Durability In Patients Research Articles

Dupilumab Induces Long-term On-Treatment Clinical Remission in Patients With Type 2 Asthma

Remission is proposed as a multicomponent outcome for patients with severe asthma. This post hoc analysis of QUEST (NCT02414854) and TRAVERSE (NCT02134028) evaluated whether dupilumab treatment leads to clinical asthma remission (≥12 months with no severe exacerbations, zero oral corticosteroid use, stabilized or improved lung function, patient-reported asthma control <1.5) and assessed its durability in patients with uncontrolled, moderate to severe type 2 asthma (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide ≥20 ppb at parent-study baseline) who are not receiving maintenance oral corticosteroids. In QUEST, patients (aged ≥12 years) were randomized to dupilumab 200/300 mg or placebo every 2 weeks for 52 weeks. In TRAVERSE, all patients received dupilumab 300 mg every 2 weeks for up to 96 weeks. We assessed the proportion of patients meeting criteria for on-treatment clinical remission up to 48 weeks of TRAVERSE. At QUEST baseline, 1,040 patients receiving dupilumab and 544 taking placebo had type 2 asthma; of those, 842 (dupilumab/dupilumab) and 437 (placebo/dupilumab) enrolled in TRAVERSE. At QUEST week 52 (year 1), 37.2% of patients receiving dupilumab met clinical remission criteria, compared with 22.2% taking placebo (all P < .001). At week 48 of TRAVERSE (year 2 overall), 42.8% (dupilumab/dupilumab) and 33.4% (placebo/dupilumab) of patients met clinical remission criteria. Overall, 29.5% of patients in the dupilumab/dupilumab group met the criteria at both years 1 and2. Dupilumab treatment enabled approximately one third of patients with type 2 asthma to meet the multicomponent end point for on-treatment clinical asthma remission for up to 2 years.

Dupilumab response onset, maintenance, and durability in patients with severe CRSwNP

Responder analyses of SINUS phase 3 study data have shown clinically meaningful improvements across multiple outcomes of treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) with dupilumab. Our aim was to gain a better understanding of dynamics of the response to dupilumab over 52 weeks. We used data from the SINUS-52 (ClinicalTrials.gov identifier NCT02898454) intention-to-treat population to perform a post hoc analysis of patients with severe CRSwNP who had received dupilumab, 300 mg once every 2 weeks, or placebo. Response, which was defined as an improvement from baseline of a least 1 point in Nasal Polyp Score (NPS), nasal congestion (NC) score, and loss of smell (LoS) score, as well as an improvement of at least 8.9 points on the 22-Item Sino-Nasal Outcome Test (SNOT-22), was assessed for rapidity, maintenance, and durability. The study included 303 patients (150 of whom received dupilumab and 153 of whom received placebo). For each outcome measure, a greater proportion of patients achieved a first response by week 16 (rapidity) with dupilumab versus with placebo; specifically, the respective differences in indicators between the 2 groups by week 16 were as follows: NPS, 75.3% versus 39.2%; NC score, 60.0% versus 24.2%; LoS score, 60.7% versus 15.7%; and SNOT-22 score, 83.3% versus 66.0%. Of those patients given dupilumab who had a response by week 16, more than 80% maintained their response at week 52 (maintenance). Over 52 weeks, greater proportions of those patients given dupilumab were responders on at least 80% of time points; specifically, the respective differences in indicators between the 2 groups by week 16 were as follows: NPS, 46.7% versus 2.6%; NC score, 46.7% versus 9.2%; LoS score, 47.3% versus 3.9%; and SNOT-22 score, 62.0% versus 21.6% (durability). Most patients with CRSwNP achieve clinically meaningful responses to dupilumab by week 16, and most such patients in our study had maintenance and durability of response with continued treatment over time.

