of genetic alterations is a common mechanism in the clonal evolution of AML. Some mutations(DNMT3A, ASXL1, TET2)often persist during remission and disease progression, while relapse can either be driven by the acquisition of mutations in the founder clone or by the selection of resistant subclones (Blood,2021,137:3093-3104). However, the relationship between complete remission(CR)/relapse and the critical dynamic changes in genetic mutations is still not well covered. This study aimed to explore the dynamic changes of genetic mutations in AML patients from diagnosis to CR and relapse.

Methods

A total of ninety-seven AML patients with sequential serial samples were sequenced by our reported targeted exome-seq for human leukemia driver genes (Blood Cancer J,2022;12:145) from 28 May, 2019 to 7 June, 2024. Sixty-six Patients were sequenced at diagnosis and CR, twenty-four patients were sequenced at diagnosis, CR and relapse, while seven patients were sequenced at diagnosis and relapse.

Results

Ninety-three de novo AML patients and four secondary AML patients were analyzed with a median age of 60(15~86) years, including 53 males and 44 females. The median interval time between diagnosis to CR was 2(1~5) months, the median interval time from CR to relapse was 5(1~16) months, as well as the interval time from diagnosis to relapse was 8(2~28) months.

The median number of mutations detected at CR was significantly less than the mutations detected at diagnosis( 1 vs. 3, P<0.001), moreover, 40 patients(44.5%)lost all of the mutations detected at diagnosis and had no mutations at CR. Although the other patients still had mutations detected at diagnosis, the variant allele frequency of these mutations significantly decreased. Furthermore, we found that patients who still had mutations detected at diagnosis had worse relapse-free survival than patients who lost all of the mutations detected at diagnosis (5 vs 11 months, P =0.042 ).

Then, to explore the critical mutations that may promote relapse in AML patients, we found the median number of mutations detected at relapse had no difference than at the diagnosis(3 vs. 3, P= 0.401 ). However, most (20/31,64.5%)patients had newly acquired mutations at relapse, the median number of newly acquired mutations at relapse was 1(0~5).The most frequent newly acquired mutations were RAS(NRAS,KRAS,PTPN11,CBL,NF1)pathway(n=5 ,16.1 %),NPM1(n=4,12.9%) and FLT3(n= 3,9.7%) mutations.

Conclusion

The study clarified the dynamic changes of genetic mutation in AML patients from diagnosis to CR and relapse. Sweeping away and decreasing the genetic mutations detected at diagnosis promotes patients to CR. Newly acquired mutations and Reappeared mutations detected at the diagnosis lead to relapse. Newly acquired RAS pathway, NPM1 and FLT3 mutations may promote patients to relapse and should be targeted as potential intervention points.
Clinical Observation of Sequential Prophylaxis with Letermovir Injection and Tablets for Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Pang Aiming , Zheng Yawei , Chen Shulian , Shen Yuyan , Zhao Xiaoli , Ni Xiaofei , Zhang Lining , Wang Jiali , Cao Wenbin , Chen Xin , Cao Yigeng , Jiang Erlie
Published: December 2024

Objective: To evaluate the efficacy and safety of sequential prophylaxis with letermovir injection and tablets for Cytomegalovirus(CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods: The study included 18 patients who completed allo-HSCT at the Blood Disease Hospital, Chinese Academy of Medical Sciences from December 2023 to March 2024. Letermovir injection was initiated on day 0 post-transplant, followed by a switch to letermovir tablets for sequential prophylaxis up to day 90. The primary outcome was the CMV breakthrough rate at 90 days post-transplant, and the second outcomes were the incidence of viral infections such as EBV and the status of hematopoietic reconstitution.

Results: At 90 days post-transplant, among the 18 allo-HSCT patients who received sequential prophylaxis with letermovir injection and tablets, no CMV infection was observed in all patients, resulting in a CMV infection breakthrough rate of 0%. Four patients had EB virus (EBV) viremia (22.22%), of which one patient developed PTLD (5.6%). The median time for neutrophil engraftment was 15 (11-18) days; no related liver and kidney function damage was observed during the medication process.

