bluuebunny/crossref_metadata_2025 huggingface dataset:
Bleeding Associated with Prophylactic Anticoagulation for Hospital Related Venous Thromboembolism Prevention: A Case Series
Authors: Latef Taroob , Jadoon Yamna , Bhardwaj Prarthna , Loke Chandravathi
Published: December 2023

The use of heparin products for prophylaxis of venous thromboembolism (VTE) have decreased the prevalence of VTE in all hospitalized patients, however the possibility of bleeding from prophylactic heparin cannot be disregarded. While life-threatening bleeding is less common with prophylactic doses, it can occur in the presence of other risk factors for bleeding. We aim to describe characteristics that may increase bleeding risk from prophylactic use of heparin. We present a single-center, retrospective case series of patients who received protamine for bleeding complications from prophylactic heparin administration at our facility between 2016-2020. We assessed patient demographics, medical history, types of heparin formulations administered, and patient outcomes. We observed that all patients were female. Patients who developed bleeding events from VTE prophylaxis had at least two of these attributes; BMI <18.5 kg/m2, weight <50kg, trauma within 1-month, surgery within 1-month or were taking anti-platelet agents. We suggest that the collective presence of two or more of these characteristics should lend consideration to dose adjustment and/or closer monitoring. In the absence of rigorous research comparing alternative doses to standard doses for prophylaxis in these patients, these decisions fall largely to the discretion of individual physicians. Designing larger studies following patients over long periods of time can help conclusively identify risk factors that predispose patients to bleeding.
Gender Disparities in Outcomes of Autoimmune Hemolytic Anemia Admissions: An Analysis of the National Inpatient Sample
Authors: Abdelhay Ali , Jain Tripti , Srivastava Arnav , Avalos Sugastti Eduardo , Mostafa Mariam , Reghis Mouna , Kharel Himal , Orakzai Abdullah
Published: December 2023

Introduction

Autoimmune hemolytic anemia (AIHA) is a condition characterized by the immune destruction of red blood cells, which can necessitate hospitalization in severe cases. The purpose of this study is to compare outcomes of AIHA hospitalizations between genders.

Methods

We utilized the International Classification of Diseases (ICD) codes to identify all hospitalizations with the primary diagnosis of AIHA in the National Inpatient Sample (NIS) from 2002 to 2019. We excluded all pediatric (age < 18 years) and elective hospitalizations. We described the baseline characteristics of both groups including demographics and comorbidities. We fitted multivariable logistic regression models to compare outcomes between males and females while adjusting for age, race, and comorbidities.

Results

A total of 60,529 met the inclusion and exclusion criteria. The majority of these were females (59.1% vs 40.1%, p < 0.001). Males were older (median age 67 vs. 66 years, p < 0.001) and had more white race (73.4% vs. 67.9%, p < 0.001). The distribution of associated comorbidities also differed different between both groups ( (Table 1). On adjusted analysis, males had higher in-hospital mortality rates. They also had higher rates of most secondary outcomes; including rates of circulatory shock, need for mechanical ventilation, bacterial pneumonia, acute myocardial infarction, deep vein thrombosis, hemorrhagic stroke, acute kidney injury, and requiring new hemodialysis. Females had higher rates of urinary tract infections. No significant differences were found in the rates of requiring blood transfusions, sepsis, acute heart failure, pulmonary embolism, ischemic stroke, encephalopathy, and gastrointestinal bleeding (Figure 1). Furthermore, male hospitalizations were associated with higher costs (median [IQR] of $11,400 [6,700-20,500] vs. $10,000 [6,000- 17,200]) despite similar length of stay (median [IQR] of 4 days [3-7] vs. 4 days [3-7]).

Conclusion

Male patients hospitalized with AIHA experience poorer in-hospital compared to females. More research is essential to understand the underlying causes for these disparities and to tailor management to improve outcomes for both male and female AIHA patients.
The Effect of Ciprofloxacin Prophylaxis during Haematopoietic Cell Transplantation on Infection Episodes, Exposure to Treatment Antimicrobials and Antimicrobial Resistance: A Single-Centre Retrospective Cohort Study
Authors: Baltas Ioannis , Kavallieros Konstantinos , Konstantinou Giannis , Koutoumanou Eirini , Gibani Malick M , Gilchrist Mark , Davies Frances , Pavlu Jiri
Published: December 2023

Objectives

Fluroquinolone prophylaxis during haematopoietic cell transplantation (HCT) remains controversial. We aimed to determine its effectiveness and association with exposure to treatment antimicrobials and antimicrobial resistance.

Methods

All admissions for HCT in a tertiary centre between January 2020 and December 2022 (N=400) were studied. Allogeneic haematopoietic cell transplantation (allo-HCT) recipients had prophylaxis with ciprofloxacin during neutropenia, while autologous haematopoietic cell transplantation (auto-HCT) recipients not.

Results

Allo-HCT was performed for 43.3% (173/400) of patients, auto-HCT for 56.7% (227/400). In multivariable analysis, allo-HCT was associated with 1.01 (95% confidence intervals [CI] 0.62 - 1.40, p<0.001) fewer infection episodes per 100 admission days compared to auto-HCT. In allo-HCT, total exposure to all antimicrobials (+24.8 days of therapy [DOT]/100 admission days, p<0.001) and ciprofloxacin (+40.5 DOT/100 admission days, p<0.001) was higher, while exposure to meropenem (-4.5 DOT/100 admission days, p=0.02), piperacillin-tazobactam (-5.2 DOT/100 admission days, p<0.001), aminoglycosides (-4.5 DOT/100 admission days, p<0.001), glycopeptides (-6.4 DOT/100 admission days, p<0.001), was lower. Enterobacteriaceae isolated during allo-HCT were more likely to be resistant to ciprofloxacin (65.5%, 19/29 versus 6.1%, 2/33, p<0,001), ceftriaxone (65.5%, 19/29 versus 9.1%, 3/33, p<0.001), and other antimicrobial classes. Vancomycin-resistant enterococci were more common in allo-HCT recipients (11%, 19/173 versus 0.9%, 2/227, p<0.001). Inpatient mortality during allo- and auto-HCT was 9.8% (17/173) and 0.4% (1/227) respectively (p<0.001).