Pulmonary vein isolation durability in patients undergoing very high-power short-duration temperature-controlled ablation

Abstract Background The very high-power short-duration (90W for 4 s) temperature-controlled ablation (vHPSD) improves the efficiency of pulmonary vein (PV) isolation procedures. However, atrial fibrillation (AF) recurrences directly related to PV reconnections are still a concern. Purpose The purpose of the current study was to assess PV lesion durability in patients undergoing a reablation procedure. Methods From September 2020 to July 2023, 327 patients with paroxysmal and persistent AF underwent first ablation aiming at PVI using vHPSD. During a mean follow-up of 25±11 months, 48 patients (14.7%) had an AF recurrence. Patients with reablation procedures were retrospectively consented and enrolled. Results Eighteen patients were included in this study. A PV reconnection was observed in 15/72 (21%) PVs, with a mean number of reconnected PV per patient of 0.8 ±0.7. In 7 patients no PV reconnection was observed, one PV reconnected was observed in 9 patients and 2 PVs in 3 patients. A PV reconnection was observed in 8/18 (44%) left superior PV, 1/18 (6%) left inferior PV, 3/18 (17%) right superior PV, and 3/18 (17%) right inferior PV (p=0.03). Conclusions PV isolation performed with vHPSD is highly effective and is associated with a low rate of late PV reconnection. A higher percentage of PV reconnection was observed in the left superior PV.

Pulsed field ablation for atrial fibrillation: efficacy, safety and lesion durability in patients with recurrences

Abstract Background Initial findings from feasibility studies regarding pulsed field ablation (PFA) for atrial fibrillation (AF) indicated substantial efficacy and safety of the procedure, including high rates of lesion durability upon systematic remapping. However, data regarding PFA for AF in real-life settings remains scarce. Objective This pooled analysis was conducted to provide insights into PFA’s practical performance and safety profile in real-life settings, as well as information regarding lesion durability in patients with arrhythmia recurrences. Methods MEDLINE/EMBASE databases were searched up to August 31, 2023 for studies including patients undergoing catheter ablation for AF using PFA. Independent searches were performed by 2 investigators (K.B. and K.V.). Feasibility studies, first-in-human studies, small studies with population overlap, and those with a follow-up duration shorter than one year were excluded from the analysis. Authors were contacted for missing information or to confirm the absence of population overlap. Two investigators (K.B. and K.V.) independently extracted data from studies meeting inclusion criteria. Any discrepancies were resolved by a third experienced reviewer. Results We assessed for relevance a total of 952 references. Five studies met the inclusion criteria (comprising of 1 randomized trial, 2 single arm prospective trials, and 2 post-market registries), with a combined cohort of 2,359 patients who underwent PFA for AF. The pooled rate of acute PVI was 99.6% (95%CI 99.2-99.8, I2:7%). The pooled one-year rates of freedom from atrial arrhythmia for individuals with paroxysmal or persistent AF were 79.5% (95%CI 75.7-83.1, I2:70%) and 67.5% (95%CI 60.9-73.7, I2:60%), respectively. Among patients who underwent repeat catheter ablation for AF recurrences (n=197), the pooled rate of durable PVI per patient was 48.9% (95%CI 30.4-67.7, I2:71%), while durable PVI per vein was 74.1% (95%CI 65.1-82.2, I2: 75%). Incidence of overall complications and serious procedure-related complications were 1.8% (95% CI: 0.2-4.8, I2: 92%) and 0.9% (95% CI: 0.3-1.7, I2:59%), respectively. The most prevalent complication types were access site complications (48.6%), pericardial effusions/tamponades (24.8%) and stroke/transient ischemic attack (9.5%). No esophageal damage or PV stenosis were reported . There was one case of persistent phrenic nerve palsy and two cases of reversible coronary spasm (during ablation along the posterior mitral isthmus, and during PVI, both resolving with intracoronary nitroglycerin). Conclusion This pooled analysis confirms that catheter ablation of atrial fibrillation using pulsed field ablation is associated with high rates of atrial arrhythmia-free survival at one year while maintaining low rates of procedure-related complications. Durable pulmonary vein isolation is observed in approximately half of the patients undergoing a repeat procedure for atrial fibrillation recurrence.

Durability of thermal pulmonary vein isolation in persistent atrial fibrillation assessed by mandated repeat invasive study

