Dose Of Prophylaxis Research Articles

Antibiotic prophylaxis practices in cesarean section with focus on timing – a Danish national survey

Introduction: The last Danish survey in 1995 on the antibiotic prophylactic practices in cesarean section found that there was no consensus between delivery wards. Since then national guidelines have been established. We therefore wanted to see if clinical practice regarding antibiotic prophylaxis had become more uniform. Methods: In February of 2019 the delivery wards in Denmark (n=21) were contacted to answer an online questionnaire regarding type and dose of antibiotic prophylaxis used, timing of the administration, and differences between elective and emergency cesarean section. Results: All twenty-one wards applied a single dose of 1500 mg Cefuroxime, a 3rd generation cephalosporin. Three wards (14%) administered antibiotic prophylaxis after cord clamping and eighteen (86%) prior to clamping, with nine (43%) wards having changed practice during the last 10 years. Three wards recalled the precise year for the change, six wards gave an approximate range of years, and five wards did not remember. The exact timing of the antibiotic varied from 0-60 minutes prior to incision, with sixteen (76%) wards reporting giving antibiotics usually 0-30 minutes prior to and of those, eleven (52%) immediately prior. All wards had the same prophylactic antibiotics principles for emergency and elective cesarean sections. Conclusion: Most wards adhere to national guideline recommendations, but recollection was imperfect as to when changes in practices were implemented. We suggest that current and previous guidelines from hospitals in Denmark be stored in a national database, or more preferably that a national cesarean birth registry be established, accounting for the frequent local changes and interpersonal differences in clinical practice.

Thromboprophylaxis in Hospitalized Non-Critically Ill Patients With Mild-to-Moderate COVID-19 Infection: A Systematic Review and Meta-Analysis.

The prevalence of venous thromboembolism is high in patients with COVID-19, despite prophylactic anticoagulation. The evidence that supports the preferred thromboprophylaxis regimen in non-critically ill patients with mild to moderate COVID-19 is still limited. Therefore, this systematic review and meta-analysis aimed to compare the clinical outcomes of hospitalized patients with mild to moderate COVID-19 who received standard thromboprophylaxis anticoagulation with intermediate to high prophylaxis regimens. We systematically searched MEDLINE and Embase databases for published studies until August 17th, 2022. We included studies on patients with mild to moderate COVID-19 who received thromboprophylaxis during their hospital stay. Patients who received standard prophylaxis dose "control group" were compared to patients who received intermediate to high prophylaxis "intervention group". Random effect models were used when pooling crude numbers and adjusted effect estimates of study outcomes. A comprehensive analysis was conducted, encompassing seven studies involving a total of 1931 patients. The risk of all-cause thrombosis was not statistically different between the two groups (risk ratio [RR] 1.48, 95% confidence interval [CI] [0.11, 20.21]). The risk of minor bleeding was reported to be lower in patients who received intermediate to high prophylaxis (RR 0.64, 95% CI 0.21, 1.97), while had a higher risk of major bleeding compared with the standard prophylaxis (RR 1.40, 95% CI 0.43, 4.61); however, did not reach the statistical significance. The overall risk for all hospital mortality favored the utilization of intermediate to high doses over the standard thromboprophylaxis dosing (RR 0.47, 95%CI 0.29, 0.75). In medically ill patients with COVID-19, there is no difference between standard and intermediate to high prophylaxis dosing regarding thrombosis and bleeding. However, it appears that intermediate to high prophylaxis regimens are linked to additional survival benefits.

Post COVID Thrombotic Sequelae: Once Bitten, Twice Shy!

Introduction Long Covid has been recognized as a distinct entity with thrombotic sequelae [1]. Persistent systemic vascular inflammation caused by thrombosis drives the complications associated with long COVID. The risks of arterial and venous thrombosis after COVID-19 extend well beyond the hospitalization period. Early prophylactic anticoagulation has been shown to reduce the incidence of post-covid thrombotic sequelae [2]. Some evidence suggests the use of a higher than prophylactic dose for primary venous thromboembolism prophylaxis, especially in patients with a history of venous thromboembolism (VTE) [1]. We present a case of long Covid who developed recurrent thrombosis despite being on a therapeutic dose of anticoagulation. Case Presentation A 55-year-old male was brought to our Emergency Department with complaints of diffuse abdominal pain and black-coloured stools for three days. Contrast-enhanced CT abdomen (CECT) showed distal superior mesenteric artery (SMA) thrombosis and splenic infarct (Figure 1). He was treated for mild Covid-19 infection three months back. History also revealed he was hospitalized two months ago with a diagnosis of non-ST segment elevated myocardial infarction (NSTEMI) and acute ischemic stroke (Figure 2), which was managed with antiplatelets, statins and anticoagulants. He was discharged on oral anticoagulants (Tab Rivaroxaban 15 mg twice daily) for three months and was on regular follow-up. There was no history of smoking or hypertension. Protein C, Protien S, homocysteine levels were normal. After the diagnosis of SMA thrombosis, his anti-coagulation was increased to Tab Rivaroxaban 20 mg twice daily. No further thrombotic episodes have been noted as of date. Discussion This case suggests that unexplained repeat thrombotic events at multiple sites may have been a consequence of Covid-19 infection. Covid-19 patients experience both arterial and venous thromboembolism [3]. Most commonly, the former presents as myocardial infarction and ischemic stroke, whereas the latter as deep venous thrombosis and pulmonary embolism. Mechanisms include changes in lung structure secondary to chronic hypoxia, persistent immune dysfunction, and endothelial damage [1]. Risks of thrombotic events after mild Covid-19 are less clear, with the need and intensity of prophylactic anti-coagulation in this subset of patients being a matter of future research [4]. Shabaka et al. have shown that patients with a history of Covid-19 infection and previous thromboembolic events were at higher risk of developing a repeat thrombotic event [5]. Physicians need to be vigilant about the thrombotic events in patients with long Covid, even in patients receiving therapeutic anti-coagulation. Such patients require more frequent monitoring for signs of thrombotic events, risk factor management, and adherence to preventive therapies [3].