Conclusion: Preliminary research results indicate that sequential prophylaxis with letermovir injection and tablets is safe and effective for post-allo-HSCT CMV infection.
Modulating the Vasoactive Intestinal Peptide (VIP) Pathway Reprograms Superior CAR T Cells
Authors: Lin Heather K. , Blake Dejah , Wells Kory , Freeman Ruby , Mudigonda Abhijay , Liu William , Evans Alysa N , Goyal Subir , Liu Tongrui , Funk Christopher Ronald , Sinha Tanisha , Christensen Elyse , Mahmood Naeman , Fei Fan , Heller Brad , Chun Paul , Passang Tenzin , Ravindranathan Sruthi , Dougan Jodi , Porter Christopher C. , Paulos Chrystal , Patgiri Anupam , Yang Lily , Waller Edmund K. , Rafiq Sarwish
Published: December 2024

Chimeric antigen receptor (CAR) T cell therapy is a highly potent cellular immunotherapy that still faces significant obstacles that limit clinical success. Novel immunomodulatory approaches to improve the CAR T cell phenotype, metabolic fitness, and the engagement of endogenous immunity are necessary to create effective CAR T products. Vasoactive intestinal peptide (VIP) is a neuropeptide that dampens adaptive immune responses and is abundantly produced by several hematologic malignancies. Here, we have engineered CAR T cell therapies that secrete a synthetic short peptide drug that antagonizes VIP receptors (CAR/VIPRa).

CAR/VIPRa T cells are less activated and less exhausted by the manufacturing process, which lends to better viability and preservation of memory phenotypes. Furthermore, VIPR antagonism increases the number of mitochondria and enriches the utilization of oxidative phosphorylation. This metabolic reprogramming results in quiescent CAR/VIPRa T cells that have greater potential and plasticity to achieve improved energetic profiles after antigen stimulation. In vivo, CAR/VIPRa T cells demonstrate significantly greater expansion with less exhausted phenotypes and are enriched for memory phenotypes in xenograft tumor models. Additionally, the small peptide drug produced by CAR/VIPRa T cells increases the number of endogenous tumor-infiltrating T cells in syngeneic tumor models. To investigate clinical relevance, CAR/VIPRa T cells manufactured from patient-derived T cells recapitulated lower activation profiles and enrichment for memory phenotypes.

Collectively, this approach to antagonize the VIP/VIPR pathway serves to improve CAR T cell phenotype and function before and after tumor engagement to drive enhanced anti-tumor efficacy. Therefore, CAR/VIPRa T cells are uniquely equipped to overcome many key obstacles that are required for success of CAR T therapy in the clinic.
Chemical Modulation of ELF1 Binding to RUNX1 Target Genes Leads to Increased Hematopoietic Stem Cell Self-Renewal
Authors: Robertson Anne L. , Yue Lu , Choudhuri Avik , Kubaczka Caroline , Wattrus Samuel J. , Mandelbaum Joseph , Avagyan Serine , Yang Song , Freeman Rebecca J. , Chan Victoria , Blair Megan C. , Daley George Q. , Zon Leonard I.
Published: December 2024

Hematopoietic stem cell (HSC) expansion and self-renewal are important for stem cell therapy. Expanding HSCs ex vivo remains challenging. To identify novel compounds that increase HSCs, we screened 3,840 small molecules using a zebrafish blastomere culture screening system with a HSC specific Runx1+23:GFP reporter and identified a RUNX1/CBFβ modulator, Ro5-3335, which increases Runx1+ cells. Using spinning disk confocal time-lapse imaging in live zebrafish embryos, we found that Ro5-3335 treatment increases HSC number as much as 1.79 fold (p<0.0001) and significantly increases HSC divisions (5 vs 3.5 divisions, p=0.009) in the stem cell niche during early hematopoiesis. Transplantation of Ro5-3335 treated Runx1+ cells into zebrafish embryos revealed enhanced engraftment by 1.60 fold (p<0.001). To determine whether the increased HSC production during development increases HSC clones in adulthood, we used a brainbow color barcoding system to lineage trace each HSC and its blood progenies. Treatment of Ro5-3335 during definitive hematopoiesis significantly increases HSC clones in adulthood (23 vs 18.6 clones, p<0.0001). To determine whether the effect of Ro5-3335 on HSC expansion is conserved in mammalian systems, we cultured human CD34+ HSPCs and found that Ro5-3335 promotes CD34+CD38-CD45RA-CD90+ HSC expansion in 6-day ex vivo culture (20.3 vs 15.8 fold (p=0.0157)). RUNX1 is an important transcription factor for HSC proliferation and differentiation. Chromatin immunoprecipitation sequencing (ChIP-seq) of RUNX1 showed that Ro5-3335 treatment increased RUNX1 binding to target genes in human CD34+ HSPCs, independent of CBFβ binding. Motif analysis of the genes with increased RUNX1 binding and increased transcription suggested binding of ELF family transcription factors to RUNX1 target genes upon Ro5-3335 treatment. ELF1 ChIP-seq confirmed that ELF1 has increased binding to RUNX1 targets, including cell cycle genes CDC45, CDC37L, CCND2, and CCND3 upon Ro5-3335 treatment. Knocking down Elf2b in zebrafish embryos abolished the effect of Ro5-3335 both on HSC expansion and HSC clonality. Together, our studies provide the first evidence to show that it is possible to pharmacologically increase stem cell clonality in vivo.
Clinical Trial Success Rate in Lymphoma: Fate of Trials and Agents from 2000 to 2023
Authors: Luo Zhiping , Li Meng , Flowers Christopher R. , Chihara Dai
Published: December 2024