BackgroundNo study has assessed the durability of pulmonary vein isolation (PVI) with radiofrequency (RF) and cryoballoon (CB) in patients with persistent atrial fibrillation. These data are especially lacking for those with significantly diseased left atria (LA). ObjectivesThe goals of this study were to assess PVI durability in patients with significant LA disease and to compare reconnection rates between RF and CB. MethodsForty-four patients (mean age 63 years; 34 (77%) male; median time since atrial fibrillation diagnosis 22.5 months; median indexed LA volume 36 mL/m2) were randomized 1:1 to RF or CB PVI. A redo procedure using ultra-high-density electroanatomic mapping was mandated at 2 months, where PV reconnections were identified and reisolated. ResultsThirty-eight patients underwent both procedures (CB n = 17; RF n = 21). Index RF procedures were longer (median 158 minutes vs 97 minutes; P < .001) but required less fluoroscopy (9.5 minutes vs 23 minutes; P < .001). At the index RF procedure, a median of 47% of LA myocardium had voltage < 0.5 mV, suggesting that half of the mapped LA comprised scar. PV reconnection was observed in 73 of 152 PVs (48.0%) and was more frequent with CB (58.8%) than with RF (39.3%) (P = .022). Reconnection of at least 1 PV was detected in >75% of patients. Significantly more ablation was required during the redo procedure to reisolate PVs in the CB arm (median 10.8 minutes vs 1.2 minutes; P < .001). ConclusionPVI durability may be poor in those with significant LA scarring and dilatation, even with modern thermal ablation technologies. RF resulted in significantly better PVI durability than did CB in this complex population.

Outcomes of severely ill patients with AIDS treated with efavirenz or dolutegravir: a multicenter, observational study.

Currently, integrase inhibitors (INIs)-based ART regimens are the preferred initial therapy for AIDS patients. There is scarce information on the use of dolutegravir (DTG) among late-presenter people living with HIV (PLHIV). To compare the effect of DTG- or efavirenz (EFV)-based regimens on the outcomes of patients with advanced AIDS. We compared two cohorts of consecutive symptomatic AIDS patients (WHO stage 4, CD4 count<50 cells/mL) starting therapy with DTG-based (2018-2021, prospective cohort) or EFV-based regimens (2013-2016, retrospective cohort) from five Brazilian cities. The main endpoints were early (all-cause) mortality, viral suppression at 24 and 48 weeks, changes in CD4 count, and changes in initial therapy (for any reason). We included all eligible patients in a consecutive way (in both groups) until we reached 92 individuals per arm. The median baseline CD4 count (20 vs. 21 cells/mL) and the median HIV plasma viral load (5.5 copies/mL log10) were identical across the groups. Viral suppression rates were higher in the DTG group than in the EFV group at 24 (67.4% vs. 42.4%,) and 48 weeks (65.2% vs. 45.7%, p < 0.001 for both comparisons). More patients in the DTG group presented with CD4 > 200 cells/mL compared to the EFV group at 48 weeks (45% vs. 29%, p = 0.03). Treatment changes (ITT, M = F) were significantly more frequent in the EFV group (1% vs. 17%, p < 0.0001). The relative mortality rate was 25% lower in the DTG group, but without statistical significance. We detected a higher rate of virological suppression and greater treatment durability in patients with advanced AIDS treated with DTG than in those treated with EFV.

Pulsed field ablation for atrial fibrillation in real-life settings: Efficacy, safety, and lesion durability in patients with recurrences

Pulsed field ablation for atrial fibrillation in real-life settings: Efficacy, safety, and lesion durability in patients with recurrences

Pulmonary Valve Replacement in Tetralogy of Fallot: Procedural Volume and Durability of Bioprosthetic Pulmonary Valves

BackgroundRobust data on changes in pulmonary valve replacement (PVR) procedural volume and predictors of bioprosthetic pulmonary valve (BPV) durability in patients with tetralogy of Fallot (TOF) are scarce. ObjectivesThis study sought to assess temporal trends in PVR procedural volume and BPV durability in a nationwide, retrospective TOF cohort. MethodsData were obtained from patient records. Robust linear regression was used to assess temporal trends in PVR procedural volume. Piecewise exponential additive mixed models were used to estimate BPV durability, defined as the time from implantation to redo PVR with death as a competing risk, and to assess risk factors for reduced durability. ResultsIn total, 546 PVR were performed in 384 patients from 1976 to 2021. The annual number of PVR increased from 0.4 to 6.0 per million population (P < 0.001). In the last decade, the transcatheter PVR volume increased by 20% annually (P < 0.001), whereas the surgical PVR volume did not change significantly. The median BPV durability was 17 years (Q1: 10-Q3: 10 years-not applicable). There was no significant difference in the durability of different BPV after adjustment for confounders. Age at PVR (HR: 0.78 per 10 years from <1 year; 95% CI: 0.63-0.96; P = 0.02) and true inner valve diameter (9-17 mm vs 18-22 mm HR: 0.40; 95% CI: 0.22-0.73; P = 0.003 and 18-22 mm vs 23-30 mm HR: 0.59; 95% CI: 0.25-1.39; P = 0.23) were associated with reduced BPV durability in multivariate models. ConclusionsThe PVR procedural volume has increased over time, with a greater increment in transcatheter than surgical PVR during the last decade. Younger patient age at PVR and a smaller true inner valve diameter predicted reduced BPV durability.