Adherence and Cost Effectivity of Home-Based Prophylaxis Over Institutionalized Prophylaxis in Patients with Hemophilia

Purpose: Home-based prophylaxis in hemophilia facilitates the treatment of patients with hemophilia (PwH) at home resulting in an improved quality of life, experiencing less pain and greater flexibility in daily activities. This literature studies the cost effectivity and adherence to prophylaxis treatment after the implementation of home-based prophylaxis therapy in PwH registered under the Hemophilia Treatment Centre (HTC) of Assam Medical College and Hospital. Materials and Methods: PwH and their parents were advised for self/home infusion after being trained by a medical professional for 6 months. Data were collected on the skip in prophylaxis treatment by PwH and their traveling cost to access the prophylaxis treatment before and after the implementation of home infusion, through questionnaire and telephonic interview. Results: The mean number of days of skip in prophylaxis was significantly reduced from 25 (±11) to 4 (±2) days after implementation of home infusion. The mean transportation cost was also found to be significantly decreased from Rs. 3297 (±2251) to 440 (±279). Before home/self-infusion, 77% of the registered PwH were found to skip prophylaxis doses more than 12 times a year but after home infusion, no PwH were found to skip more than 12 doses a year. Conclusion: Home therapy facilitates the PwH to strictly adhere to the prophylaxis regime significantly reducing the skipping of doses to be administered to the PwH. The risks of regular traveling and the burden of transportation expenditure to avail the prophylaxis treatment was also found to be reduced significantly.

Venous thromboembolism in burn patients – low incidence or underdiagnosis?

Venous thromboembolism (VTE), essentially deep venous thrombosis and pulmonary embolism, urinary tract infection, and renal failure are the main unplanned hospital events with negative long-term impact on burn patients’ rehabilitation. Due to the hypercoagulable state induced by severe critical burns, either in the acute or recovery phase and the intimal vascular damage, the risk of VTE is increased, with an incidence varying from 0.4% to almost 60%. Other risk factors for VTE in burn patients are prolonged immobilization, long and multiple surgical interventions, central venous catheterization, wound infection and sepsis, extensive burns, and red blood cell transfusion. To avoid underdiagnosing VTE, in face of increased incidence of asymptomatic venous thromboembolism, high risk-patients should be routinely screened using Doppler ultrasound. Patients’ weight and burn size, as well as the high incidence of heparin resistance in the first weeks after injury, should be considered when establishing the optimal dose for venous thromboembolism prophylaxis, targeting an anti-Xa level of 0.2-0.5 IU/mL.

Evaluation of cytomegalovirus infection/disease in IgG positive renal transplantation recipients on valaciclovir prophylaxis

The reactivation of CMV (Cytomegalovirus) in renal transplant recipients may be manifested across a clinical spectrum from asymptomatic viraemia to organ rejection. The purpose of this study is to evaluate the patients who have experienced CMV infection after renal transplantation in the last twelve years, and to assess the efficacy of valacyclovir. Renal transplant recipients' demographic, clinical and laboratory data were evaluated retrospectively between 2006-2018. Valaciclovir was given at the standard prophylaxis dose of 2000 mg/daily. CMV Polymerase Chain reaction (PCR) was performed in 2-week intervals until 1 year after transplantation, and upon any symptoms attributable to CMV. The entire study group had D+/R+ (donor-positive, recipient-positive) serological status of the CMV virus. 171 (59.2%) patients had only CMV infection, 60 (20.8%) had overall CMV antigen positivity until the end of the follow-up period and 7 (2.4%) patients had CMV disease. Rejection episodes were diagnosed in 31 (10.8%) patients; 20 (64.5%) of those were PCR positive for CMV; mortality rate was 12 (4.2%) but those who died had a non-CMV related disease. Valaciclovir may be preferred in prophylaxis instead of valganciclovir as we used in our study since valganciclovir has prolonged treatment time, rapid development of drug resistance, drug toxicity and high cost.

Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer

BackgroundNeratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies. MethodsPatients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L. Results563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed. ConclusionsThese complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective. ClinicalTrials.gov registration numberNCT02400476.

The Pattern of Heparin Dosing as Venous Thromboembolism Prophylaxis in Adult Underweight Patients Admitted to Critical Care Units at a Tertiary Hospital.

Venous thromboembolism (VTE) is one of thecauses of hospital-related deaths in critically ill patients. Guidelines recommended VTE prophylaxis with standardized, fixed doses for most patients. The underweight population has limited data to guide the appropriate drug and dosing regimen. The aim of this study was to describe the pattern of VTE prophylaxis dose regimens for underweighted critically ill adult patients and the prevalence of associated VTE and bleeding. This study is a retrospective cohort study, conducted at the King Abdulaziz Medical City, Riyadh, Saudi Arabia. It included all critical patients admitted to the intensive care units (ICUs) and were above 14 years old with weight less than 50 kg or body mass index (BMI) of 18.5 kg/m2 or less, and were on heparin as VTE prophylaxis for more than 72 h from January 2016 until January 2020. After screening 270 patients, only 40 patients were included in this study according to our inclusion and exclusion criteria. Only six patients (15%) received VTE prophylaxis as an adjusted dose of heparin 2500 U Q12, while the rest of the patients were taking standard dosing of heparin; 5000 U Q12 was given to 21 (52.50%) patients, and 5000 U Q8 was given to 13 (32.50%) patients. None of the adjusted doses developed any complications such as VTE or bleeding. There was no significant difference compared with the standard dose group. In this study, we described the pattern of heparin doses as VTE prophylaxis in underweight patients. We also compared the standard dosing and adjusted dosage of VTE prophylaxis on underweight patients and any complications. There was no significant difference in the complications outcome or benefits between the two groups.