Introduction:Only 7.5% of investigational agents tested in phase 1 trials resulted in new drug approvals by the FDA for hematologic malignancies from 2011 to 2020 (©BIO 2024). Although approximately half of investigational agents tested in phase 1 trials progress to phase 2 trials, just 27.8% transition to phase 3 trials, illustrating the low success rate transitioning agents from early phase trials. However, comprehensive studies examining development success of agents for patients with lymphoma have not been performed.

Methods: We conducted a retrospective analysis of clinical trials investigating lymphoma treatments between January 1, 2000, and May 25, 2023. Clinical trial data were obtained from the Biomedtracker® database and were supplemented with information from ClinicalTrials.gov to ensure data completeness and accuracy. We identified phase 1, 2, and 3 trials conducted during this period focused on or including patients with lymphoma and reviewed agents approved by FDA for patients with lymphoma from 2006 to 2024. We assessed the numbers of patients enrolled and trial enrollment period and calculated the phase transition success rates for the identified trials to assess the efficiency and success of the clinical development process.

Results: A total of 2,222 phase 1 trials were conducted during the study period of which patients of lymphoma were eligible for participation in 1,868 phase 1 trials that evaluated 858 agents. 1,132 phase 1 trials evaluated single agents and 736 trials evaluated combinations. Overall, 60,809, 68,325 and 53,848 patients were treated in phase 1, 2 and 3 trials. The median duration of opening to closing the trial was 42, 44 and 49 months in phase 1, 2 and 3, respectively. During this period, 1,769 phase 2 trials and 188 phase 3 trials were conducted to further assess the safety and efficacy in lymphoma. From 2006 to 2024, 44 new agents (including rituximab biosimilar) in 91 indications received approval from FDA. and common lymphoma subtypes that received new agent approval were follicular lymphoma (n=15), chronic lymphocytic leukemia (n=16), diffuse large B-cell lymphoma (n=11) while little to no new agents approved for peripheral T-cell lymphoma (n=4), classical Hodgkin lymphoma (n=3), Burkitt lymphoma (n=1), and primary CNS lymphoma (n=0). For 26 agents, FDA granted accelerated approval which requires phase 3 confirmatory trial. The success rate from phase 1 to phase 2, phase 2 to phase 3, and phase 3 to approval for lymphoma were 94.7%, 10.6% and 48.4%, respectively. The overall success rate from agents evaluated in phase 1 to approval was 5.1% (95%CI: 3.7%-6.6%).

Conclusions:Our study defines the clinical development landscape and timelines of new therapies for lymphoma and illustrates the unmet need for further clinical trials focusing on rare subtypes. Success rate in lymphoma is still low suggesting the critical role of better pre-clinical data conducting phase 1 trials.
Morbidity and Mortality of Major Adverse Cardiovascular Events in Hospitalized Acute Myeloid Leukemia Patients
Authors: Eltaher Basant , Shah Purva , Kharel Himal , Mahmoud Amir , Abdelhay Ali
Published: December 2024

Introduction: Patients with acute myeloid leukemia (AML) undergo different intensive chemotherapy regimens, with possible side effects including cardiovascular toxicity. This could be challenging when managing AML with its complex pathophysiology.

