Prophylactic Regimens Research Articles

Comparison of different regimens of short-term antibiotic prophylaxis in transrectal prostate biopsy

Prostate cancer is the most common malignant solid tumour in men aged >70 years and is the second most common cause of death from oncological circumstances. To evaluate the effect of different short-term prophylactic antibiotic regimens in transrectal prostate biopsy (PB) on the incidence of infectious complications. Patients who underwent transrectal ultrasound-guided PB between January 2021 and December 2022 were included in the prospective randomized study. According to the regimen of prophylaxis, patients were randomized into three groups: (1) fosfomycin trometamol 3g, 3h before the procedure+ ciprofloxacin 500mg, 2h before the procedure; (2) fosfomycin trometamol 3g, 3h before and 24h after the procedure; (3) ciprofloxacin 500mg 12, 2h before the procedure, and 12h after the procedure. A rectal swab was performed 1-2 weeks before PB to evaluate the culture findings. Complications were evaluated during follow-up visits within one month after PB. In the monitored period, 605PBs were performed, and 544 patients met the inclusion criteria (184, 161, and 199 in groups 1, 2, and 3). Infectious complications occurred in 10 cases (1.83%), namely 3, 4, and 3 according to patient groups. There was no statistically significant difference between the individual groups. None of the patients required hospitalization and all were free of symptoms of sepsis. Short-term antibiotic prophylaxis in PB using fosfomycin trometamol, ciprofloxacin, or their combination appears to be effective. Fosfomycin trometamol is a suitable alternative to fluoroquinolone antibiotics.

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies.

BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTSGroup 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONSThis study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.

Azithromycin targets the CD27 pathway to modulate CD27hi T-lymphocyte expansion and type-1 effector phenotype.

Macrolide antibiotic azithromycin is widely used in clinical practice to treat respiratory tract infections and inflammatory diseases. However, its mechanism of action is not fully understood. Given the involvement of the CD27 pathway in the pathophysiology of various T-lymphocyte-mediated inflammatory, autoimmune, and lymphoproliferative diseases, we examined the impact of AZM on CD27 regulation and potential consequences on CD4+ and CD8+ T-cell phenotypes. Using cellular immunology approaches on healthy donors' peripheral blood mononuclear cells, we demonstrate AZM-mediated downregulation of surface CD27 expression as well as its extracellular release as soluble CD27. Notably, AZM-exposed CD27high (hi) cells were defective in their ability to expand compared to CD27intermediate (Int) and CD27low (lo) subsets. The defective CD27hi subset expansion was found to be associated with impaired cell proliferation and cell division. At the molecular level, the CD27hi subset exhibited lower mTOR activity than other subsets. Functionally, AZM treatment resulted in marked depletion of helper CD4+ (Th1) and cytotoxic CD8+ T-lymphocyte (Tc1)-associated CXCR3+CD27hi effector cells and inhibition of inflammatory cytokine IFN-γ production. These findings provide mechanistic insights on immunomodulatory features of AZM on T-lymphocyte by altering the CD27 pathway. From a clinical perspective, this study also sheds light on potential clinical benefits observed in patients on prophylactic AZM regimens against various respiratory diseases and opens avenues for future adjunct therapy against Th1- and Tc1-dominated inflammatory and autoimmune diseases.

Potential antitumor effects of short-chain fatty acids in breast cancer models.

The effects of short-chain fatty acids (SCFAs) have been explored against cancer due to the crosstalk between gut microbiota alterations and the immune system as a crucial role in cancer development. We evaluated the SCFAs effects in both in vitro and in vivo breast cancer models. In vitro, the SCFAs displayed contrasting effects on viability index, according to the evaluation of breast cancer cells with different phenotypes, human MCF-7, SK-BR-3, MDA-MD-231, or the mouse 4T1 lineage. Acetate displayed minimal effects at concentrations up to 100 mM. Alternatively, propionate increases or reduces cell viability depending on the concentration. Butyrate and valerate showed consistent time- and concentration-dependent effects on the viability of human or mouse breast cancer cells. The selective FFA2 4-CMTB or FFA3 AR420626 receptor agonists failed to overtake the SCFA actions, except by modest inhibitory effects on MDA-MB-231 and 4T1 cell viability. The FFA2 CATPB or FFA3 and β-hydroxybutyrate receptor antagonists lacked significant activity on human cell lines, although CATPB reduced 4T1 cell viability. Butyrate significantly affected cell morphology, clonogenicity, and migration, according to the evaluation of MDA-MB-231 and 4T1 cells. A preliminary examination of in vivo oral effects of butyrate, propionate, or valerate, dosed in prophylactic or therapeutic regimens, on several parameters evaluated in an orthotopic breast cancer model showed a reduction of lung metastasis in post-tumor induction butyrate-treated mice. Overall, the present results indicate that in vitro effects of SCFAs did not rely on FFA2 or FFA3 receptor activation, and they were not mirrored in vivo, at least at the tested conditions. Overall, the present results indicate potential in vitro inhibitory effects of SCFAs in breast cancer, independent of FFA2 or FFA3 receptor activation, and, in the metastatic breast cancer model, the butyrate-dosed therapeutic regimen reduced the number of lung metastases.