The Empower Study - Design of a Randomized Clinical Trial to Assess the Efficacy and Safety of a Plasma-Derived Von Willebrand Factor / Factor VIII Concentrate for Heavy Menstrual Bleeding in Women with Von Willebrand Disease

Background: Although von Willebrand disease (VWD) is inherited by men and women equally, women are more likely to experience bleeding symptoms due to the challenges of menstruation and childbirth. Heavy menstrual bleeding (HMB) is the most common symptom observed in women and girls with VWD, and increases risk of iron deficiency anemia, blood transfusion, hospitalization and decreased health-related quality of life. While replacement therapy with von Willebrand factor (VWF) is recommended for prophylaxis in patients with VWD with severe and frequent bleeding, recommendations on its use for prophylaxis of HMB are limited due the lack of clinical trial data. Aims: The EMPOWER pilot trial will determine the feasibility of the trial design, as well as explore assay sensitivity to inform the determination of the primary outcome for the definitive randomized trial which will evaluate the effect of prophylaxis with plasma-derived VWF/FVIII (1:1; pdVWF:FVIII) concentrate compared with placebo on HMB in women with VWD. Methods: EMPOWER is a pilot, randomized, placebo-controlled, crossover, double-blind (patient and outcome assessor blinded), 2-year trial in female outpatients with VWD and HMB. We will evaluate the effect of 2-3 doses of prophylaxis with 40-60 IU VWF:RCo/kg pdVWF/FVIII concentrate when provided on the 2 heaviest days within the first 4 days of menstruation compared with placebo (normal saline). For the first treatment period, participants will be randomized to receive either pdVWF/FVIII concentrate or placebo for 4 cycles, crossing over to the comparator treatment during the second treatment period (see Figure 1). Non-pregnant female patients, ≥18 years of age with a diagnosis of inherited VWD (any type) with HMB defined as a modified pictorial blood assessment chart (mPBAC) score >100, on stable treatment for HMB and iron-deficiency anemia will be eligible. Patients with diagnosis of another bleeding disorder or the presence of >2 risk factors for venous thromboembolism will be excluded. The pilot trial viability outcomes include blinding index scores and participant drop-out rates. Feasibility outcomes include data completeness and rate of enrolment. The proposed primary clinical efficacy outcome is the mPBAC score and the key secondary efficacy outcome is the need for rescue therapy (i.e. >2 days of oral tranexamic acid use, additional treatment with pdVWF:FVIII concentrate, additional hormonal therapy for HMB, urgent/emergent gynecological surgery for HMB, treatment with intravenous iron, red blood cell transfusion, or hospital admission for HMB). Other secondary outcomes include major bleeding, clinically relevant non-major bleeding, red blood cell transfusion, fatigue and quality of life scores. Given the uncertainty in this area of research and the relative comparable clinical importance of proposed clinical efficacy outcomes, we will evaluate assay sensitivity to determine the outcome that has the greatest chance of detecting a difference between treatment periods. Assay sensitivity is defined as the ability of a scale to distinguish an effective from a less effective intervention or placebo. Assay sensitivity along with the proportion of missing data per clinical efficacy outcome and sample size considerations will influence the choice of primary outcome for the definitive trial. Safety will be evaluated by monitoring for hypersensitivity reactions, thromboembolic events and VWF inhibitors. The pilot trial will recruit 20 participants from Hemophilia Treatment Centres in Canada over 2 years. Results: The pilot trial is aiming to launch by the fall 2022. If the pilot trial is deemed feasible and viable, we will subsequently conduct a definitive international randomized controlled trial. Conclusion: Data from the EMPOWER trial will fill an important knowledge gap to facilitate evidence-based management of HMB in women with VWD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Follow-up and Evaluation of the Efficacy of the Hemostatic Treatment in Congenital FVII Deficiency during Development of Inhibitor