Conclusions

Ciprofloxacin prophylaxis in allo-HCT was associated with fewer infection episodes and reduced exposure to treatment antimicrobials compared to auto-HCT. Mortality in auto-HCT remained low. Significant burden of antimicrobial resistance was detected in allo-HCT recipients.
Global Prevalence of Anemia Among Women of Reproductive Age, 2000-2019
Authors: Deloughery Emma P
Published: December 2023

Introduction: A common disease with significant impacts on health and quality of life, anemia is particularly prevalent in women of reproductive age due to blood losses during menstruation and pregnancy. Data from the World Health Organization (WHO) was analyzed to compare trends in prevalence of anemia in women aged 15-49 among countries and over time with the goal of identifying regions both successful and in need of assistance in combatting anemia.

Methods: Publicly available data was obtained from the WHO on the prevalence of anemia among women aged 15-49 from 194 countries from 2000-2019, data being reported as percentages. Anemia was defined as hemoglobin < 12 g/dL for non-pregnant women and < 11 g/dL for pregnant women, with severe anemia being defined as hemoglobin < 8 g/dL for non-pregnant women and < 7 g/dL for pregnant women. WHO data was from both individual-level and summary statistics sources and hemoglobin was adjusted for altitude. Human development index (HDI) data and categories (low, medium, high, and very high) were obtained from the United Nations. Data was analyzed based on year, country, geographic region, and HDI, with ANOVA and Tukey HSD tests being used to analyze the relationship between HDI and anemia.

Results: Worldwide from 2000 to 2013 the prevalence of anemia decreased, and then increased from 2013 to 2019 though remained lower than at 2000 levels; severe anemia decreased throughout the world from 2000 to 2019. Throughout all years, African countries had the highest prevalence of anemia and severe anemia while American and European countries had the lowest (Figure 1). When analyzed by HDI category, there was a significant difference among HDI categories with both total and severe anemia ( P < 0.001 for both). With each decrease in HDI category (very high to high, etc.) there was a significant increase in prevalence of total anemia (Table 1, P < 0.001 for all). For severe anemia, there was a significant difference in prevalence of anemia between all HDI levels except very high and high ( P = 0.09).

Discussion: This data suggests that although the prevalence of anemia among reproductive age women has decreased over time there is still much work remaining, particularly in low HDI countries, where the prevalence of anemia was over twice that of very high HDI countries in 2019, and the prevalence of severe anemia was over three times as high. More research is needed into the relationship of anemia and socioeconomic status as well as preventing, recognizing and treating anemia.
Do We Still Need to Perform Bone Marrow Examination in All Subjects Suspected of MDS? Evaluation and Validation of Non-Invasive (Web-Based) Algorithm
Authors: Oster Howard S , Polakow Ariel M , Goldschmidt Noa , Mittelman Moshe
Published: December 2023

Background : The gold standard of diagnosing myelodysplastic syndromes (MDS) still requires a bone marrow examination (BME), an old invasive procedure, with possible associated pain and bleeding, and subjective interpretation with 20-25% inter-observer variability. We first developed a logistic regression formula [Oster HS et al., Leuk Res 2018], and then a non-invasive web-based diagnostic algorithm [Oster HS et al., Bld Adv 2021]. The app requires input of 10 readily available clinical and laboratory parameters (age, gender, Hb, MCV, WBC, ANC, monocytes, PLT, glucose, creatinine), resulting in diagnosing or excluding MDS, perhaps obviating the BME (Figure). Here, we performed external validation of the model, using data of MDS patients and non-MDS controls, who had not been included in the development of the model.

Methods: The BM registry of Tel Aviv Sourasky Medical Center (1/2017-12/2021) was reviewed. Inclusion criteria for the MDS group were BME diagnosis, and for the controls, age >50yr, and unexplained anemia requiring BME. We excluded patients with other causes of anemia (renal failure; B12/folic acid or iron deficiency), active malignancy and other hematologic diseases.

The relevant parameters were entered into the online model (at https://shiny.york.ac.uk/mds/) and the results of both groups were compared. In a sub-analysis, the model performance was tested in patients with lower risk (LR, IPSS-R<3.5) and higher risk (HR, IPSS-R≥3.5) MDS.

Results: In total, 204 patients were included and compared, 103 with MDS, and 101 anemic non-MDS control patients, all with BME. The analysis of model performance (Table, upper portion) showed a sensitivity of 85.6%, specificity of 92.3%, positive predictive value (PPV) of 90.3% and a negative predictive value (NPV) of 88.4%. The algorithm was indeterminate in 26.2% of patients with MDS (BME proven), compared with 9.9% in the control group.

In the sub-analysis (Table, lower portion), the model performance in the patients with LR-MDS (n=61) demonstrated sensitivity 85.1%, specificity 92.3%, PPV 90.3% and NPV 88.1%. The performance in HR-MDS (n=32), was 89.3%, 92.3%, 90.6% and 91.1%, respectively.