Living, Caring, Learning – Collaborating across borders to support a haemophilia patient with a rare complication

Abstract Cyrus, a haemophilia nurse in Kenya, reflects on his experience of treating a patient with a rare complication of haemophilia in a setting with limited access to treatment. The patient developed a debilitating abdominal pseudotumor following an inadequately treated traumatic bleed. After consulting with experts in other countries, surgery was deemed too great a risk. Initiating FVIII prophylaxis with the aim of shrinking the pseudotumour was identified as the most appropriate approach to treatment, however supply issues made it difficult to maintain a prophylactic regimen. When the pseudotumour continued to grow, posing a risk to adjacent organs, an international partnership enabled the initiation of emicizumab prophylaxis through a clinical trial. It was hoped that emicizumab would prevent further bleeding into the pseudotumour and allow it to shrink over time. The patient continued to experience breakthrough bleeding and was withdrawn from the trial after 2.5 years. By this time the supply of FVIII to Kenya through the through the WFH Humanitarian Aid Program had increased and the patient was able to resume FVIII prophylaxis. The pseudotumour is now stable and he continues to be cared for by the same nursing team. Reflecting on this case, Cyrus highlights the value of sharing expertise across borders and working in partnership to try to ensure the best treatment outcome for a patient with a rare complication in a resource-constrained setting. He also reflects on being compassionate in his practice and the importance of a holistic approach to patient support.

Use of Aprepitant (80 mg) for Prevention of Postoperative Nausea and Vomiting in Patients Undergoing Laparoscopic Sleeve Gastrectomy

ABSTRACT Introduction Postoperative nausea and vomiting (PONV) is a complication after surgery, and more significantly after bariatric surgery (up to 79%) leading to increased treatment costs associated with prolonged hospital stays. In a community hospital setting, a standard prophylactic regimen was compared with the addition of aprepitant. Methods A retrospective chart review of PONV among patients who underwent laparoscopic sleeve gastrectomy. Primary outcomes: efficacy of aprepitant 80 mg plus standard prophylaxis on PONV by measuring the number of antiemetics administered postoperatively to a standard prophylactic regimen. Results A total of 354 patients showed that the aprepitant group required significantly fewer doses in four time periods: within 1 hour of post-anesthesia care unit (PACU) admission [74 vs 97 (p = 0.049)], 12 hours [192 vs 234 (p = 0.049)], 24 hours [293 vs 426 (p < 0.001)], and total doses during admission 365 vs 581 (p < 0.001). Average length of stay (LOS) was 1.19 days for the aprepitant group and 1.33 days for the control group (p < 0.001). Conclusion Aprepitant significantly reduced antiemetic use postoperatively and should be considered in addition to a standard PONV prophylaxis regimen to prevent PONV in patients undergoing laparoscopic sleeve gastrectomy and to potentially reduce LOS.

Fc-fused IL-7 provides broad antiviral effects against respiratory virus infections through IL-17A-producing pulmonary innate-like T cells

Repeated pandemics caused by the influenza virus and severe acute respiratory syndrome coronavirus (SARS-CoV) have resulted in serious problems in global public health, emphasizing the need for broad-spectrum antiviral therapeutics against respiratory virus infections. Here, we show the protective effects of long-acting recombinant human interleukin-7 fused with hybrid Fc (rhIL-7-hyFc) against major respiratory viruses, including influenza virus, SARS-CoV-2, and respiratory syncytial virus. Administration of rhIL-7-hyFc in a therapeutic or prophylactic regimen induces substantial antiviral effects. During an influenza A virus (IAV) infection, rhIL-7-hyFc treatment increases pulmonary Tcells composed of blood-derived interferon γ (IFNγ)+ conventional Tcells and locally expanded IL-17A+ innate-like Tcells. Single-cell RNA transcriptomics reveals that rhIL-7-hyFc upregulates antiviral genes in pulmonary Tcells and induces clonal expansion of type 17 innate-like Tcells. rhIL-7-hyFc-mediated disease prevention is dependent on IL-17A in both IAV- and SARS-CoV-2-infected mice. Collectively, we suggest that rhIL-7-hyFc can be used as a broadly active therapeutic for future respiratory virus pandemic.

Single-Dose enoxaparin for portomesenteric venous thrombosis prophylaxis after sleeve gastrectomy.