Introduction The development of inhibitors is an extremely rare complication in patients with factor (F)VII deficiency treated with replacement therapies such as recombinant activated FVII (rFVIIa), and represents a major therapeutic challenge in the treatment of this disorder. When inhibitors result in loss of response to high doses of rFVIIa, activated prothrombin complex concentrate (aPCC) is often used as an alternative treatment for these patients. The use of high-dose rFVIIa or aPCC might be accompanied by an increased risk of thromboembolic events, so it is important monitoring properly the effect of the hemostatic treatment Here we describe the therapeutic management and follow-up of a patient with elevated inhibitor titres, resistant to rFVIIa treatment who switched to prophylaxis with aPCC, using several global coagulation tests. Methods The coagulation status of the patient and the reponse to in vitro spiking of different doses of rFVIIa or aPCC were assessed with several global tests: Prothrombine time (PT) was tested using HemosIL®RecombiPlasTin 2G. Clot formation was evaluated with Rotational Thromboelastometry (ROTEM®) using blood with CTI (to inhibit contact activation) and activated with a low amount of Tissue Factor (TF) as trigger (dilution 1:50,000 of EXTEM reagent). The thrombin generation (TG) was tested with the Calibrated Automated Thrombogram (CAT) system using plasma collected with CTI and activated with 1 pM TF plus phospholipids (PPP-Low®, Stago). Thrombus formation under flow conditions was assessed with the Total Thrombus-formation Analysis System (T-TAS®) in AR-chips coated with collagen and thromboplastin. The Area under the flow pressure curve (AUC) was calculated over 30 min after starting. Results Three year-old girl affected by severe congenital FVII deficiency (FVII 9.1%) with significant severe bleeding history (spontaneous intracranial hemorrhage at 1st month of life). Since then she is in prophylaxis treatment with rFVIIa. At 6 months of life she developed an inhibitor (9.8 BU). Despite prophylaxis she presents frequent spontaneous mucocutaneous bleedings. When she was 2 years old she needed to be admitted at hospital because of port-A-Cath infection. Due to the administration of intensive treatment with rFVIIa during admission she developed thrombosis of peripheral venous access, so prophylaxis treatment was temporary suspended. After 5 days without prophylaxis treatment, and increasing inhibitor titres, she developed a new intracranial haemorrhage, which needed intensive treatment with continuous rFVIIa infusion (90 µg/Kg/12h), immunoglobulines and rituximab for lowering inhibitor titre. Hemostatic parameters improved during the administration of these treatments and inhibitor level was reduced. After restarting prophylaxis treatment with rFVIIa (50 µg/Kg/48h), inhibitors and a hypocoagulable state were observed with all global coagulation test showing extended PT, clotting time (CT), TG Lag-time (LT) and anomalous thrombus formation (AUC) but presented very good response to low dosis (2.5 IU/Kg) of aPCC in vitro (Table-1). At the age of three years she required admission at hospital because of port-A-Cath infection again, needing its replacement by a new one after administration of high doses of rFVIIa without bleeding complications. After this, inhibitor titre raised again (> 50 BU), presenting frequent bleeding episodes (spontaneous muscle bleedings and tonsillar bleeding), and due to the clinical worsening, treatment was modified to prophylaxis with aPCC (30 UI/Kg/48h). Despite the treatment change she continued presenting bleeding episodes, global tests continued showing an hypocoagulable state, and required 10 times higher doses in vitro of aPCC (25 IU/Kg) to restore all the monitored hemostatic parameters (Table-1), probably related to the important increase in inhibitor titre. This situation led to employing higher doses of aPCC prophylaxis (60 UI/Kg/48 h) to try to avoid bleeding episodes without increasing the risk of suffering thrombotic events. Conclusions Global coagulation tests used in this study were sufficiently sensitive methods to show an abnormal hemostatic profile in FVII-deficient patients with clinical hemorrhagic symptoms with inhibitor development, supporting their use to manage the risk of bleeding or thrombosis in this life-threatening condition. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epcoritamab Monotherapy Provides Deep and Durable Responses Including Minimal Residual Disease (MRD) Negativity: Novel Subgroup Analyses in Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background: Epcoritamab, a subcutaneously administered (SC) bispecific CD3xCD20 antibody, has shown potent antitumor activity as a single agent and in combination. Results of the EPCORE NHL-1 LBCL expansion cohort demonstrated clinically meaningful and compelling efficacy across a highly refractory population and a manageable safety profile, consistent with prior findings (Thieblemont et al, EHA 2022). Here, we present additional subgroup data on the efficacy and safety of epcoritamab in the LBCL expansion cohort of the EPCORE NHL-1 phase 2 trial (NCT03625037). Methods: Adults with R/R CD20+ LBCL were treated with 1-mL SC priming and intermediate doses, followed by full doses of epcoritamab in 28-d cycles (QW: cycles 1-3; Q2W: cycles 4-9; Q4W: cycles ≥10). Step-up dosing and corticosteroid prophylaxis were administered in cycle 1 to mitigate CRS. Prespecified and exploratory subanalyses were performed; response was assessed by independent review committee. Results: As of Jan 31, 2022, 157 patients (pts) with LBCL, including double/triple-hit (DH/TH) lymphoma, were treated. Per protocol there was no minimum life expectancy requirement. Median age was 64 y (range, 20-83), median number of prior lines of therapy was 3 (range, 2-11), and median time from initial diagnosis was 1.6 y. Overall, 39% of pts had received prior CAR T, 20% had prior autologous stem cell transplantation, and 61% had primary refractory disease; 14% of pts with diffuse LBCL (DLBCL; 12/88 tested) were confirmed DH/TH by central FISH. At a median follow-up of 10.7 mo, the overall response rate (ORR) for the total population was 63%, with a complete response (CR) rate of 39%. The median duration of response (mDOR) was 12.0 mo (95% CI, 6.6-not reached [NR]) overall. In subgroup analyses, mDOR was NR (95% CI, 2.8-NR) for primary refractory pts, 9.7 mo (95% CI, 5.4-NR) for pts with prior CAR T, 12.0 mo (95% CI, 5.6-NR) for CAR T-naive pts, and 12.0 mo (95% CI, 1.1-NR) for DH/TH pts. Responses occurred early, with a median time to response of 1.4 mo. The mDOR in pts who achieved a CR was 12 mo for DH/TH pts and not reached in other subgroups. MRD negativity was assessed by a ctDNA NGS assay in this LBCL population with 52 of 112 evaluable pts (46.4%) being MRD negative at any time point on treatment. MRD negativity was reached early (median of 8 wk for complete responders), and high MRD negativity rates were observed across all subpopulations: 50% in pts with prior CAR T, 44% in CAR T-naive pts, 33% in DH/TH pts, and 49% in non-DH/TH pts. MRD-negative responses were durable (Table) and correlated with PFS. Durability of CR was also demonstrated in a cohort of pts with DLBCL from the dose-escalation portion of this trial with extended follow-up (median, 21.1 mo; longest follow-up, 26.7 mo), of which 6 pts (at ≥12 mg) remain on Q4W treatment and in CR, with median duration of CR not reached. Overall, epcoritamab was well tolerated. Incidence of AEs declined after wk 12, and only 1 pt experienced any related serious treatment-emergent AE after wk 12 (CRS grade 1/2). CRS was reported in 78 pts (49.7%), and all but 1 event resolved. Events were primarily low grade (31.8% grade 1, 15.3% grade 2, and 2.5% grade 3), and timing was predictable, with 5.7% of pts experiencing CRS after the priming dose, 11.8% after the intermediate dose, 42.9% after the first full dose, 4.9% after the second full dose, and 2.9% after the third full dose or later doses. Median time to CRS onset after the first full dose was 20.0 h (range, 12-126). Ten pts had ICANS events; 9 events were grade 1 or 2, and there was 1 grade 5 event (the only treatment-related death, pt with multiple confounding factors). All but 1 ICANS event occurred in cycle 1. There were 8 pts (5%) who experienced both CRS and ICANS. Grade 3 or 4 neutropenia occurred in 33 pts (21.0%; 10.8% grade 3, 10.2% grade 4). Grade 3 anemia was reported in 16 pts (10.2%). Few pts discontinued epcoritamab treatment due to AEs (n=11). Notably, there were no treatment discontinuations due to neutropenia or anemia. Conclusions: SC epcoritamab is a convenient, off-the-shelf therapy that has demonstrated deep and durable responses including high MRD negativity rates as a single agent. The safety profile was favorable, and CRS events were mostly low grade and transient, with most events occurring after the first full dose. These subgroup analyses demonstrate consistent, clinically meaningful activity of epcoritamab across subgroups of pts with R/R LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Subcutaneous Epcoritamab in Combination with Rituximab + Lenalidomide (R2) for First-Line Treatment of Follicular Lymphoma: Initial Results from Phase 1/2 Trial