Conclusions : This study validates the potential role of this non-invasive, easy-to-use model to assist in diagnosis, and mainly exclusion of MDS, perhaps allowing to avoid bone marrow examination in some patients. This might be especially relevant for patients suspected to have LR-MDS. Emerging technologies with data generated from peripheral blood (genetics, morphometrics) may be incorporated in the model in the future.
Pre-Existing Chromatin States Regulate KLF4 Binding to Eliminate Leukemia Stem Cells
Authors: Lu Ting , Yang Shangda , Chen Cong , Liu Shan , Sun Guohuan , Cheng Hui , Cheng Tao , Yen Kuangyu
Published: December 2023

Transcription factors collaborate with chromatin's epigenetic states to regulate cell fate decisions. While recent in vitro work using cryo-EM (Sinha et al., Nature, 2023) suggested that histone modifications could regulate the activity of pioneer transcription factors, it was not clear whether these findings applied in vivo, or if chromatin states could influence transcription factor binding to affect cell fate. Our previous work (Liu et al., Leukemia,2014; Wang et al., Nat Commun,2019) showed that reprogramming factors (Oct4, Sox2, Klf4, and cMyc, collectively known as OSKM) selectively eliminated leukemia cells in vivo, with minimal impact on normal Hematopoietic Stem and Progenitor Cells (HSPCs). This suggested that cell fates induced by OSKM could be influenced by pre-existing chromatin states.

Building on this hypothesis, we profiled the pre-existing chromatin states of leukemia cells and HSPCs using MNase-ChIP-seq, ATAC-seq, and WGBS-seq. In our Tet-on-induced models, Klf4 activation resulted in the targeting of distinct gene sets and exhibited similar dynamic changes in chromatin accessibility, despite these regions sharing the same active chromatin state. Using machine learning algorithms, we identified H3K18ac –a feature of the active chromatin states preferred by Klf4– as a dominant factor influencing Klf4's genomic binding. We then altered H3K18ac through an enzymatically deficient SIRT7, which is an H3K18ac deacetylase, and examined where Klf4 binds. We observed an increase in Klf4 binding at sites where H3K18ac levels were elevated. This result suggested that Klf4 binding was influenced by changes in H3K18ac. We exposed human CD34+ cells, several leukemia cell lines, and samples from leukemia patients to ATPO-253. This small molecule, currently in phase 1 clinical trials, has been found to enhance the levels of the KLF4 protein. This treatment led to an increase in KLF4 protein levels and we observed activation of apoptosis genes in the tested leukemia cell lines that possessed high pre-existing H3K18ac levels. In addition, we observed a decline across all tested leukemia samples, while the population of CD34+ cells essentially remained stable.

In conclusion, our work demonstrated that pre-existing chromatin states, such as H3K18ac, regulate Klf4's genomic binding, thereby influencing distinct cell fates in leukemia cells and HSPCs. This opens potential avenues for clinical applications in targeted leukemia cell clearance using KLF4 or ATPO-253.
Increase in Total Protein Level of Bruton's Tyrosine Kinase in Myeloproliferative Neoplasms
Authors: Cacciola Rossella Rosari , Cacciola Emma
Published: December 2023

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by atherosclerosis and cardiovascular risk. The mechanisms that connect MPNs with atherothrombosis remain elusive. It is known that atherosclerotic plaque causes Glycoprotein VI (GPVI)-dependent platelet activation and hence activation of bruton kinase (Btk) and that Btk inhibitors in vivo and ex vivo suppress GPVI-mediated paltelet activation. Aim of this study is to measure the levels of GPVI and Btk. In addition, we measured the CXCL12 as marker of atherothrombosis. We studied 25 JAK2V617F positive MPNs patients (WHO criteria) (mean age 58 years) including PV 12, ET 8, and PMF 5. We measured platelet count by automated analyzer, GPVI by flow cytometry, total Btk (T-Btk) protein by immunoblot and total CXCL12 (T-CXCL12) protein by ELISA. All patients had thrombocytosis (630±40x109/L) and allele burden ≥ 50%. We found high GPVI expression (mean fluorescence intensity (MFI) 20±5.8) and high T-Btk (mean value 1.0) as well as high T-CXCL12 (15±2 μg/ml). A positive correlation there was between GPVI and Btk. We further investigated Btk mRNA tran script levels using RT-PCR assay in triplicate from each samples and found mean values ≥ 1.0. On the basis of these results the use of GPVI- and Btk- inhibiting agents as atherothrombosis-focused antiplatelet drugs is conceivable. Therefore, clinical trials are eagerly awaited.
Anti-Hemojuvelin Monoclonal Antibody DISC-0974 Elicits a Durable and Consistent Response with Repeated Dosing in Cynomolgus Monkeys
Authors: Reisman Scott A , Savage William , Liu Guowen , Yang Hua
Published: December 2023

Introduction

DISC-0974 is a monoclonal antibody (mAB) targeting hemojuvelin and is currently in clinical trials evaluating effects on anemia in patients with myelofibrosis or chronic kidney disease. Inhibition of hemojuvelin (HJV) results in decreased hepcidin and reduction in ferroportin degradation, enabling more iron to be exported out of cells and into the bloodstream for transport to other cells and tissues.

Methods

A study was conducted in healthy, naïve cynomolgus monkeys to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DISC-0974 following once-monthly dosing for 6 months. Male and female cynomolgus monkeys (n=6/sex/dose group) were intravenously administered DISC-0974 at doses of 0, 0.3, 1, or 6 mg/kg on Days 1, 29, 57, 85, 113, and 141. An additional IV dose was administered on Day 165 for males and Day 166 for females. Dose levels were selected where the high dose would maximally mobilize iron for sustained periods over the treatment regimen, with lower doses selected to provide a dose-response. Male and female monkeys (n=4/sex/group) were euthanized on Day 168 and 169, respectively, and subgroups were monitored for an additional 6 months (n=2/sex/group) to evaluate reversibility of any effects. PK was evaluated after the 1 st, 3 rd, and 6 th dose in all monkeys, as well as during the 6-month period after the final dose in the remaining monkeys. PD effects (i.e., serum iron and transferrin saturation [TSAT]) were monitored at the same timepoints as those collected for PK.