Portomesenteric venous thrombosis (PMVT) may complicate sleeve gastrectomy. We believe that single dose of enoxaparin postoperatively can reduce the risk of PMVT. The objective was to study the outcomes of enoxaparin single dose compared to other perioperative prophylactic doses in preventing PMVT. Participants included 590 patients who underwent laparoscopic sleeve gastrectomy (LSG). These retrospective cohort data were collected from patient medical charts after bariatric surgery. Patients were followed up in the close postoperative period and at 1, 3, 6, 12, and 18 months. Descriptive statistical analysis was carried out. The objective was to estimate the incidence of PMVT with postoperative single 40 mg subcutaneous enoxaparin prophylactic regimen. From January 2017 to December 2021, 590 patients with obesity underwent LSG. Five patients developed PMVT with an estimate incidence of 0.85%. Three patients had unexplained tachycardia and three patients had postoperative bleeding. Single-dose enoxaparin 40 mg is an effective thrombosis prophylaxis without increasing risk of bleeding.

2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following high-emetic-risk antineoplastic agents

PurposeThis systematic review updates the MASCC/ESMO recommendations for high-emetic-risk chemotherapy (HEC) published in 2016–2017. HEC still includes cisplatin, carmustine, dacarbazine, mechlorethamine, streptozocin, and cyclophosphamide in doses of > 1500 mg/m2 and the combination of cyclophosphamide and an anthracycline (AC) in women with breast cancer.MethodsA systematic review report following the PRISMA guidelines of the literature from January 1, 2015, until February 1, 2023, was performed. PubMed (Ovid), Scopus (Google), and the Cochrane Database of Systematic Reviews were searched. The literature search was limited to randomized controlled trials, systematic reviews, and meta-analyses.ResultsForty-six new references were determined to be relevant. The main topics identified were (1) steroid-sparing regimens, (2) olanzapine-containing regimens, and (3) other issues such as comparisons of antiemetics of the same drug class, intravenous NK1 receptor antagonists, and potentially new antiemetics. Five updated recommendations are presented.ConclusionThere is no need to prescribe steroids (dexamethasone) beyond day 1 after AC HEC, whereas a 4-day regimen is recommended in non-AC HEC. Olanzapine is now recommended as a fixed part of a four-drug prophylactic antiemetic regimen in both non-AC and AC HEC. No major differences between 5-HT3 receptor antagonists or between NK1 receptor antagonists were identified. No new antiemetic agents qualified for inclusion in the updated recommendations.

A clinical evaluation of patients with known mutations (plasminogen and factor XII) with a focus on prophylactic treatment

Background Hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) is a rare genetic disease. The symptoms can resemble other forms of hereditary angioedema (HAE), but the specific laboratory values are inconspicuous. The knowledge about treatment strategies in HAE-nC1-INH remains insufficient; most of the drugs are only licensed and approved for other types of HAE. Methods An analysis of all patients with HAE-nC1-INH was carried out in a certified angioedema treatment center in southern Germany. Only patients with a confirmed HAE-nC1-INH mutation were included. The impact of disease was monitored with validated questionnaires. Results Eighteen patients were included: two families with a factor XII mutation and seven families with a plasminogen mutation. All individuals received icatibant for on-demand therapy—efficient treatment response was reported. Three patients were severely affected, and prophylaxis was initiated with lanadelumab. According to the questionnaires, the clinical course and symptoms improved significantly under this prophylactic regime. Conclusion This is one of the first descriptions of the clinical outcomes as a response to prophylactic treatment with lanadelumab in HAE-nC1-INH patients with a known mutation. The therapeutic management of HAE-1 and HAE-2 should also be the basis of HAE-nC1-INH, including prophylaxis.

The current challenges faced by people with hemophilia B.

Hemophilia B (HB) is a rare, hereditary disease caused by a defect in the gene encoding factor IX (FIX) and leads to varying degrees of coagulation deficiency. The prevailing treatment for people with HB (PWHB) is FIX replacement product. The advent of recombinant coagulation products ushered in a new era of safety, efficacy, and improved availability compared with plasma-derived products. For people with severe HB, lifelong prophylaxis with a FIX replacement product is standard of care. Development of extended half-life FIX replacement products has allowed for advancements in the care of these PWHB. Nonetheless, lifelong need for periodic dosing and complex surveillance protocols pose substantive challenges in terms of access, adherence, and healthcare resource utilization. Further, some PWHB on prophylactic regimens continue to experience breakthrough bleeds and joint damage, and subpopulations of PWHB, including women, those with mild-to-moderate HB, and those with inhibitors to FIX, experience additional unique difficulties. This review summarizes the current challenges faced by PWHB, including the unique subpopulations; identifying the need for improved awareness, personalized care strategies, and new therapeutic options for severe HB, which may provide future solutions for some of the remaining unmet needs of PWHB.

From early risk to 1-year mortality: a comprehensive assessment of postoperative venous thromboembolism in upper gastrointestinal cancer patients - a nationwide cohort study.

