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Christos Varelas,1 Athina Tampaki,2 Ioanna Sakellari,1 &Agr;chilles Anagnostopoulos,1 Eleni Gavriilaki,1,* Efthymia Vlachaki2,* 1Hematology Department – BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece; 2Adults Thalassemia Unit, 2nd Department of Internal Medicine, Hippokration Hospital, Thessaloniki, Greece*These authors contributed equally to this workCorrespondence: Eleni GavriilakiHematology Department - BMT Unit, G. Papanicolaou Hospital, Exochi, Thessaloniki, 57010, GreeceEmail elenicelli@yahoo.grAbstract: Sickle cell disease (SCD) is a widely spread inherited hemoglobinopathy that includes a group of congenital hemolytic anemias, all characterized by the predominance of sickle hemoglobin (HbS). Its features are anemia, predisposal to bacterial infections and complications such as vaso-occlusive crisis (VOC) or delayed hemolytic transfusion reaction (DHTR), which lead to increased rate of morbidity and mortality even in the era of hydroxyurea. The interaction between sickle cells, neutrophils, platelets or endothelial cells in small vessels results in hemolysis and has been considered the disease’s main pathophysiological mechanism. Complement activation has been reported in small cohorts of SCD patients, but the governing mechanism has not been fully elucidated. This will be important to predict the patient group that would benefit from complement inhibition. Until now, eculizumab-mediated complement inhibition has shown beneficial effects in DHTR, with limited reports in patients with VOC. In the meantime, several innovative agents are under clinical development Our state-of-the-art review summarizes current data on 1) complement activation in SCD both in steady state and crisis, 2) underlying mechanisms of complement over-activation for the clinician in the context of SCD, 3) actions of hydroxyurea and new therapeutic approaches including indirect involvement in complement activation, and 4) novel paradigms in complement inhibition.Keywords: sickle cell disease, complement system, eculizumab, complement inhibition

Simple Summary: Our real-world experience confirmed that commercial CART therapy can be administered with minimal toxicity. The early referral of patients with low tumor burdens is important as CAR T indications continue to expand. Furthermore, close monitoring and the early recognition of side effects are beneficial to preventing major toxicities and may potentially expand the use of CAR T therapy. Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity. [ABSTRACT FROM AUTHOR]

To review current literature on the role of endothelial dysfunction in coronavirus disease-2019 (COVID-19) infection in terms of pathophysiology, laboratory features and markers, clinical phenotype in adults and children, as well as long COVID-19.

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Bacterial infections frequently occur in haematological patients, especially during prolonged neutropenia after intensive chemotherapy, often leading to bloodstream infections and pneumonia., Objective: Routine antimicrobial prophylaxis (AMP) for high-risk haematology patients is still debated while prevalence of multi-drug resistant (MDR) Gram-negative bacteria (GNB) is rising globally. We aimed to assess the current practice of AMP in this population., Design: Cross-sectional observational survey study., Methods: Haematologists and infectious diseases physicians Europewide were invited to an online survey including questions on routine screening for GNB, incidence of MDR-GNB colonization, antimicrobial prophylaxis practices, rates of bloodstream infections (BSI), ICU admission and mortality differentiated by infections due to GNB versus MDR-GNB., Results: 120 haematology centres from 28 countries participated. Screening for MDR-GNB is performed in 86.7% of centres, mostly via rectal swabs (58.3%). In 39.2% of routine AMP is used, mostly with fluoroquinolones. Estimates of GNB-BSI yielded higher rates in patients not receiving anti-GNB prophylaxis than in those who do for E. coli (10% vs 7%) Klebsiella spp. (10% vs 5%), and Pseudomonas spp. (5% vs 4%). Rates for MDR-GNB infection were estimated lower in centres that administer AMP for MDR E. coli (5% vs 3%) Klebsiella spp. (5% vs 3%), and Pseudomonas spp. (2% vs 1%). In an exploratory analysis, Southern and Eastern European countries expected higher rates of MDR-GNB infections with lower ICU admission and mortality rates which may be subject to estimation bias., Conclusion: Screening for MDR-GNB is frequently performed. AMP against GNB infections is still often implemented. Estimated BSI rates are rather low, while the rate of MDR-GNB infections rises. Tailored prophylaxis including antimicrobial stewardship becomes more important., (© The Author(s), 2024.)