Results

DISC-0974 was well tolerated, and no DISC-0974-related adverse effects were observed. Systemic exposure, based on area under the curve (AUC) and maximum plasma concentrations (C max), increased with dose. Systemic exposures were achieved that reached and exceeded those observed in clinical trials. The high dose of 6 mg/kg achieved systemic exposures, based on AUC, that were >15-fold those observed in humans. Half-lives were consistent with an mAb, and repeated exposure did not result in accumulation with monthly dosing. Increases in serum iron (up to approximately 3-fold baseline) (Figure 1) and TSAT (>90%), representative of PD activity, correlated with systemic exposures of DISC-0974, with similar activity maintained after each of the 7 monthly doses.

Conclusion

Overall, these data demonstrate that DISC-0974 is well tolerated after repeated monthly exposure in cynomolgus monkeys, and an appropriate and durable PK/PD profile was observed, supporting clinical development of chronic once-monthly dosing.
Study on the Changes of Immune Cells in the Evolution of Myelodysplastic Syndromes
Authors: Wang Jing , Zhang Xiaoyuan , Zhao Yue , Zhang Jingjing , Zhou Yibin , Hou Li
Published: December 2023

ABSTRACT Objective: To analyze the differences of peripheral blood immune cells in healthy people, and patients with myelodysplastic syndromes (MDS) patients or acute myeloid leukemia (AML), and to investigate their correlations with International Prostate Symptom Score(IPSS), blasts and other factors in MDS patients. Methods: 55 patients with MDS(MDS group), 67 patients with AML(AML group) and 25 heathy people(healthy group) were selected as research objects from Dongzhimen Hospital Affiliated with Beijing University of Chinese Medicine from January, 2012 to April, 2022 for this retrospective analysis. By comparing peripheral blood lymphocyte subsets count and peripheral blood lymphocyte subsets percentage, we studied the expression of T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+, CD3+CD4+CD25+FoxP3+), B cells (CD19+) and NK cells (CD3-CD16+CD56+). The correlations between the different indexes and IPSS and blasts were analyzed. Results: (1) Peripheral blood lymphocyte subsets count: There were differences among the three groups. Through pairwise comparison, MDS group had lower peripheral blood lymphocyte subsets count(P＜0.025), probably owing to the low peripheral blood lymphocyte count. (2)Peripheral blood lymphocyte subsets percentage: The percentages of Treg cells, B cells and T cells varied among the three groups. Compared with the healthy group, the percentages of T cells ( P＜0.025) and Treg cells ( P＞0.025) in MDS group were higher, and the percentage of B cells ( P＜0.025) was lower. Compared with MDS group, the percentage of Treg cells ( P＜0.025) in AML group was higher and the proportion of B cells was lower ( P＜0.025). (3)Correlations with IPSS and blasts: The percentage of Treg cells was positively correlated with IPSS and blasts. Conclusion: Treg cells showed an increasing trend in turn by healthy people group, MDS group and AML group. The high expression of Treg cells may have great significance in prognosis and progression of MDS.

Key words: Acute myeloid leukemia; Blasts; Immune cells; Myelodysplastic syndromes.
Survival and Causes of Death in Patients with Alpha and Beta-Thalassemia
Authors: Tantiworawit Adisak , Kamolsripat Thansita , Piriyakhuntorn Pokpong , Rattanathammethee Thanawat , Hantrakool Sasinee , Chaiadisaksopha Chatree , Ekarat Rattarittamrong Ekarat , Norasetthada Lalita , Fanhchaksai Kanda , Charoenkwan Pimlak
Published: December 2023

Background: Thalassemia is the most common hereditary anemia worldwide. The prevalence is high in the malaria-endemic areas, including Southeast Asia, and Thailand. Severe thalassemia can result in shortened survival due to disease-related complications. In the last three decades, with regular red cell transfusions and iron chelators, the survivals of patients with thalassemia, especially for TDT, have significantly improved. The most distinctive change was the decrease in the iron-overloaded cardiomyopathy. Both alpha and beta-thalassemia are prevalent in Thailand. We aimed to study the survival, and the causes of death in the patients with thalassemia across the disease severity from NTDT to TDT, and to explore the factors influencing the survival.

Methods: A retrospective review of patients with thalassemia who were followed up at Chiang Mai University Hospital was conducted. The survival status was determined from medical records and the Thai National database (Official statistics registration systems). The survival and clinical factors associated with survival were analyzed.

Results: Our study cohort comprised 789 patients with thalassemia, who were registered in the Departments of Internal Medicine and Pediatrics. The median age (IQR) at the end of follow-up was 18∙8 (11∙7) years. There were 301 patients (38∙1%) with Hb H disease, 279 patients with Hb E/beta-thalassemia (35∙4%), and 209 patients (26∙5%) with beta-thalassemia major, respectively. Half of the patients (395, 50∙1%) had transfusion-dependent thalassemia (TDT). Sixty-five (8∙2%) patients had died. The mean age at death was 17∙0 ± 0∙9 years. Multivariable analysis showed that TDT (adjusted HR 3.68, 95%CI 1.39-9.72, p 0∙008) and mean serum ferritin level ≥3,000 ng/mL (adjusted HR 4∙18, 95%CI 2.20-7.92, p<0∙001) were independently associated with poorer survival. The two major cause of death were infection-related causes (36∙9%), cardiac complications (27∙7%), thalassemia/anemia (13∙8%), trauma (6∙2%), and other causes (15∙4%).

Conclusions: TDT and mean serum ferritin level ≥3,000 ng/mL were the main factors associated with poorer survival in thalassemia patients. Infections and cardiac complications were the two major causes of death.
Score to Guide Donor Choice in Haploidentical Stem Cell Transplant Using Post-Transplant Cyclophosphamide for Patients with Acute Myeloid Leukemia: A Study from the Acute Leukemia Working Party of the EBMT
Authors: Sanz Jaime , Labopin Myriam , Blaise Didier , Raiola Anna Maria , Busca Alessandro , Vydra Jan , Tischer Johanna , Chevallier Patrice , Bramanti Stefania , Fanin Renato , Socié Gerard , Forcade Edouard , Kröger Nicolaus , Koc Yener , Itäla-remes Maija , Zecca Marco , Nagler Arnon , Brissot Eolia , Spyridonidis Alexandros , Bazarbachi Ali , Giebel Sebastian , Piemontese Simona , Mohty Mohamad , Ciceri Fabio
Published: December 2023

Introduction: There is paucity of information to guide selection of the most appropriate stem cell donor for haploidentical (Haplo) hematopoietic stem cell transplant (HSCT).