Background: Epcoritamab is a subcutaneously administered bispecific antibody that binds to CD3 on T cells and CD20 on B cells to kill malignant B cells. In the phase 1/2 EPCORE NHL-1 trial, single-agent epcoritamab produced deep responses in patients with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) and demonstrated a manageable safety profile. In the phase 1/2 EPCORE NHL-2 trial (NCT04663347), epcoritamab is being evaluated in combination with standard therapies in B-cell NHL. Despite some advances in first-line therapy, follicular lymphoma (FL) remains an incurable disease in most cases, and better treatment options are still needed. Due to the distinct mechanisms of action of each agent, the combination of epcoritamab with rituximab + lenalidomide (R2) may result in deeper and more durable responses compared to R2 alone. Lenalidomide has immunomodulatory properties that may enhance epcoritamab activity. This epcoritamab combination has shown promising activity in patients with R/R FL in arm 2 of EPCORE NHL-2 (Falchi et al, ASCO 2022). Here we present initial data from arm 6 of EPCORE NHL-2, which is investigating the safety and efficacy of epcoritamab + R2 as first-line therapy in patients with FL. Methods: Adults with previously untreated CD20+ FL grade 1-3A who met GELF criteria for treatment were enrolled and received subcutaneous epcoritamab 48 mg + R2 for 12 cycles of 28 d each. Epcoritamab was administered QW in cycles 1-2 and Q4W thereafter, for up to 2 y of treatment. Step-up epcoritamab dosing and corticosteroid prophylaxis were required during cycle 1 to mitigate CRS. Response to treatment was assessed by PET-CT per Lugano criteria. Results: As of the data cutoff date of June 10, 2022, 41 treatment-naive patients with FL had received epcoritamab + R2. The median age was 57 y (range, 39-78), and median time from initial diagnosis to first dose of epcoritamab was 12 wk (range, 2-352). The majority (85%) had grade 2 or 3A FL; 39% and 51% had stage III and IV disease, respectively. With a median follow-up of 4.4 mo (range, 0.7-7.5), treatment was ongoing in 36 (88%) patients; 5 (12%) discontinued treatment, 3 due to AEs and 2 due to disease progression. All patients experienced a treatment-emergent AE (TEAE), with 36 (88%) having events that were deemed related to epcoritamab. CRS (51%; 34% grade 1, 17% grade 2, no grade 3-4), neutropenia (41%; 17% grade 1-2, 24% grade 3-4), pyrexia (41%; all grade 1-2), injection-site reactions (37%; all grade 1-2), fatigue (29%; all grade 1-2), headache (29%; 27% grade 1-2, 2% grade 3-4), constipation (27%; all grade 1-2), and rash (27%; 20% grade 1-2, 7% grade 3-4) were the most common TEAEs. Most CRS events (in 41% of all patients) occurred after the first full dose of epcoritamab, all resolved (median time to resolution, 4 d; tocilizumab administered in 5 patients), and none led to treatment discontinuation. ICANS and clinical tumor lysis syndrome were not observed. One fatal TEAE was observed (COVID-19 pneumonia, considered not related to epcoritamab). Among efficacy-evaluable patients (n=29), the overall response rate was 90% (26/29), with 69% (20/29) having a complete metabolic response (CMR) as their best overall response. All CMRs and partial metabolic responses were ongoing at the time of data cutoff. Conclusions: Subcutaneous epcoritamab + R2 demonstrated a manageable safety profile, similar to that observed in the R/R setting, with no new safety signals, no ICANS events, and only low-grade CRS events, all of which resolved. This regimen showed encouraging efficacy, based on high response rates, when used as a first-line treatment for FL. These data support further clinical evaluation of epcoritamab + R2 in previously untreated patients with FL.