Methods: This is a retrospective analysis conducted using ICD-10 codes from the National Inpatient Sample (NIS) between 2016 and 2020 and analyzed with STATA BE software. Our aim is to identify major adverse cardiovascular events (MACE) in patients with AML. Descriptive analysis was used to illustrate baseline characteristics of hospitalized patients with AML. Logistic regression was further employed to examine the association between AML and MACE. Underlying comorbidities including hypertension, hyperlipidemia, diabetes, chronic kidney disease (CKD), smoking, and thrombophilia were adjusted for.

Results: This study consisted of 103,697 hospitalized AML patients with a mean age of 61 years, most of whom were of white race (69%) and male gender (55.6%). The most common underlying comorbid condition was hypertension (34%), followed by hyperlipidemia (30.5%), smoking (25%), congestive heart failure (17.3%), and chronic kidney disease (16.4%). Cardiovascular-related death accounted for 34%. AML patients not in remission (AMLniR) made up most of our cohort (73.6%) and were generally older than AML in remission (AMLiR) and AML with relapse (rAML) (mean age of 63 years vs 54.6 and 54.1 in other two groups, respectively). rAML had higher rates of death (11%) compared to AMLiR (2.8%) and AMLniR (8.2%). Hospitalized patients with relapse were more likely to undergo bone marrow transplant (23.6%).

The effect size of the association between AMLniR and AMLiR with MACE rounded to 1 (p=0.98 and p=0.043, respectively). This could be due to underlying cardiac risk factors rather than the presence of AML. Interestingly, AML with relapse were less likely to have major cardiovascular events (Odds ratio (OR) 0.9, 95% CI, 0.86-0.98; p value <0.01), possibly related to younger age observed in this group. Patients who underwent bone marrow transplant and received chemotherapy had less odds of developing major adverse cardiovascular events (OR 0.8, 95% CI, 0.7-0.95 and OR 0.6, 95% CI, 0.5-0.63). MACE in AML patients ((OR 2, 95% CI, 1.9-2.12,), AMLniR (OR 1.46, 95% CI, 1.2-1.9), and rAML (OR 2.5, 95% CI, 2-3.2) were associated with increased in-hospital deaths. However, AMLiR had lower likelihood of deaths (OR 0.6, 95% CI, 0.45-0.74).

Conclusion: Hospitalized AML patients with relapse had lower rates of major cardiovascular events, possibly due to the younger age of this group. Bone marrow transplant and chemotherapy were associated with less major cardiovascular events, while AMLniR and rAML were associated with increased in-hospital mortality. More research is needed to evaluate MACE in AML patients undergoing intensive chemotherapy.
Recombinant Human Thrombopoietin Combined with Thrombopoietin Receptor Agonists Can Facilitate the Recovery of Platelet after Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma
Authors: Xu Xuezhu , Liu Rui , Yang Ruoyu , He Aili , Zhao Wanhong , Wang Fangxia
Published: December 2024

Abstract

Background

Autologous hematopoietic stem cell transplantation (ASCT) has been widely used in the treatment of hematologic tumors and has achieved significant efficacy, especially for multiple myeloma (MM). The high-dose conditioning regimen of ASCT always causes myelosuppression which might lead to neutropenia and thrombocytopenia. In clinical practice, thrombopoietin receptor agonists (TPO-RAs) and recombinant human thrombopoietin (rh-TPO) have been applied to refractory thrombocytopenia after ASCT and has shown a certain efficacy, respectively. But very few clinical data are available regarding the use of TPO-RAs combined with rh-TPO after ASCT for NDMM patients.

Aims

To compare the effect of rh-TPO plus TPO-RA (hetrombopag) on white blood cell and platelet (PLT) recovery, adverse events, post-operative complications, and cost effectiveness after autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma (NDMM).

Methods

Ninety-five cases with NDMM had been enrolled from January 2018 to December 2023. The hematopoietic reconstitution was compared between these 35 cases receiving rh-TPO combined with TPO-RA after stem cell reinfusion as observation group and 60 cases only receiving rh-TPO classified as the control group.

Results

There were no significant differences in the baseline clinical characteristics between two groups. In the observation group, the median time to platelet was the 10th day after stem cell reinfusion, which were significantly shorter than those of the control group (P＜0.001). The mean units of platelet transfusion in the observation group were significantly lower than those in the control group (1.0 vs 1.5 units, P=0.007). All the patients tolerated rh-TPO and TPO-RA well and no thrombotic events occurred. Survival analysis showed no decrease in time to progression (TTP) or overall survival (OS) by TPO-RA administration. There were no statistical differences in the incidence of adverse events, total expense and hospital stay between two groups (P > 0.05).