Patients and Methods: We retrospectively analyzed the characteristics of haploidentical family donors that may affect transplant outcomes in patients with acute myeloid leukemia (AML) who received graft-versus-host disease (GVHD) prophylaxis with postransplant cyclophosphamide (PTCy) registered in the EBMT database. The primary endpoint was GVHD and relapse-free survival (GRFS).

Results: Overall, 2200 patients were included with a median age of 56 years (range, 18-75); 1742 (79%) were in complete remission and 1246 (56.6) received reduced intensity conditioning. Regarding donors, the median age was 37 years (range, 8-71), 820 (37%) were females of which 458 (21%) were used for male recipients, 1252 (57%) had positive CMV serostatus, 1631 (74%) donated peripheral blood (PB) and 1638 (75%) had ≥ 4/8 HLA mismatch with the recipient. 100-day acute GVHD grade II-IV and III-IV and 2-year chronic and chronic extensive GVHD were 28% (95% CI 26-30), 11% (95% CI 10-12), 33% (95% CI 31-35) and 14% (95% CI 12-15), respectively. After median follow-up of 24 months, the cumulative incidence of relapse and non-relapse mortality (NRM) and the probability of leukemia-free survival (LFS), overall survival (OS) and GRFS were 26% (95% CI 24-28), 22% (95% CI 20-24), 52% (95% CI 50-55), 57% (95% CI 55-60) and 41% (95% CI 39-43), respectively. In multivariable analysis, donor-related risk factors with a negative impact on GRFS were older age (HR 1.1; 95% CI 1.04-1.15), use of PB (HR 1.19; 95% CI 1.04-1.37), and female donors to male recipients (HR 1.25; 95% CI 1.09-1.43). We further developed a score that distinguished 4 groups with 0 (241), 1 (913), 2 (863) or 3 (183) donor-related risk factors. GRFS was 57% (95% CI 50-63), 43% (95% CI 39-46), 37% (95% CI 33-40), and 30% (95% CI 23-38), respectively (P < 0.001) (Figure 1). The score was also able to stratify risk groups for acute and chronic GVHD, NRM, LFS and OS.

Conclusion: Donor variables have an important impact on AML patient's outcome after Haplo-HSCT using PTCy. With three simple donor characteristics, age, gender and stem cell source, we were able to generate a score that may help to select the most appropriate donor in clinical practice.
Development of a Targeted NGS Panel for Hematologic Malignancies According to Who/ICC 2022 Guidelines
Authors: Lee Young Eun , Kim Hye Ran , Lim Ha Jin , Choi Yong Jun , Park Joo Heon , Choi Hyun-Woo , Choi Hyun-Jung , Kee Seung-Jung , Kim Soo Hyun , Shin Jong Hee , Park Chang Soo , Shin Myung Geun
Published: December 2023

Introduction: Since 2020, we have successfully developed a targeted blood cancer NGS panel and have been using it efficiently in clinical settings. However, it needed to be upgraded due to recent new blood cancer diagnosis and classification guidelines by the World Health Organization and the International Collaboration for Cancer Classification (ICC) in 2022. Therefore, in this study, an updated targeted NGS panel that covers the updated guidelines was evaluated using clinical samples.

Methods: To adhere to the recent guidelines, the currently used targeted NGS panel (KBB DNA/RNAseq NGS Leukemia PHB; KBlueBio Inc., Hwasun, Korea) was reviewed. Its analytical performance was validated using standard NA12878 and clinical samples. The clinical samples consisted of 19 genomic DNA and 20 total RNA samples extracted from the bone marrow or peripheral blood of patients with hematologic malignancies, including acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome/myeloproliferative neoplasm, multiple myeloma, and lymphoma.

Results: The updated DNA panel comprises 125 genes including 6 new genes ( BCORL1, BLM, GNB1, PRPF8, SAMD9 and SAMD9L). The updated RNA panel has 116 genes including 31 new genes ( FLT3, CBFA2T3, RPN1, BCL11B, ZNF362, HLF, NUTM1, UBRF, CDX2, ZEB2, CDK6, ZMYM2, AFDN, ELL, NSD1, HOXA9, KDM5A, ZBTB16, GLIS2, PRDM16, NPM1, KAT6A, MNX1, TAF15, MLLT1, P2RY8, HNRNPUL1, ECM1, ENAM, JCHAIN (IGJ) and MDFIC). The accuracy, repeatability, reproducibility, sensitivity, and detection limit of the updated NGS panels were evaluated using standard materials, and the results met the predefined criteria. A comparison of the updated DNA panel with the old panel using 19 clinical samples revealed an overall concordance rate of 100% between the two panels for all mutations (95% confidence interval (CI): 99.72-100.00%). Similarly, the updated RNA panel also met the predefined criteria. The overall concordance rate between the updated RNA panel and the old panel was 99.72% in 20 clinical samples (95% CI: 99.00-99.72%).