Venous thromboembolism (VTE) is a well-recognized complication following gastrointestinal cancer surgery, particularly early postoperatively. The incidence and risk factors of VTE within 1-year after esophageal (including esophago-gastric junction) (ECS) and gastric (GCS) cancer surgeries, and especially its impact on 1-year global mortality, are yet under-explored. This nationwide observational population-based cohort study used data extracted from all patients undergoing ECS and GCS in France between 1 January 2015 and 31 December 2017. Multivariate logistic regression was used to identify risk factors for 90 postoperative days (POD) VTE (OR 95% CI). Cox proportional hazards models investigated the impact of 1-year postoperative VTE on 1-year global mortality [HR (95% CI)]. During the study period, 8005 patients underwent ECS ( N =3429) or GCS ( N =4576) (31.8% female; 66.7±12.1 years old). Majority ( N =4951) of patients had preoperative treatment (chemotherapy or radiochemotherapy). Ninety POD incidence of VTE were 4.7% (ECS=6.2%) (GCS=3.6%) (44.7% during first hospitalization, 19.0% needing readmission, and 36.3% ambulatory management). Main risk factors were three and two field esophagectomy [3.6 (2.20-5.83) and 2.2 (1.68-3.0)], obesity [1.9 (1.40-2.58)] and history of VTE [5.1 (2.72-9.45)]. Late-onset VTE rates (occurring between the 6th and 12th month) represented 1.80 and 1.46% of the overall ECS and GCS groups. Patients with VTE within 1-year had higher risks of 1-year global mortality: (2.04 1.52; 2.73) and 2.71 (2.09; 3.51), respectively. Our extensive analysis of a nationwide database highlights the significant risk of postoperative VTE after ECS and GCS, persisting within 90 POD and up to 1-year. Crucially, a higher risk of global mortality within 1-year for patients experiencing early or late VTE was found. These findings could advocate for further research into extended prophylactic regimens, particularly for those most at risk.

REMAP Periop: a randomised, embedded, multifactorial adaptive platform trial protocol for perioperative medicine to determine the optimal enhanced recovery pathway components in complex abdominal surgery patients within a US healthcare system

IntroductionImplementation of enhanced recovery pathways (ERPs) has resulted in improved patient-centred outcomes and decreased costs. However, there is a lack of high-level evidence for many ERP elements. We have designed...

Post-Transplantation Cyclophosphamide and Tacrolimus for Graft-versus-Host Disease Prevention after Allogeneic Hematopoietic Cell Transplantation from HLA-Matched Donors Has More Advantages Than Limitations

This study compared the efficacy of graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy) and tacrolimus (Tac) versus other regimens in 272 adults undergoing peripheral blood (PB) allogeneic hematopoietic cell transplantation (allo-HCT) from HLA-matched donors. Of these 272 patients, 95 (34.9%) received PTCy/Tac. The times to neutrophil and platelet engraftment were longer in the PTCy/Tac group (20 days versus 16 days for neutrophils and 19 days versus 12 days for platelets). The day +30 cumulative incidence (CuI) of bacterial bloodstream infection was higher in the PTCy/Tac group (43.2% versus 13.0%; P < .001). The CuIs of grade II-IV and grade III-IV acute GVHD (aGVHD) at day +180 were 14.7% and 4.2%, and the CuI of moderate/severe cGVHD at 2 years was 2.4% in the PTCy/Tac group and 41.8% (hazard ratio [HR], .29; P < .001), 15.8%, (HR, .24; P = .007), and 47.0% (HR, .05; P < .001), respectively, in the no-PTCy group. The duration of immunosuppression was shorter in patients receiving PTCy/Tac (6.2 months versus 9.0 months; P < .001). PTCy/Tac patients had higher OS (2 years: 74.3% versus 60.9%; HR, .54; P = .012), lower NRM (2 years: 8.6% versus 15.8%; HR, .54; P = .11), comparable CuI of relapse (2 years: 26.0% versus 24.4%; HR, 1.03; P = .89), and higher GRFS (2 years: 59.1% versus 16.7%; HR, .32; P < .001). Using PTCy/Tac in HLA-matched PB allo-HCT improved transplantation outcomes at out institution compared with previous prophylactic regimens, including a higher probability of survival despite more delayed engraftment and a higher rate of bacterial infection.

Monocyte Subpopulations and Their Expression of HLA-DR and CD300e after Allogeneic Stem Cell Transplantation in Patients with or without GvHD