Neuroforaminal Stenosis in the Lumbosacral Spine: A Scoping Review of Pathophysiology, Clinical Manifestations, Diagnostic Imaging, and Treatment

OBJECTIVE To conduct the first scoping review of lumbosacral neuroforaminal stenosis with respect to the pathophysiology, symptomatic manifestations, diagnostic imaging, and treatment options. METHODS A scoping literature review was conducted in accordance with the recommendations set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), with English language restrictions stipulated to include articles pertaining to lumbosacral neuroforaminal stenosis. Databases maintained by PubMed, National Library of Medicine, Cochrane Central Register of Controlled Trials (Ovid), Scopus (Elsevier), Web of Science (Thomson Reuters), and Google Scholar were queried from their inception date through December 2022. SUMMARY OF THE EVIDENCE A total of 276 articles were reviewed and 29 articles were included within the study. Within these articles, the anatomic origins of neuroforaminal stenosis were reviewed in detail and the resulting clinical manifestations were discussed. Recent studies evaluating the efficacy of existing diagnostic imaging modalities were summarized, along with potential future methods to improve sensitivity for detecting this entity and measuring foraminal stenosis via novel imaging techniques. Based on the literature, the conservative management and surgical treatment of lumbosacral foraminal stenosis were discussed. CONCLUSIONS Lumbar neuroforaminal stenosis represents a significant source of radicular pain that is often compounded by delayed diagnosis and incomplete treatment. This article represents the first scoping review of lumbosacral neuroforaminal stenosis with focus on diagnosis, management, and treatment for associated radicular pain. The goal is to reduce the incidence of untreated or unrecognized neuroforaminal stenosis in the setting of a complex decompression and fusion, as well as to promote minimally invasive surgery to address radicular pain from neuroforaminal stenosis. Recent advances in diagnostic imaging and surgical techniques have the potential to improve the timeliness and durability of patients’ treatment options. Future directions for the diagnostic imaging of foraminal stenosis include efforts aimed at developing the nascent field of computerized mapping to reliably quantify stenosis and its impact on the exiting nerve root and associated dorsal root ganglia.

Jejunal levodopa infüzyonu alan Parkinson hastalarında PEG-J tüpünün kısa ve uzun dönem güvenilirliği ve devamlılığı

Aims: To investigate PEG-J related adverse events and tube durability in patients with Parkinson’s disease who underwent PEG-J procedure for jejunal drug infusion. &#x0D; Methods: PEG-J implanted patients, who were planned jejunal levodopa infusion, were included in the study. The demographic characteristics of the patients, tube durability, tube replacement, reason for tube replacement, number of procedures, and adverse events related to procedures were retrospectively analyzed. &#x0D; Results: Thirty-four patients with a mean age of 65.7±9.8 years included in the study. The mean total PEG-J follow-up period of the patients was 33.6±21.1 months. Functions of PEG-J tubes were preserved in 82.5% at 6 months, 78.4% at 12 months, and 65.2% at 18 months. Twenty-one (% 61,8) patients required at least one PEG-J replacement. Of the PEG-J replacements, 90.4% were due to device-related advers events. A total of 29 procedure or stoma related adverse events occurred in 21 (61.8%) patients, and a total of 28 PEG-J tube related adverse events occurred in 19 (55.9%) patients. A total of 6 (17.5%) early procedure-related adverse events (acute abdomen and peritonitis, prolonged bleeding, stoma leakage, stoma infection) were observed, all occurring in the first 7 days. Twenty-three (67.6%) stoma-related late adverse events (stoma leakage, stoma infection, abscess) were detected. Two patients who developed peritonitis were successfully treated with conservative treatments.&#x0D; Conclusion: PEG-J used for drug application is a safe method and can be used for a long time without the need for frequent replacement. Most of advers events can be managed with conservative treatments.