Conclusions: The old targeted DNA/RNA NGS panel was successfully updated according to the 2022 WHO and ICC guidelines, and can be used to accurately and efficiently detect the genetic variants of blood cancers.
The Impacts of Genetic Polymorphisms on the Von Willebrand Factor Level in Type 1 Von Willebrand Disease
Authors: Chen Yeu-Chin , Chang Chia-Yau , Cheng Shin-Nan , Lai Shiue-Wei , Hu Shu-Hsia
Published: December 2023

Background: von Willebrand disease (VWD) is the most common inherited bleeding disease, which results from deficiency or defect of von Willebrand factor (VWF). In type 1 VWD, there are only 53-81% patient whose mutations of VWF gene can be identified. Some studies reported that variants outside the VWF gene may also contribute to the VWF level. There are 7 genetic variants of single nucleotide polymorphism ( SNP ) reported to be associated with the variation of VWF levels, including CLEC4M, STXBP5, SCARA5, ABO, VWF, STAB2 and UFM1. The aims of this study were to explore the frequency of SNPs of the 7 genes among type 1 VWD patients and the effects of the 7 genetic variants on the VWF levels in type 1 VWD patients.

Patients and methods: There were 62 patients ( the ratio of M/F: 1 ) with type 1 VWD enrolled in this study, including 35 (56.5%) patients with found mutations of VWF gene. Each patient's bleeding symptoms were assessed by the MCMDM-1 VWD bleeding score. The results of VWF levels: VWF:Ag and VWF activity ( VWF:ACL or VWF:RCo ) and FVIII: C at the VWD diagnosis were retrospectively collected, as shown in Table 1. Each enrolled patient's genomic DNA was extracted and the SNPs of the 7 gene were targeted by PCR amplification followed by direct sequencing.

Results: There was high correlations between VWF:Ag and VWF activity ( r = 0.73, p < 0.0001 ) and between VWF:Ag and FVIII:C ( r = 0.60, p < 0.0001 ), respectively. The patients without variant ( A/A) of UFM1 has significantly lower median VWF:Ag of 33% than 44.7% of patients with heterozygous variant ( A/C ) type ( p = 0.033 ). Patients without variant (A/A ) of STXBP gene had both significantly lower median value of VWF:Ag ( 31.9% vs 46.1%, p = 0.017 ) and VWF activity (26.55% vs 30.4%, p = 0.0467 ) than those patients with heterozygous variant ( A/G ). Four alleles substitution of SNP of UFM1( C>A ) and STXBP genes ( G>A ) variant has remarkably lowest median VWF antigen level of 27.4%, which was significantly lower than 43.05% of the three alleles substitution ( p = 0.0014 ) and the 48.6% of the two alleles substitution ( p = 0.0279 ), as shown in Figure 1.

Conclusions: Our study demonstrates that both C to A variant of UFM1 gene and G to A variant of STXBP5 gene were associated with lower VWF: Ag level than those without variant, respectively. The combination of four allelic variant of UFM1 and STXBP5 genes had the most reducing effect on VWF: Ag level.
Increased Circulating 2-Methylbutyrate Following Fecal Microbiota Transplantation in Patients with Refractory-Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation
Authors: Du Jing , Huang Fen , Yang Kaibo , Xu Na , Fan Zhiping , Xuan Li , Liu Qifa
Published: December 2023

Introduction

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment for patients with hematological malignancies. Steroid-refractory chronic GVHD (SR-cGVHD) remains the major cause of non-relapse mortality and life-threatening disease late after allo-HCT. Several groups reported that perturbation in the gut microbiome and impaired production of microbial metabolites such as short chain fatty acids (SFCAs) have involved in cGVHD pathogenesis and severity. Currently, there is no acceptable consensus and no standard second-line treatments for patients with SR-cGVHD. Our pilot study (NCT04622475) using fecal microbiota transplantation (FMT) from healthy donor to treat patients with SR-cGVHD provide a new insight into therapeutic strategies for SR-cGVHD. To investigated whether FMT improves the SR-cGVHD clinical outcome through SCFAs, the measurement of SCFAs concentration was performed in the plasma from SR-cGVHD patients after FMT. Here we report the preliminary results of this study.

Method

12 patients aged 16-60 years with SR-cGVHD after allo-HCT were enrolled. A total of 31 FMTs were performed via colonoscopy in 12 patients with SR-cGvHD over three consecutive months. FMT courses were repeated from the same donor. To characterize the impact of the FMT on the gut microbiota, stool samples and plasma from recipients were collected the day before FMT treatment and 4 weeks after each FMT treatment then carried out 16s rRNA sequencing and LC-MS. Complete response was defined as the complete resolution of GVHD manifestations in all organs. Partial response was defined as a decrease at least one stage in severity of GVHD or able to taper steroid dose. No response was defined as unable to taper steroid dose or need to increase or add immunosuppressor for controlling GVHD progression.

Result

The circulating SCFAs levels of SR-cGVHD patients associated to FMT outcome (Figure A). After FMT, the concentrations of butyric acid, isovaleric acid, valeric acid, 4-Methylvaleric acid and hexanoic acid had a higher trend in the plasma of responders, but not in the non-responders (Figure B). Notably, 2-Methylbutyrate markedly increased in the plasma of responders after FMT, when compared to non-responder after FMT(Figure C).

Conclusion

The present study indicates that FMT improved SR-cGVHD patients by increasing the circulating SCFAs, particularly 2-Methylbutyrate levels. 2-Methylbutyrate might play a role in FMT therapy for SR-cGVHD.

Disclosures

No relevant conflicts of interest to declare.
A 5-Stage System for ASCT Multiple Myeloma
Authors: Guo Wancheng , Mery David E. , Siegel Eric , Sun Fumou , Cheng Yan , Wanchai Visanu , Ashby Cody , Bailey Clyde , Alapat Daisy V. , Peng Hongling , Al Hadidi Samer , Thanendrarajan Sharmilan , Schinke Carolina , Zangari Maurizio , van Rhee Frits , Tricot Guido , Shaughnessy, Jr John D , Zhan Fenghuang
Published: December 2023

652. Multiple Myeloma: Clinical and Epidemiological

INTRODUCTION:

In the last three decades, significant advancements in multiple myeloma (MM) treatment, including immunomodulators, targeted therapies, chemotherapy combinations, autologous stem cell transplantation (ASCT), and CAR-T therapy, have emerged. ASCT offers hope for MM patients by using high-dose chemotherapy with stem cell support. However, it carries risks of severe toxicity. Despite evaluating factors like age, performance status, and co-morbidities for ASCT eligibility, outcomes for MM patients still vary greatly. Various models, such as the ISS-series systems, have been developed to assess risk factors for progression-free and overall survival We conducted a study on 5,259 ASCT patients since 1989, identifying 7 easy variables (ISS stage, diagnosis-transplant interval, ferritin, transferrin, LDH, age, and gender) and creating a 5-stage system. This system helps evaluate the risk of MM patients before ASCT.