Subcutaneous Epcoritamab with Rituximab + Lenalidomide in Patients with Relapsed or Refractory Follicular Lymphoma:Phase 1/2 Trial Update

Background: For patients with relapsed or refractory (R/R) follicular lymphoma (FL), therapies such as rituximab + lenalidomide (R2) have demonstrated efficacy and acceptable safety. However, better treatments are needed to help more patients achieve deeper and more durable responses. Epcoritamab is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on B cells to kill malignant B cells. R2 and epcoritamab have nonoverlapping toxicity profiles and, therefore, may be safely combined. In addition, the immunomodulatory properties of lenalidomide may enhance the therapeutic potential of epcoritamab. Preliminary results from arm 2b of the phase 1/2 EPCORE NHL-2 trial (NCT04663347), which tested R2 and epcoritamab in patients with R/R FL, showed an overall response rate of 93% and a complete metabolic response rate of 61% at the first assessment (6 wk; Falchi et al, ASCO 2022). Here we present updated data on a larger cohort and longer follow-up from arm 2b of EPCORE NHL-2. Methods: Adults with R/R CD20+ FL were treated with subcutaneous epcoritamab 48 mg + standard R2 for 12 cycles of 28 d each. Epcoritamab was dosed as follows: QW, cycles 1 and 2; Q4W, cycles ≥3 up to 2 y. Step-up epcoritamab dosing and corticosteroid prophylaxis were required during cycle 1 to mitigate CRS. PET-CT was used to assess responses per Lugano 2014 criteria. Results: As of the data cutoff date of June 10, 2022, 62 patients had received epcoritamab (48 mg) + R2. The median age was 65 y (range, 30-79), 58% of patients had stage IV disease, 52% had FLIPI 3-5, 31% had primary refractory disease, and 47% had experienced disease progression within 24 mo after starting first-line treatment. Half of patients (50%) had received 1 prior line of therapy (range, 1-9). Treatment was ongoing in 56 patients (90%), with a median follow-up of 4.0 mo. Six patients discontinued therapy due to disease progression (n=4) or other reasons (death due to COVID-19, n=1; reason unknown, n=1). The most common treatment-emergent AEs of any grade were CRS (37%; 27% grade 1, 10% grade 2, no grade 3-4), neutropenia (29%; 5% grade 1-2, 24% grade 3-4), fatigue (26%; 24% grade 1-2, 2% grade 3-4), and injection-site reactions (26%; all grade 1-2). Most CRS events (in 35% of all evaluable patients) occurred after the first full dose of epcoritamab. All CRS events resolved (median time to resolution, 2 d; range, 1-4), no patients discontinued treatment due to CRS, and 5 patients received tocilizumab. ICANS (grade 1) occurred in 1 patient 22 d from the start of treatment, and it resolved in 7 d. There were no clinical tumor lysis syndrome events. Among 41 efficacy-evaluable patients, the overall response rate was 95% (39/41), with 73% of patients (30/41) achieving a complete metabolic response (CMR) as their best overall response. Most CMRs (27/30) were achieved by the first assessment (6 wk), and nearly all (29/30) were ongoing at the time of data cutoff. Of the 9 patients with a partial metabolic response, 6 had an ongoing response at the time of data cutoff. The longest duration of response was 4.5+ mo. Median progression-free survival was not reached (Figure). Conclusions: In patients with R/R FL, subcutaneous epcoritamab + R2 demonstrated a manageable safety profile with only low-grade CRS events, mostly observed following the first full dose and all of which resolved. No new safety signals were detected. Data from this cohort are very encouraging with a high CMR rate observed in patients with R/R FL. These data are consistent with prior results from the EPCORE NHL-2 trial and supportive of ongoing investigation of epcoritamab + R2 in patients with R/R FL. A phase 3 trial of epcoritamab + R2 compared with R2 alone in patients with R/R FL (EPCORE FL-1) will open in 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Personalized Prophylaxis with Simoctocog Alfa in Adult Japanese Previously Treated Patients with Severe Hemophilia a

Background: It is recommended that hemophilia A patients with a severe phenotype are treated with regular prophylaxis in order to prevent bleeds, and ideally prophylaxis should be individualized. The NuPreviq study (GENA-21) conducted in Europe showed that pharmacokinetic (PK)-guided personalized prophylaxis with simoctocog alfa (Nuwiq Esplorhem Study Design and Progress: Evaluation®) provides excellent bleeding protection, with 83% of patients having zero spontaneous bleeds during 6 months of prophylaxis. The GENA-21b study conducted also in North America and Japan further assessed personalized prophylaxis with simoctocog alfa; patients in Japan who took part on the study were also eligible to enter a long-term extension study. Aim: To assess the long-term efficacy and safety of simoctocog alfa in Japanese patients receiving personalized prophylaxis with simoctocog alfa. Methods: GENA-21b was a prospective, open-label, multicenter, phase 3b study investigating the efficacy and safety of personalized prophylaxis with simoctocog alfa in previously treated adult patients with severe hemophilia A. Male patients ≥18 years of age with severe hemophilia A (FVIII:C <1%) who have been previously treated with any FVIII products for at least 150 exposure days were eligible for this study. The study consisted of three phases: a 72-hour initial PK evaluation phase, a 1-3-month standard prophylaxis phase, and a 6-month personalized prophylaxis phase. After 6 months of personalized prophylaxis, Japanese patients were eligible to enter an optional extension phase. During the personalized prophylaxis phase, the dose and dosing interval were recommended for each patient based on their individual PK data. The primary outcome was the annualized bleeding rate (ABR) for total bleeds. Results: 58 patients were enrolled in the GENA-21b study, including 11 Japanese patients. In the 6 months prior to entering the study, all 11 Japanese patients had received FVIII prophylaxis, with a mean (SD) weekly dose 91.9 (30.9) IU/kg and a mean (SD) ABR of 7.5 (11.7). Of the patients enrolled, 56 received personalized prophylaxis, including 10 Japanese patients. The mean (SD) terminal half-life, as measured using the one-stage assay was 17.2 (4.6) h in the 10 Japanese patients compared with 15.6 (3.9) in all 56 patients. During personalized prophylaxis with simoctocog alfa, the median (interquartile range [IQR]) ABR in the Japanese patients was 3.04 (0-7.69) for total bleeds, 0 (0-5.99) for spontaneous bleeds, and 0.98 (0-5.99) for joint bleeds. 70% of Japanese patients were treated twice weekly or less while on personalized prophylaxis, with a median weekly dose that was 14% lower than during standard prophylaxis (94 vs 106 IU/kg). 9 patients entered the extension phase and remained on simoctocog alfa prophylaxis for a further 2.1 years. During the extension phase, the median (IQR) total ABR was 16% lower than during the personalized prophylaxis phase (1.76 [0-6.30] vs 2.09 [0-5.99]). The median (IQR) ABRs for spontaneous bleeds were 0.81 (0-3.36) and for joint bleeds were 0.84 (0-1.74) during the extension phase. There were no treatment-related serious adverse events, no inhibitors, and no adverse events that lead to the discontinuation of simoctocog alfa. Conclusions: Personalized prophylaxis with simoctocog alfa was efficacious in a sub-population of Japanese patients, and no treatment-related serious adverse events were reported during long-term prophylaxis. A high proportion of the patients were treated twice weekly or less. Notably, the mean ABRs decreased during long-term prophylaxis.