Conclusions

Our data shows that the treatment protocol of TPO-RA (hetrombopag) combined with rh-TPO may boost a faster platelet growth rate. Importantly, no additional adverse effects occurred when the addition of TPO-RA.
Thromboprophylaxis By Direct Oral Anticoagulants Versus Low Molecular Weight Heparin in Patients Undergoing Surgery for Gynecological Cancer: A Systematic Review and Meta-Analysis
Authors: Dave Prashil , Uddin Anwar , Shastri Dipsa , Irfan Sohaib , Winer Andrew
Published: December 2024

Introduction: Anticoagulants are used prophylactically to prevent venous thromboembolism (VTE) in the perioperative period for patients undergoing surgery for gynecological cancer. However, they carry a substantial risk of bleeding. This meta-analysis aims to study the efficacy and safety of Apixaban and Rivaroxaban compared to the traditional Enoxaparin.

Methods: PRISMA guidelines were followed, and PubMed, Cochrane, and Google Scholar were searched using MeSH terms ‘gynecological cancer’ AND ‘DVT prophylaxis’ OR ‘thromboprophylaxis’ OR ‘Enoxaparin’ from January 2004 to December 2023. Five studies were included in analysis. Demography, type and duration of surgery, treatment efficacy, and safety data was extracted. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions and 95% Confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.3.3).

Results: A total of 1797 patients from the five studies (Apixaban n=326, Rivaroxaban n=343, Enoxaparin n=1138) reporting the perioperative outcomes of Apixaban and Rivaroxaban versus Enoxaparin therapy were included, of which 2 were clinical trials (40%), and 3 were retrospective analyses (60%). The mean age for Apixaban and Rivaroxaban was 57.3 years, and the mean age for Enoxaparin was 59.1 years. The mean BMI for Apixaban, Rivaroxaban and Enoxaparin was 27.1. The pooled composite venous thromboembolism relative risk for Apixaban vs Enoxaparin was 0.64 (95% CI 0.22-1.89, 12=0%, p=1.00). The pooled composite VTE, the relative risk for Rivaroxaban vs. Enoxaparin, was 0.58 (95%CI 0.24-1.41, 12=0%, p=0.69). The pooled DVT relative risk for Apixaban vs Enoxaparin was 1.11 (95% CI 0.1-12.75, 12=75%, p=0.13). The pooled major bleeding relative risk for Rivaroxaban vs Enoxaparin was 4.31 (95% CI, 1.18-15.79, 12=0%, p=0.47). No pooled major bleeding relative risk for Apixaban vs. Enoxaparin could be calculated as only one study mentioned outcome.

Conclusions: Our analysis suggests that direct oral anticoagulants offer superior efficacy compared to Enoxaparin for preventing venous thromboembolism. However, Rivaroxaban is associated with a significantly higher risk of bleeding compared to Enoxaparin. Further clinical trials and randomized studies to evaluate the comparative effectiveness and safety of these anticoagulants in various patient populations are essential. Such studies are important for the development of comprehensive international guidelines for VTE management, ensuring optimal evidence-based treatment.
Investigating Prognostic Value of Immunoglobulin Next-Generation Sequencing in B Cell Non-Hodgkin Lymphoma Patients Undergoing Chimeric Antigen Receptor T-Cell Therapy
Authors: Zhang Yi-Lun , Sheng Lingshuang , Shen Rong , Wu Wen , Zheng Xin , Wang Li , Cheng Shu , Xu Peng-Peng , Jian Qi-Jie , Peng Bo , Zhang Ke , Pang Fei , Wang Kai , Yan Zi-Xun , Zhao Wei-Li
Published: December 2024

Background

In B cell non-hodgkin lymphoma (B-NHL), circulating tumor DNA (ctDNA)-based liquid biopsy for minimal residual disease (MRD) detection correlates strongly with post-treatment relapse. Immunoglobulin next-generation sequencing (Ig-NGS) is more sensitive and cost-effective compared to targeted capture sequencing. Improved biomarkers are essential to guide autologous chimeric antigen receptor T-cell (CAR-T) therapy, particularly in early stages. Currently, there is a lack of research on the prognostic value of Ig-NGS MRD in B-NHL patients undergoing CAR-T therapy.