METHODS:

In this retrospective study, data from 5,259 MM patients receiving ASCT (1989-2022) were collected (median follow-up: 57 months). We assessed 30 clinical variables pre-ASCT. Multiple imputation was used to deal with the missing values. Patients were split into a 70% training set and a 30% validation set. Univariate/multivariate Cox regression analysis identified 7 clinical and demographic signatures. Signatures were scored based on hazard ratios normalized to ISS III vs. ISS I&II. K-adaptive partitioning generated a 5-stage system, ATM5S, evenly distributed and validated in the training set. Harrel's c-index was used to compare ATM5S with the current myeloma systems.

RESULTS:

3683 patients (70%) in the test cohort had a median age of 59.6, median PFS 38.8 month and median OS 56.1 month. IgG was the most common isotype (55%). Univariate Cox analysis showed that 27 variables were significant predictors for both PFS and OS. Multivariate Cox analysis showed that time from diagnosis to transplant, ferritin, transferrin, LDH, ISS stage, lymphocytes, platelets, calcium, gender and age were independent prognostic factors for both OS and PFS. We selected the most easy, understandable and well-distributed (with high-risk group>20%) 7 variables: ISS, time from diagnosis to transplant, ferritin, transferrin, LDH, age and gender and developed a score system, which resulted into a 5-stage system (ATM5S) by k-adaptive partitioning. This staging system also demonstrated a significant discriminatory effect in the validation set (30%, 1576 patients).

CONCLUSIONS:

The Arkansas Transplant-Myeloma 5-Stage System (ATM5S) showed a promising performance in both training and validation cohorts.
Efficacy and Safty of Stem Cell Mobilization with Etoposide +Cytarabine Plus G-CSF in Patients with Lymphoma at High-Risk of Mobilizing Failure
Authors: Zhu Zhijuan , Li Xiaofan , Li Nainong
Published: December 2023

Objective：Sufficient peripheral blood stem cell (PBSC) mobilization is important for performing successful autologous stem cell transplantation (ASCT) in patients with lymphoma. However, the optimal mobilization strategy remains a matter of debate in lymphoma.The aim of the study was to explore efficacy and safety of PBSC mobilization using etoposide combined with Cytarabine (EA) plus G-CSF in patients with lymphoma at high-risk of mobilizing failure.

Methods：This retrospective study explored efficacy and safety of PBSC mobilization using EA (etoposide 50~100 mg/m2 , qd d1~3; AraC 0.5 g/m2 , q12h d1~3) plus G-CSF (5 µg/kg/day, from d5 until the day of apheresis) in 81 patients with lymphoma at high-risk of mobilizing failure. As previously reported, patients were defined at high-risk of mobilizing failure if (i) previous collection attempts failed (no special instructions); (ii) previous extensive radiotherapy or a complete course of treatment had affected stem cell activity; or (iii) any of these conditions: advanced disease (2 lines of chemotherapy), refractory disease, extensive bone marrow involvement or cellularity <30% at the time of mobilization or age 65 years.

Results：The mean total and first apheresis trial CD34+ cells collection was 20.37(range 1.08~138.96) and 18.56(range 0.1~138.96)×10^6 CD34+ cells/kg, respectively. Overall, 79(97.5%) patents harvested adequate mobilization (≥2×10^6 CD34+ cells/kg), while 65(80.2%) patients achieved optimal mobilization(≥5×10^6 CD34+ cells/kg). A single apheresis was sufficient to reached the target yield of adequate apheresis in 67(82.7%) patients on median 15th day (range 11~19). We observed acceptable hematological toxicity and exposure of antibiotic usage in 57 patients with a median of 4 days. No severe infections or mobilization-related mortality were observed.

Conclusion：Our resluts suggest that EA plus G-CSF is an effective and safe PBSC mobilization strategy for patients with lymphoma, including those predicted as poor mobilizers. The outcome should be evaluated in a randomized study.
The Potent and Selective Antitumor Activity of CO-1 and Fully Humanized CO-1bi in Treatment of B Cell Non-Hodgkin's Lymphoma
Authors: Matar Sittana , Skah Seham , E Diomande Liza , Kiil Blomhoff Heidi , Hestdal Kjetil , D Pettersen Rolf , Richartz Nina
Published: December 2023

Recent advancements have identified CD47 blockade as a promising approach for the treatment of B cell Non-Hodgkin's Lymphoma (B-NHL). CD47 blockade inhibits the CD47-SIRPα axis, which inhibits a “don't eat me” signal that facilitates the phagocytosis of tumor cells by macrophages [1,2]. While the effect of anti-CD47 monoclonal antibodies (mAbs) as monotherapy has been limited in B-NHL, combining CD47 mAbs with conventional treatment such as rituximab has demonstrated more encouraging outcomes. This combinatory approach may be attributed to the need for additional cytotoxic mechanisms to achieve clinically meaningful responses with CD47-mediated therapy in B-NHL [3]. Additionally, CD47 blockage has raised concerns about off-target effects and red blood cell depletion [4].