Introduction: Graft versus host disease (GvHD) is a complex immune process that can affect up to 50% of patients undergoing allogeneic stem cell transplantation (allo-SCT). Even though prophylactic immunosuppressive regimens have been established over the last decades, GvHD is still one of the main causes of morbidity and mortality among these patients. Monocytes are cells of the innate immune system, that represent, as professional antigen-presenting cells, a connection to the adaptive immune system, and play a role in several autoimmune disorders. They are classified according to the expression of CD14 and CD16 into classical (CD14++/CD16-), intermediate (CD14++/CD16+), and non-classical (CD14+/CD16++) monocytes. Previous research has shown higher levels of intermediate monocytes in pediatric patients with GvHD. Furthermore, non-classical monocytes in allogenic bone marrow grafts have also been correlated with the development of GvHD. The expression of other surface markers such as HLA-DR and CD300e (IREM-2) are related to monocyte function and engagement in inflammatory processes. Nevertheless, the role of CD300e in GvHD remains unclear. Here, we present a description of monocyte subgroups and their expression of HLA-DR and CD300e in allo-SCT patients with or without GvHD as well as in healthy subjects. Methods: Transversal observational study with patients undergoing allo-SCT. Peripheral blood of patients was collected once after engraftment. Both acute and chronic GvHD patients were enrolled. Five healthy volunteers served as controls. Flow cytometry was performed to determine the immunophenotype of monocytes according to their expression of CD14 and CD16 stratifying into classical, intermediate, and non-classical subgroups as described above. In addition, the expression of HLA-DR and CD300e was analyzed for all monocytes and individual subgroups. Clinical characteristics are described in the table below. Statistical analysis was performed using GraphPad Prism 9. Comparisons between groups were made using non-parametrical tests and tests for multiple comparisons (Mann-Whitney and Kruskal-Wallis respectively). Results: 29 patients were enrolled. Two patients with GvHD were excluded due to neutropenia. 19 patients presented GvHD grade II or higher. Of those, ten had acute GvHD, five had prolonged acute GvHD, two had late onset acute GvHD, and two had chronic GvHD. Eight patients did not show GvHD or had only mild skin disease (grade one). The mean age was 60 years for all patients, 62.5 and 58.5 years among GvHD and non-GvDH patients, respectively. The image summarizes patient characteristics and comparisons. We compared transplant recipients with and without GvHD which each other and with healthy controls. In single comparisons, patients with GvHD showed significantly lower percentages of total monocytes as well as CD14+/HLA-DR+, total HLA-DR+, and intermediate monocytes compared to patients without GvHD. In addition, we observed a trend toward lower levels of CD16+/HLA-DR+ and CD300e-expressing monocytes in GvHD patients. When compared to healthy controls, allogeneic recipients without GvHD showed significantly higher levels of total monocytes, intermediate monocytes, and CD16+/HLA-DR+ monocytes and lower levels of classical and non-classical monocytes. Compared to controls, patients with GvHD showed significantly lower levels of total monocytes expressing CD300e (also true in all subgroups) as well as lower levels of classical monocytes, but higher levels of intermediate and non-classical monocytes. P values are shown in Table 1. Means and ranges for all groups are represented in Image 1. Conclusions: In our cohort, patients with GvHD showed higher levels of intermediate and non-classical monocytes compared to controls, however, these populations were lower when compared to allogeneic recipients without GvHD. This could indicate a consumption process similar to that observed in COVID-19 patients and a direct involvement of these monocytes in the GvHD process. In addition, we report for the first time the involvement of CD300e in GvHD, which was significantly lower expressed in the GvHD patients, compared to controls. However, there was only a strong trend compared to transplanted non-GvHD patients. This indicates a possible contribution of CD300e in the pathogenesis of GvHD. Further studies are needed in order to confirm these findings.

“Hermes” - Hemophilia Related Mental Illness: A Cross-Sectional, Multicenter Study in Switzerland

Background: The availability of clotting factor concentrates and prophylactic home treatment for patients with hemophilia (PWH) A and B in developed countries greatly improved clinical outcomes. As the life expectancy of affected patients has increased, the management of comorbidities has become a greater focus within the comprehensive care setting. However, most studies focus on somatic complications. The past two decades revealed a growing body of work reporting increased prevalence of mental health problems in PWH. Given the severity and chronicity of the disease, internalizing disorders (i.e. anxiety, depression) as well as externalizing disorders (i.e. substance dependency, irritability and aggression) seem to go hand in hand with hemophilia. We aimed to assess the prevalence of comorbid mental health problems among PWH in Switzerland. We investigated age effects on this relationship as well as potentially influencing factors (illness factors and environmental factors) that may account for these. We also aimed to assess health-related quality of life (HRQoL) and age dependency in this setting. We are heading to identify targets of prevention/early intervention of mental health problems and foster improvement of evidence-based interdisciplinary treatment in PWH. Methods:This multicenter, cross-sectional study was conducted within six hemophilia treatment centers in Switzerland. Study participants were aged 6-99 years with congenital hemophilia of any severity. All participants or their legal guardians provided written informed consent, and the study was approved by the cantonal medical ethics committee of the responsible states. Participants aged 12 or older underwent a detailed personal psychological assessment followed by completing an online survey utilizing validated psychological measures (HRQoL, psychosocial functioning, somatic comorbidities/parental factors). Participants younger than 12 years underwent a detailed personal psychological assessment with one parent/legal guardian followed by an online survey to be completed by their parent/guardian. In all participants younger than 18 years, we assessed one parent/legal guardian additionally. Results:A total of n=164 PWH participated in the study (133 adult and 31 pediatric participants). Data analyses showed a median age of 39.26 years (SD 20.41). The majority of participants had hemophilia A (n=134, 82%), while hemophilia B was diagnosed in n=30 (18%) of participants. A severe hemophilia was reported in n=85 (52%), a moderate in n=31 (19%) and a mild hemophilia in n=48 (29%). Prophylactic treatment regimen was used in n=97 (59%). Out of n=156 participants with completed neuropsychiatric diagnostic interview, n=38 (24%) participants showed a psychiatric disorder over lifetime. This was significantly associated with disease severity, being more prevalent in moderate and severe hemophilia. We could not detect an association with age, so age does not moderate this association. In n=153 participants with available data on HRQoL, we found a lower HRQoL also to be associated with disease severity (moderate and severe). Moderation analyses could not confirm an association with age. Conclusion:Our data show an association of (lifetime) psychiatric diagnoses and a lower health-related quality of life in hemophilia depending on disease severity. This association is evident in moderate and severe hemophilia and is independent of age despite recent progress in development and use of new therapies going along with suggested lower hemophilia disease burden. Further analyses including somatic and treatment factors as well as parenting are ongoing and will be presented.