Factors Associated With Willingness to Use Daily Antibiotics as Sexually Transmitted Infection Prophylaxis Among HIV Preexposure Prophylaxis-Experienced Gay and Bisexual Men in Australia.

Gay and bisexual men (GBM) who use HIV preexposure prophylaxis (HIV-PrEP) have high rates of bacterial sexually transmitted infections (STIs). The use of daily antibiotics as STI preexposure prophylaxis (STI-PrEP) may be appealing to GBM who are using or have previously used HIV-PrEP (HIV-PrEP-experienced) for the prevention of bacterial STIs. We examined willingness to use daily STI-PrEP among a cross-sectional sample of HIV-PrEP-experienced GBM in Australia who participated in an observational online cohort study from August 2018 to March 2020. Factors associated with willingness to use daily STI-PrEP were determined using bivariate and multivariate logistic regression. Of the 1347 participants, half (54.3%) were willing to use daily STI-PrEP. Factors independently associated with greater willingness to use daily STI-PrEP included having >10 sexual partners in the last 6 months, using methamphetamine in the last 6 months, being more conscious about avoiding STIs, having a greater number of STIs since commencing HIV-PrEP, being willing to take HIV-PrEP for as long as they were at risk of acquiring HIV, and only using condoms when a sexual partner requested them. Conversely, factors associated with less willingness to use daily STI-PrEP included being university educated, using nondaily dosing regimens of HIV-PrEP, preferring event-driven HIV-PrEP, and being concerned about long-term HIV-PrEP adverse effects. Sexually transmitted infection PrEP is likely to be appealing to many HIV-PrEP-experienced GBM, especially those who engage in activities associated with a higher risk of STI transmission. However, they are less likely to be willing to use STI-PrEP unless it aligns with their HIV-PrEP dosing regimen, suggesting that research into the safety and efficacy of alternative STI prophylaxis dosing options should be prioritized.

Improved survival after single-unit cord blood transplantation using fludarabine and melphalan-based reduced-intensity conditioning for malignant lymphoma: impact of melphalan dose and graft-versus-host disease prophylaxis with mycophenolate mofetil.

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100mg/m2) and FM140 (melphalan dose: 140mg/m2), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.

A Case of Deep Vein Thrombosis After Recovery From COVID-19 and Its Association With Elevated D-dimers

The coronavirus disease 2019 (COVID-19) continues to be a devastating disease for the elderly population, especially in long-term care facilities, and it presents with varying clinical presentations. We have ample evidence that COVID-19 can predispose to deep vein thrombosis (DVT) and pulmonary embolism (PE) during an active infection. Still, very few cases of DVT have been reported after recovery from COVID-19. The imbalance of the coagulation cascade and the increased release of certain coagulation factors play an essential role in promoting hypercoagulability and vascular endothelial dysfunction. It leads to a rise in the level of fibrin degradation products, D-dimers, which can remain elevated for up to several weeks, even after recovery. It has been suggested that the risk of DVT occurring after recovering from COVID-19 remains high for up to three months. We report a case of a 77-year-old long-term care female resident at a nursing facility, ambulatory at baseline, who was noted to be COVID-19 positive upon routine facility-wide testing per department of health guidelines. She was asymptomatic during her 10-day quarantine period. D-dimer levels during routine labs were high (initial D-dimer level of 1.87 mg/L FEU {normal value: 0.19-0.52 mg/L FEU}), but the patient had no clinical signs and symptoms of DVT. Ultrasound of the bilateral legs was not performed due to low clinical suspicion. The patient received an enoxaparin DVT prophylaxis dose during the quarantine period. Follow-up D-dimer levels were done at frequent intervals after recovery, but D-dimer levels continued to remain elevated up till six weeks after her 10-day quarantine period ended.Based on previous experience with other long-term care residents who suffered from COVID-19, bilateral lower extremity ultrasound was performed, which showed bilateral DVT. Elevated D-dimer levels are a predictor of hypercoagulation complications in COVID-19. Patients with persistently elevated D-dimer levels after recovery from COVID-19 should be screened for thromboembolic complications, even if they are asymptomatic. DVT can occur up to three months post-recovery from COVID-19 infection.