Method

We recruited B-NHL patients scheduled for CAR-T therapy, collecting tissue and/or peripheral blood samples prior to leukapheresis. Plasma and peripheral blood mononuclear cells were immediately separated and used for dominant clonotypes identified by Ig-NGS assay (Origimed, Shanghai, China) as the baseline assessment. Post-therapy, serial peripheral blood samples were collected at days 7, 14, 28, and every 3 months for MRD assessment via Ig-NGS assay. Imaging examinations were performed at 3, 6 and 12 months after therapy.

Result

In a cohort of 51 B-NHL patients treated with CAR-T therapy, including 45 diffuse large B-cell lymphoma patients, two follicular lymphoma patients, two primary bone marrow B-cell lymphoma patients, and two high-grade B-cell patients, clonality was identified in 94% (48/51) of patients, with at least one identifiable clonotype (median 2; range 1-3). In matched baseline samples, the dominant clonotypes identified in tissue samples were detectable in 83% (19/23) of ctDNA samples and 71% (15/21) of gDNA samples. After a median follow-up of 12 months post-treatment, the objective response rate was 78% (40/51). In post-CAR-T therapy surveillance, MRD was detected in 50% (11/22) of patients, significantly correlated with poorer progression-free survival than MRD negative patients (1-year PFS: 36% vs. 100%, P<0.001). MRD positivity had a sensitivity and specificity for progression of 64% (7/11) and 100% (11/11), respectively. The median lead time from MRD detection to clinical relapse was 23 days (range: 2-166 days).

Conclusion

Our research provides substantive evidence that Ig-NGS testing on ctDNA, rather than gDNA from peripheral blood, is more suitable for MRD monitoring. ctDNA effectively serves as a reliable indicator for impending disease progression. A positive plasma MRD result directly correlates with a significantly heightened risk of disease progression. Consequently, MRD surveillance following CAR-T therapy holds potential for timely evaluation and early re-initiation of treatment upon molecular relapse, thereby optimizing therapeutic strategies.
Targeting the Protein Kinase Α Pathway to Overcome Chemotherapy Resistance in AML
Authors: Willis Stephen D. , Platanias Leonidas C. , Small Sara H.
Published: December 2024

Acute myeloid Leukemia (AML) is the most common form of acute leukemia in adults. Each year over 20,000 adults will be diagnosed with AML in the United States and almost 70% will perish within 5 years of diagnosis, frequently due to relapsed disease. AML is primarily treated with intensive chemotherapy using DNA-damaging agents such as cytarabine (AraC) and daunorubicin. In many cases, however, AML is either refractory to chemotherapy treatment or initially responsive but resistant at relapse. Therefore, developing new strategies for eradicating chemotherapy-resistant disease is vital to improving outcomes for AML patients. Previous data from our group have shown that low expression of the DNA damage response gene Schlafen 11 (SLFN11) correlates with lower overall survival in AML patients and predicts resistance to AraC in TP53-mutated AML cell lines (Small et al, Blood Neoplasia, accepted 07/2024). We have expanded upon this work using a genetically diverse panel of human AML cell lines (including wild-type TP53 cell lines) and observed that the expression of SLFN11 negatively correlated with response to the DNA damaging agents AraC and daunorubicin. This correlation was not observed using other AML-directed drugs such as venetoclax or azacitidine, further corroborating previous data from our group. Additionally, the expression of SLFN11 and the DNA damage drug response were independent of the diverse genetic mutations present in these cell lines, suggesting SLFN11 expression is an independent variable that determines sensitivity to these drugs. To find novel targets for SLFN11-deficient cells, RNA sequencing was performed on SLFN11 knockout cells developed in the human monocytic AML cell line, U937. We observed that the protein kinase A (PKA) pathway genes AKAP7 and PDE7B were upregulated in SLFN11 knockout cells compared to control cells. We then combined PKA pathway modulation with DNA damage induction to test whether this strategy could restore sensitivity to chemotherapeutics in SLFN11-deficient cells. We found that targeting the PKA pathway using the PDE7-specific inhibitor BRL-50481 partially restored sensitivity to AraC in the SLFN11 knockout cells, without further sensitizing the parental cell line. This study expands upon the role of SLFN11 as a novel biomarker in AML for predicting patient response to DNA-damaging agents. It also demonstrates that alternative treatment strategies, such as combining AraC and PKA pathway inhibitors, may be a viable treatment option in SLFN11-deficient AML patients.