Design of an Observational Study (PROVE) to Assess the Long-Term Effects of Prophylaxis with Simoctocog Alfa or Emicizumab on Joint and Bone Health in Hemophilia a Patients

Background: Arthropathy caused by repeated joint bleeding is a major complication in patients with severe hemophilia A and is associated with long-term morbidity. Factor VIII (FVIII) prophylaxis has proven benefits for prevention of bleeding, including joint bleeding, in these patients. Alongside preservation of joint health, FVIII prophylaxis may preserve bone mineral density (BMD) and reduce the risk of fractures. Emicizumab is a bi-specific monoclonal antibody with no structural homology to FVIII and is approved for prophylaxis in hemophilia A patients. However, data on the long-term impact of emicizumab on joint and bone health are limited. Aims: To assess the impact of long-term prophylaxis with simoctocog alfa (Nuwiq ®; a fourth generation recombinant FVIII) versus emicizumab on joint and bone health in people with hemophilia A. Methods: PROVE is a multinational, prospective, two-arm, low-interventional study that will collect clinical data on joint and bone health in patients receiving prophylaxis with simoctocog alfa or emicizumab in routine clinical practice. Approximately 200 male participants (100 in each treatment arm) at least 12 years of age with severe hemophilia A (FVIII activity [FVIII:C] &amp;lt;1%) will be enrolled. Written, informed consent will be obtained from each patient or their legal representative. The primary objective of the study is to evaluate the long-term effect of simoctocog alfa versus emicizumab on joint health as measured by magnetic resonance imaging (MRI). The primary endpoint will be a between-group comparison of the change in total score on the extended MRI (eMRI) scale (Table 1). Secondary and exploratory endpoints include the impact of simoctocog alfa vs emicizumab on bleeding rates, joint and bone health, physical activity, quality of life and safety (Table 1). Study treatments will be defined by the treating physician prior to inclusion of a patient into the study. Patients will not be randomized to the treatment groups but will continue with their current prophylactic regimen (simoctocog alfa or emicizumab). Patients will be provided with an electronic diary (eDiary) in which to record study related data, including treatment-related data, bleeding event details, fracture details, concomitant medications and adverse drug reactions. Each patient will be followed for up to 4 years. An interim analysis is planned after 2 years. Conclusion: ThePROVE study aims to generate real-world data on the long-term effects of prophylaxis with simoctocog alfa or emicizumab on joint and bone health in hemophilia A.

Post-Transplant Cyclophosphamide or ATG As Gvhd Prophylaxis in Mismatched Unrelated Stem Cell Transplantation? - a Registry Analysis By the EBMT Transplant Complications Working Party