IBCL-460 Subcutaneous Epcoritamab With Rituximab + Lenalidomide (R2) in Patients With Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Update from Phase 1/2 Trial

R/R FL is associated with a poor prognosis and remains incurable; thus, better treatment options are needed. Epcoritamab is a subcutaneously administered CD3xCD20 bispecific antibody that has shown substantial antitumor activity in R/R FL. Evaluate safety and efficacy of epcoritamab with R2 in patients with R/R FL in arm 2 of a phase 1/2 open-label trial (EPCORE NHL-2; NCT04663347). Adults with R/R CD20+ FL were included. As of December 1, 2021, 30 patients (median age, 68 y) had enrolled. Patients received subcutaneous epcoritamab (QW, cycle [C] 1-3; Q2W, C4-9; Q4W, C≥10 up to 2 y) + R2 for 12 cycles of 28 d. Step-up dosing and corticosteroid prophylaxis were required. Of the 30 patients (epcoritamab 24 mg, n=3; 48 mg, n=27), 21 (70%) had stage IV disease and 20 (67%) had FLIPI scores 3-5. Median (range) number of prior lines of therapy was 1 (1-5), 30% had primary refractory disease, and 40% had disease progression within 24 mo after starting first-line treatment. At a median (range) follow-up of 5.1 mo (0.8-12.3), 25 patients (83%) remained on treatment; 5 patients discontinued treatment due to progression (n=2), AEs (n=2), or consent withdrawal (n=1). Common treatment-emergent AEs (TEAEs) of any grade (G) included infections (57%), injection-site reactions (50%), constipation (37%), fatigue (37%), and neutropenia (37%). CRS events occurred in 15 patients (50%; G1-2 43%, G3 7%), primarily in C1. All CRS events resolved; 3 patients were treated with tocilizumab, and 1 patient discontinued treatment due to CRS. One patient experienced G2 ICANS. No fatal TEAEs occurred. Overall response rate for the 27 evaluable patients was 100%; 93% had a complete metabolic response (CMR) and 7% had a partial metabolic response by PET-CT. As of the data cut, the longest duration of response was 7.0+ mo and ongoing. Subcutaneous epcoritamab + R2 exhibits promising efficacy, including a high CMR rate, in patients with R/R FL. The safety profile was consistent with prior data. Updated data will be presented. This study was funded by Genmab A/S and AbbVie.

ABCL-452 First-Line Treatment With Subcutaneous Epcoritamab + R-CHOP in Patients With High-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Phase 1/2 Data Update

Patients with newly diagnosed high-risk DLBCL have suboptimal outcomes. Subcutaneous epcoritamab is a CD3xCD20 bispecific antibody well suited for combination with standard of care therapies. Evaluate safety and efficacy of epcoritamab + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in previously untreated patients with high-risk DLBCL in arm 1 of a phase 1/2, open-label trial (EPCORE NHL-2; NCT04663347). Adults with previously untreated CD20+ DLBCL and IPI ≥3 were included. As of December 1, 2021, 33 patients (median age, 66 y) had enrolled. Patients received subcutaneous epcoritamab (QW, cycles 1-4; Q3W, cycles 5-6) + R-CHOP for 6 cycles (21 d) followed by epcoritamab monotherapy Q4W up to 1 y (in cycles of 28 d). Step-up dosing and corticosteroid prophylaxis were required. All 33 patients treated (epcoritamab 24 mg, n=4; 48 mg, n=29) had IPI ≥3, and ≥24% had double/triple-hit DLBCL. Median follow-up was 3 mo (range, 0-9.7), median number of total cycles initiated was 5 (1-13), and 94% of patients (31/33) remained on treatment. Treatment-emergent AEs (TEAEs) in ≥35% of patients were neutropenia (48%; febrile neutropenia in 9% of all patients), CRS (45%), infections (42%), anemia (39%), and injection-site reactions (36%). No TEAEs led to epcoritamab discontinuation. Most CRS events were low grade (42% grade [G] 1-2, 3% G3), occurred in cycle 1, and resolved after a median of 2 d (1-11); 4 patients received tocilizumab. G2 ICANS occurred in 1 patient. No fatal TEAEs occurred. In efficacy-evaluable patients, the overall response rate (ORR) was 96% (24/25); 68% (17/25) had complete metabolic response (CMR) by PET-CT. In the 10 patients who completed 6 cycles of R-CHOP by the cutoff date, ORR and CMR rate were 100% and 90%, respectively; all patients remained in response at data cutoff (longest duration of response, 7.1+ mo, ongoing). Epcoritamab + R-CHOP had manageable safety, mostly low-grade CRS that did not lead to treatment discontinuation, and high response rates in patients with previously untreated DLBCL. Updated data will be presented. This study was funded by Genmab A/S and AbbVie.

Venous Thromboembolic Disease in COVID-19, Pathophysiology, Therapy and Prophylaxis.

For over two years, the world has been facing the epidemiological and health challenge of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Growing problems are also complications after the development of COVID-19 in the form of post and long- COVID syndromes, posing a challenge for the medical community, both for clinicians and the scientific world. SARS-CoV-2 infection is associated with an increased risk of cardiovascular complications, especially thromboembolic complications, which are associated with both thrombosis of small and very small vessels due to immunothrombosis, and the development of venous thromboembolism. Low molecular wight heparin (LMHW) are the basic agents used in the prevention and treatment of thromboembolic complications in COVID-19. There is still a great deal of controversy regarding both the prevention and treatment of thromboembolic complications, including the prophylaxis dose or the optimal duration of anticoagulant treatment in patients with an episode of venous thromboembolism.