To address these challenges and improve treatment possibilities we developed a fully humanized CO-1bi based on the chimeric CO-1. The bifunctional CO-1 is an agonistic IgG4 anti-CD47 mAb designed to induce direct and rapid programmed cancer cell death (PCCD) and stimulate phagocytosis through blockage of CD47-SIRPα binding. CO-1bi is a humanized bivalent scFv-Fc fusion of CO-1 with superior safety (no red blood cell hemagglutination) while maintaining the functionality of CO-1. In this study, we evaluated the antitumor activity of CO-1 and CO-1bi on different B-NHL cell lines in vitro as well as in xenografts of B-NHL established in NOD- scid IL2Rγ null (NSG) mice. Both constructs demonstrated potent and fast cell death induction in lymphoma cell lines while sparing normal B cells. The robust antitumor activity demonstrated by CO-1 and CO-1bi as single agents in xenograft models of Burkitt's lymphoma underscores the significance of their additional agonistic PCCD capabilities compared to other anti-CD47 agents.

The emergence of CO-1bi offers a unique strategy with dual functionality for the treatment of B-NHL and other malignancies without red blood cell depletion characterized by current anti-CD47 mAb in clinical trials. This innovative approach provides an improved and promising avenue for cancer treatment.
N-3 Polyunsaturated Fatty Acid (N-3 PUFA) Derived Lipid Mediators Increase Hematopoiesis during Zebrafish Embryogenesis
Authors: Nguyen Kim Uyen Cong , Wynn Carrie , Gibert Yann
Published: December 2023

Polyunsaturated fatty acids (PUFAs), which include n-3 PUFAs and n-6 PUFAs, are essential fatty acids that we can only get from diet. The richest source of PUFAs is fish oil. N-3 PUFAs have been used in the prevention and treatment of coronary artery disease, diabetes, hypertension, arthritis, cancer, and other inflammatory and autoimmune disorders in humans. Lipid mediators derived from n-3 PUFAs are implicated in mediating the resolution of inflammation. However, their effect on hematopoietic stem and progenitor cell (HSPC) proliferation and differentiation and on hematopoiesis has not been studied. Therefore, in this project, we investigated the pro-hematopoietic effects of n-3 PUFA-derived lipid mediators. We exposed wild-type zebrafish embryos to different n-3 PUFA-derived lipid mediators. After fixation, we performed whole mount in situ hybridization (WISH) using antisense RNA probes such as c-myb (hematopoietic stem cell marker), gata1 (erythroid progenitor cell marker), hbbe1 (erythrocyte marker), l-plastin (macrophage and neutrophil cell marker ), mpx (neutrophil cell marker), lyz (neutrophil cell marker), and rag1 (immature lymphocyte marker); reverse transcription-quantitative polymerase chain reaction (RT-qPCR); and fluorescence-activated cell sorting (FACS) to understand the effect of lipid mediator exposure on the proliferation of HSPCs, erythroid progenitor cells, erythrocytes, granulocytic cells, neutrophils, macrophages, and T lymphocytes in different development stages during vertebrate hematopoiesis. In addition, we also used o-dianisidine staining to study red blood cell (RBC) formation and transgenic zebrafish to observe different blood lineages including HSPCs, neutrophils, macrophages, erythroid progenitors, and erythrocytes with fluorescent microscopy. We identified two novel lipid mediators which promote HSPC proliferation, enhance erythroid progenitor cell and erythrocyte production, and increase neutrophil cell number. These two molecules could be applied as novel therapeutics for blood disorders and blood cancers such as anemia and leukemia in humans. These two compounds can be intensely investigated to become candidate supplements to enhance HSPC amplification before HSPC transplantation for leukemia patients.
Double/Triple Hit Lymphoma Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database
Authors: Haddad Philip A , Gupta Supriya , Gupta Ankita , Graham Christopher
Published: December 2023

Background

B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements is classified as double/triple-hit lymphoma (DTHL). They usually, but not always, tend to be high-grade aggressive B-cell lymphoma with a worse prognosis. Despite this classification, DTHL remains a heterogeneous group with varied molecular profiles, biological behaviors, and prognoses. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies influencing survival in this rare disease.

Methods

To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 161 cases that fit the diagnostic criteria for DTHL. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS) and disease-free survival (DFS).

Results

We compiled a dataset of 161 patients with confirmed DTHL. The median age was 62, with an F:M of 1.08. The median duration of symptoms before diagnosis was 2 months. DTHL involved the lymph nodes (41%), bone marrow (31%), bone (14%), CNS (5%), skin (4%), liver (3%), and spleen (2%). Constitutional symptoms were reported in 20% of cases. The cohort consisted of primary (50%), secondary/transformed (16%), and follicular DTHL (34%). The median OS and DFS of the cohort were 69 and 27 months, respectively. Bone marrow and extra-lymphatic organ involvement were associated with worse DFS and non-significant numerically worse OS. LDH>500 (p=0.006), PAX5-negative (p=0.01), CD79a-negative (p=0.02), and Ki67>80% (p<0.0001) were associated with worse OS. Similarly, CD5+, CD10+, and MUM1+ had worse OS but did not reach statistical significance. Follicular DTHL was associated with the best median OS and DFS, followed by primary, then secondary/transformed in decreasing order. Advanced stage and high IPI were also associated with worse non-significant numerical OS. Age and sex did not impact OS. Compared to no treatment, chemotherapy and stem cell transplant had incrementally superior median OS (3 vs. 55 vs. NR months, p=0.008). Frontline intensive chemotherapy yielded similar DFS and OS to CHOP-like regimens. Patients who attained CR as their best response also had a superior median OS (p<0.0001).

Conclusion

This study presents clinicopathologic data from a cohort of patients with primary, secondary, and follicular DTHL. It identifies the type of DTHL, IHC profile, LDH levels, type of therapy, and quality of response to treatment as critical determinants of OS. Depending on the type (de novo, secondary, or follicular), DTHL seems to behave like 3 different disease entities.