Methotrexate (MTX) is an anti-folate chemotherapeutic agent that is considered to be a gold standard in Acute Lymphoblastic Leukemia (ALL) therapy. Nevertheless, toxicities induced mainly due to high doses of MTX are still a challenge for clinical practice. MTX pharmacogenetics implicate various genes as predictors of MTX toxicity, especially those that participate in MTX intake like solute carrier family 19 member 1 ( SLC19A1 ). The aim of the present study was to evaluate the association between SLC19A1 polymorphisms and its regulatory miRNAs with MTX toxicity in children with ALL. A total of 86 children with ALL were included in this study and were all genotyped for rs2838958, rs1051266 and rs1131596 SLC19A1 polymorphisms as well as the rs56292801 polymorphism of miR-5189. Patients were followed up (48, 72 and 96 h) after treatment with MTX in order to evaluate the presence of MTX-associated adverse events. Our results indicate that there is a statistically significant correlation between the rs1131596 SLC19A1 polymorphism and the development of MTX-induced hepatotoxicity ( p = 0.03), but there is no significant association between any of the studied polymorphisms and mucositis or other side effects, such as nausea, emesis, diarrhea, neutropenia, skin rash and infections. In addition, when genotype TT of rs1131596 and genotype AA of rs56292801 are both present in a patient then there is a higher risk of developing severe hepatotoxicity ( p = 0.0104).

Endothelial injury indices, such as Endothelial Activation and Stress Index (EASIX), modified EASIX (m-EASIX), and simplified EASIX (s-EASIX) scores, have been previously associated with chimeric antigen receptor-T (CAR-T) cell immunotherapy complications. Soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor-15 (GDF-15), and soluble C5b-9 (sC5b-9) have been described as markers of endothelial injury post-hematopoietic stem cell transplantation. In the current study, we examined whether suPAR, GDF-15, and sC5b-9 levels were associated with endothelial injury indices in adult CAR-T cell recipients. The levels of these markers were measured in patients before CAR-T cell infusion and in healthy individuals with immunoenzymatic methods. We studied 45 CAR-T cell recipients and 20 healthy individuals as the control group. SuPAR, GDF-15, and sC5b-9 levels were significantly higher in the patients' group compared to the healthy control group ( p < 0.001, in all comparisons). SuPAR levels at baseline were associated with the m-EASIX scores calculated at the same time point ( p = 0.020), while suPAR and GDF-15 concentrations were correlated with EASIX scores at day 14 post-infusion ( p < 0.001 in both comparisons). Moreover, sC5b-9 levels were correlated with the s-EASIX scores at infusion ( p = 0.008) and the EASIX scores at day 14 ( p = 0.005). In our study, sC5b9, suPAR, and GDF-15 levels were found to reflect endothelial injury in CAR-T cell recipients.

Introduction: Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit., Methods: In this study, we treated tumour-bearing mice with PD-L1 blockage antibody (aPD-L1) immunotherapy, to investigate its effects on cancer-induced emergency myelopoiesis, focusing on bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). We examined the impact of aPD-L1 treatment on HSPC quiescence, proliferation, transcriptomic profile, and functionality., Results: Herein, we reveal that aPD-L1 in tumour-bearing mice targets the HSPCs in the BM, mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, observed in both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice, shifting towards an inflammatory state. Furthermore, HSPCs from aPDL1-treated mice demonstrated resistance to cancer-induced emergency myelopoiesis, evidenced by a lower generation of MDSCs compared to control-treated mice., Discussion: Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of cancer-induced emergency myelopoiesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Boumpas, Papaioannou, Bousounis, Grigoriou, Bergo, Papafragkos, Tasis, Iskas, Boon, Makridakis, Vlachou, Gavriilaki, Hatzioannou, Mitroulis, Trompouki and Verginis.)