There is an increased risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when mismatched unrelated donors (MMUD) are used. Prophylaxis with either rabbit anti-thymocyte globulin (rATG, also termed anti-T-lymphocyte globulin) or post-transplantation Cyclophosphamide (PTCy) is often used to reduce the risk of NRM and GVHD. However, it is currently impossible to give general recommendations regarding preference for rATG or PTCy since comparative evidence from larger data sets is lacking. To better understand the outcome of these GHVD prophylactic regimens, we analyzed outcomes of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies, who underwent peripheral blood alloSCT from 9/10 antigen MMUD between Jan 2018 and June 2021 in the EBMT database. We performed multivariate analyses using Cox cause-specific hazard models, adjusting for known risk factors, and variables that showed significant difference between the two comparison groups. Overall 2123 patient were included, treatment- and patient characteristics are shown in Table 1. Patients receiving PTCy (n=583) were younger and had undergone alloSCT more recently compared to patients receiving rATG (n=1540). Median follow up was 2.0 years (PTCy) and 2.4 years (rATG). Outcome graphs are shown in figure 1. All outcomes are given starting from AlloSCT (with 95% CI). NRM (fig 1A) was higher in the rATG arm (2-years NRM: PTCy 18% [14.6-21.6] vs. rATG 24.9% [22.7-27.3]; HR 0.74, p=0.03), Relapse incidence was slightly higher but not significant in the rATG arm (2-years RI: PTCy 22.9% [19.2 - 26.9] vs. rATG 26.2% [23.9 - 28.7]; HR 0.82, p=0.07), Overall survival (fig 1B) was better in the PTCy arm (2-years OS: PTCy 65.7% [61.2 - 69.9] vs. rATG 55.7% [52.9 - 58.3]; HR 0.77, p&amp;lt;0.001), same for Progression free survival (fig 1C) (2-years PFS: PTCy 59.1% [54.4 - 63.5] vs. rATG 48.8% [46.1 - 51.5]; HR 0.78, p=0.001). The incidences of chronic and acute GVHD were not significantly different between the groups; (2-years cGVHD: PTCy 31.7% [27.4 - 36] vs. rATG 30.3% [27.8 - 32.8]; HR 0.95, p=0.67. And 100-days aGVHD grades II-IV: PTCy 29.9% [25.9-34.1] vs. rATG 32.5% [30-34.9]; HR 0.83, p=0.11). In summary, we found significantly higher survival and lower NRM in recipients of peripheral blood alloSCTs from MMUD receiving PTCy as compared to rATG. The current analysis improves the evidence base for decision making on GVHD prophylaxis in MMUD alloSCT.

B-Cell Acute Lymphoblastic Leukemia: Donor Matters in Allogeneic Stem Cell Transplant Outcomes of Hispanic Patients

Introduction: Hematopoietic stem cell transplantation (HSCT) improves long term overall survival (OS) and disease-free survival (DFS) in those with intermediate or high-risk B- cell ALL. Historically, matched related donors were the ideal choice, but with improved GVHD prophylactic regimens and supportive care, haploidentical donors are being increasingly used. Due to their increased graft-versus-leukemia (GVL) effect, they may be an option for Hispanic patients, for whom matched donation may be more challenging. Methods: This is a retrospective chart review of B- cell ALL patients that received allogeneic HSCT at Norris Comprehensive Cancer Center (NCCC) from 2012 to 2023. Mismatch-unrelated donors were excluded. For OS, DFS, and cumulative incidence of relapse (CIR), match sibling donors (MSD) and match unrelated donors (MUD) were grouped. However, for GVHD outcomes including graft-versus-host disease (GVHD)-free relapse-free survival (GRFS), incidence of grade 3-4 acute GVHD (aGVHD), and incidence of severe chronic GVHD (cGVHD) requiring immunosuppression MSD and MUD were separated. Incidence outcomes were evaluated using competing risk regression (Fine-Gray method), with death as a competing outcome, while survival outcomes were analyzed using Cox proportional hazards model. Results: One hundred eighteen B- cell ALL patients were included with a median age at transplant of 43 years (range: 21-69). Donor types included 46 (40.0%) MSD, 45 (38.1%) haploidentical, and 27 (22.9%) MUD. Most were Hispanic (N= 92, 78.0%) and our median follow-up time was 23.6 months. The majority of patients achieved CR1 (N=79, 66.9%) and MRD negativity by flow (N=106, 89.8%), pre-transplant. The 3-year OS and DFS for the cohort were 82.1% (95% CI 73.8-91.3%) and 66.2% (95% CI 57.2-76.6%), respectively, while the CR1 subgroup was 90.5% (95% CI 83.3-98.3%) and 77.1% (95% CI 67.8-87.7%) respectively. When compared to haploidentical HSCT, patients who received matched donors had significantly worse CIR (HR = 2.42; 95% CI 1.06-5.51; P = 0.036) and DFS (HR = 2.14; 95% CI 1.03-4.44; P = 0.041), along with a non-significant trend towards worse OS (HR = 2.54; 95% CI 0.83-7.80; P=0.10). Additionally, pretransplant minimal residual disease (MRD) positivity demonstrated worse OS (HR = 5.01; 95% CI 1.73-14.5; P = 0.003), DFS (HR = 3.25; 95% CI 1.48-7.16; P = 0.003), and CIR (HR = 2.05; 95% CI 0.78-5.39; P = 0.15). The 1-year GRFS, 1-year incidence of severe cGVHD, and 100-day incidence of grade 3-4 aGVHD was 52.6% (95% CI 43.5-63.6%), 29.5% (95% CI 20.9-38.6%), and 7.74% (95% CI 3.79-13.5%), respectively. Compared to haploidentical donors, GRFS was worse in the MUD (HR = 2.07; 95% CI 1.08-3.96; P = 0.028) but similar in MSD. This is likely driven by differences in survival and relapse, and there were no differences in the incidence of severe cGVHD or aGVHD between donor types. Multivariate analysis, which included age, MRD status pretransplant, and stage prior to transplant, demonstrated the improved predictive effect of haploidentical donors. Matched donors exhibited worse DFS (HR = 2.25; 95% CI 1.04-4.90; P = 0.04) and CIR (HR = 2.47; 95% CI 1.09-5.60; P = 0.03), with a trend towards worse OS (HR = 2.84; 95% CI 0.92-8.79; P = 0.07). Given the heterogeneity in donor-type outcomes, we conducted a subgroup analysis of the 45 haploidentical HSCT patients on the GRFS and DFS composite outcomes. After controlling for patient age, older donor age analyzed as a continuous variable was a significant predictor of worse GRFS (HR = 1.05; 95% CI 1.00-1.11; P = 0.039) but did not affect DFS. Conclusion: In a predominantly Hispanic population of ALL patients, haploidentical donors demonstrate improved OS and CIR. In those haploidentical patients, younger donor age confers improved GRFS.