Background: The study aimed to determine the most crucial parameters associated with CVD and employ a novel data ensemble refinement procedure to uncover the optimal pattern of these parameters that can result in a high prediction accuracy., Methods and Results: Data were collected from 369 patients in total, 281 patients with CVD or at risk of developing it, compared to 88 otherwise healthy individuals. Within the group of 281 CVD or at-risk patients, 53 were diagnosed with coronary artery disease (CAD), 16 with end-stage renal disease, 47 newly diagnosed with diabetes mellitus 2 and 92 with chronic inflammatory disorders (21 rheumatoid arthritis, 41 psoriasis, 30 angiitis). The data were analyzed using an artificial intelligence-based algorithm with the primary objective of identifying the optimal pattern of parameters that define CVD. The study highlights the effectiveness of a six-parameter combination in discerning the likelihood of cardiovascular disease using DERGA and Extra Trees algorithms. These parameters, ranked in order of importance, include Platelet-derived Microvesicles (PMV), hypertension, age, smoking, dyslipidemia, and Body Mass Index (BMI). Endothelial and erythrocyte MVs, along with diabetes were the least important predictors. In addition, the highest prediction accuracy achieved is 98.64%. Notably, using PMVs alone yields a 91.32% accuracy, while the optimal model employing all ten parameters, yields a prediction accuracy of 0.9783 (97.83%)., Conclusions: Our research showcases the efficacy of DERGA, an innovative data ensemble refinement greedy algorithm. DERGA accelerates the assessment of an individual's risk of developing CVD, allowing for early diagnosis, significantly reduces the number of required lab tests and optimizes resource utilization. Additionally, it assists in identifying the optimal parameters critical for assessing CVD susceptibility, thereby enhancing our understanding of the underlying mechanisms., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hematopoietic stem cell transplantation (HCT) represents a curative treatment option for certain malignant and nonmalignant hematological diseases. Conditioning regimens before HCT, the development of graft-versus-host disease (GVHD) in the allogeneic setting, and delayed immune reconstitution contribute to early and late complications by inducing tissue damage or humoral alterations. Hemostasis and/or the complement system are biological regulatory defense systems involving humoral and cellular reactions and are variably involved in these complications after allogeneic HCT. The hemostasis and complement systems have multiple interactions, which have been described both under physiological and pathological conditions. They share common tissue targets, such as the endothelium, which suggests interactions in the pathogenesis of several serious complications in the early or late phase after HCT. Complications in which both systems interfere with each other and thus contribute to disease pathogenesis include transplant-associated thrombotic microangiopathy (HSCT-TMA), sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), and GVHD. Here, we review the current knowledge on changes in hemostasis and complement after allogeneic HCT and how these changes may define clinical impact., (© 2024. The Author(s).)

Background/Objectives: Despite novel biological agents, steroid-dependent or -refractory graft-versus-host disease (GvHD) remains a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT). Extracorporeal photopheresis (ECP) is an alternative, non-immunosuppressive treatment for patients with acute (aGvHD) or chronic (cGvHD) GvHD. The aim of this study was to investigate the safety and efficacy of ECP in the treatment of acute and chronic GvHD; Methods: We prospectively studied 112 patients with cGvHD who received one or more previous lines of treatment and 28 patients with steroid-dependent or refractory grade II-IV aGvHD post-alloHSCT. Results: In terms of severe aGvHD, most of the patients (19/28) responded to ECP treatment, while the five-year overall survival (OS) was 34%. After adjustment for several confounder factors, the reduction in immunosuppression ( p = 0.026) and number of ECP sessions ( p < 0.001) were associated with improved OS. Regarding chronic GvHD, only 19 patients failed to respond to ECP treatment; though significantly lower rates of response were presented in patients with visceral involvement ( p = 0.037) and earlier post-transplant GVHD diagnosis ( p = 0.001). Over a follow-up period of 45.2 [interquartile range (IQR): 5.6-345.1] months, the 5-year cumulative incidence (CI) of cGvHD-related mortality was 21.2% and was significantly reduced in patients with ECP response ( p < 0.001), while the 5-year OS was 65.3%. Conclusions: Our results confirm the safety and efficacy of ECP in patients with GvHD and provide sufficient data for further investigation and the best combination drugs needed such that GvHD will not be the major barrier of allo-HCT in the near future.