Real-World Use of Recombinant Von Willebrand Factor in People with Clinically Severe Congenital Von Willebrand Disease: Interim Analysis of Athn 9: A Natural History Study for People with Severe VWD

Background: People with von Willebrand disease (VWD) present with a spectrum of bleeding patterns and clinical symptoms, independent of subtype (Rugeri. Haematologica. 2007; Kalot. Haemophilia. 2021). In certain situations, prophylaxis may be appropriate, particularly when there is recurrent and severe bleeding (Connell, Blood Advances, 2021). There are limited real-world data on the use of recombinant von Willebrand factor (rVWF) in the United States. Aim: To characterize the safety and real-world effectiveness of routine prophylaxis with rVWF in people with clinically severe congenital VWD. Study Design and Methods:This is an interim analysis of a phase 4, longitudinal, prospective, observational cohort study (NCT03853486). Participants with severe VWD types 1, 2, and 3 (≤30% of normal) or “clinically severe VWD” (≤40% of normal with severe bleeding and requiring prophylaxis with factor concentrates) were identified from the ATHNdataset. The American Thrombosis &amp; Hemostasis Network (ATHN) is the steward of the ATHNdataset, a Health Insurance Portability and Accountability Act-compliant, de-identified patient health dataset containing data from individuals with bleeding disorders receiving care through ATHN affiliates who opt in to contribute. Treatment regimens were at the discretion of each participant's respective bleeding disorder provider. Participants are followed for 2 years from the time of enrollment. Safety was measured using definitions from the European Haemophilia Safety Surveillance program. Bleeding events (BEs) were measured by individual bleeding components and calculated per the International Society on Thrombosis and Haemostasis Bleed Assessment Tool and/or the Pictorial Bleeding Assessment Chart. Health-related quality of life measures, including an ATHN9 rVWF substudy form, were used to describe real-world effectiveness of rVWF treatment. Descriptive statistics were used to analyze study outcomes. This study was not designed to detect differences in safety or efficacy between individual treatment products. Interim Results:As of June 16, 2023, 23 participants enrolled in the ATHN9 study were receiving rVWF; 14 participants have been prescribed rVWF for at least 1 full year, 13 of whom received continuous prophylaxis. This abstract reports on those 13 participants in the first year of the study. Mean (SD) age was 42.9 (29.2) years; 69.2% (n=9) of participants were female. Most participants had no comorbidities. As expected, most participants had a family history of VWD (84.6%; n=11) and no documented VWF inhibitors (84.6%; n=11); inhibitor status for the remaining 2 participants was unknown. Baseline VWF and factor VIII measurements were reported for most participants ( Table 1). The majority had type 2 VWD (84.6%; n=11), 92.3% (n=12) had identifiable genetic sequence defects in VWF, and 30.8% (n=4) had an abnormal VWF multimer profile. As dictated by the local investigator, rVWF prophylactic regimens ranged from 36.6 IU/kg once weekly to 57.6 IU/kg every 3 days; 7 (53.8%) participants received 40-60 IU/kg at a frequency of 2-3 times per week. Twenty-one BEs occurred in 5 (38.5%) of the participants receiving rVWF prophylaxis during the first year ( Table 2). Most BEs were spontaneous (61.9%; 13/21), occurring in the nose (n=7), gastrointestinal tract (n=5), or ankle (n=1). The remaining BEs were associated with activity with no known trauma (n=4), trauma (n=2), or unknown cause (n=2). One participant reported 3 rVWF treatment-unrelated adverse events (AEs) of humerus shaft closed fracture, metabolic encephalopathy, and acute exacerbation of chronic obstructive airways disease. When surveyed about their experience with rVWF, participants reported very or extremely satisfied as follows: 76.9% (n=10) with infusion time, 84.6% (n=11) with breakthrough bleed control time, 46.2% (n=6) with number of infusions required for breakthrough bleed control, and 69.2% (n=9) with frequency of achieving bleed control without concomitant hemostatic medication. Discussion:In participants with clinically severe congenital VWD, continuous prophylaxis with rVWF was associated with minimal AEs. Most participants receiving rVWF prophylaxis experienced no BEs during the first year of the study. Most participants expressed overall satisfaction with the use of rVWF.