Survival and repair durability in patients undergoing concomitant aortic valve reimplantation and mitral valve repair

ObjectiveThe study objective was to determine repair durability and survival in patients with and without connective tissue disorders undergoing concomitant aortic valve reimplantation and mitral valve repair. MethodsFrom 2002 to 2019, 68 patients underwent concomitant aortic valve reimplantation and mitral valve repair, including 27 patients with Marfan syndrome (39.7%). Follow-up echocardiograms were analyzed using nonlinear multiphase mixed-effects cumulative logistic regression. The regurgitation grade over time was estimated by averaging patient-specific profiles. Survival and freedom from reoperation were estimated by the Kaplan–Meier method. ResultsAt 7 years, 11% of patients had aortic insufficiency greater than mild (severe in 2 patients). There was no difference in greater than mild aortic insufficiency between patients with or without Marfan syndrome (P = .37). Twenty percent of patients had progressed to mitral regurgitation greater than mild (severe in only 1 patient). The prevalence of recurrent mitral regurgitation was higher in those without Marfan syndrome, with greater than mild regurgitation increasing to 24% by 2 years and remaining constant thereafter (P = .04). Freedom from reoperation on the aortic valve or mitral valve was 83% at 10 years and did not differ between Marfan syndrome groups. There were no cases of perioperative mortality. Survival at 5 and 10 years was 94% and 87%, respectively, without a difference between those with and without Marfan syndrome. ConclusionsPatients can undergo a total repair strategy using combined aortic valve reimplantation and mitral valve repair procedures with a low risk of mortality and complications, with favorable freedom from both residual valve regurgitation and reoperation.

BALATON and COMINO: Phase III Randomized Clinical Trials of Faricimab for Retinal Vein Occlusion: Study Design and Rationale.

Dual inhibition of angiopoietin-2 and VEGF-A with faricimab (Vabysmo) offers excellent visual acuity gains with strong durability in patients with diabetic macular edema (ME) and neovascular age-related macular degeneration. The phase III BALATON/COMINO (NCT04740905/NCT04740931) trials will investigate the efficacy, safety, and durability of faricimab in patients with ME due to retinal vein occlusion (RVO). Two identically designed global, randomized, double-masked, active comparator-controlled studies. Anti-VEGF treatment-naive patients with branch, central, or hemiretinal RVO. Patients were randomized to 6 monthly injections of faricimab 6.0 mg or aflibercept 2.0 mg. From weeks 24 to 72, all patients received faricimab 6.0 mg administered in up to 16-week intervals using an automated treatment algorithm to generate a treat-and-extend-based personalized treatment interval dosing regimen. Personalized treatment interval adjustments were based on changes in central subfield thickness (CST) and best-corrected visual acuity (BCVA). Primary end point was noninferiority of faricimab versus aflibercept in mean change from baseline in BCVA (week 24; noninferiority margin: 4 letters). Secondary end points (weeks 0-24) were mean change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire 25 composite score; proportion of patients gaining or avoiding loss of ≥ 15/≥ 10/≥ 5/> 0 letters. Secondary end points (weeks 24-72) were treatment durability (week 68); continuation of weeks 0 to 24 end points. Ocular/nonocular adverse events will be assessed. In total, 1282 patients across 22 countries were enrolled (BALATON, 553 patients, 149 centers; COMINO, 729 patients, 193 centers). Using a novel automated interval algorithm, BALATON/COMINO will evaluate the efficacy and safety of faricimab for ME secondary to RVO and provide key insights into how to personalize treatment. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Pulsatile Deformations of a Conformable Descending Thoracic Aortic Endograft in Aneurysm, Dissection, and Blunt Traumatic Aortic Injury Patients.

This study presents analytic techniques to quantify cardiac pulsatility-induced deformations of thoracic aortic endografts in patients with thoracic aortic aneurysm (TAA), dissection (TAD), and blunt thoracic aortic injury (BTAI) after thoracic endovascular aortic repair (TEVAR). We analyzed 19 image data sets from 14 patients treated for TAA, TAD, and BTAI with cardiac-gated post-TEVAR CTs. Systolic and diastolic geometric models were constructed and diametric, axial, and bending deformations were quantified. For patients with cardiac-gated pre-op scans, the damping of pulsatile diametric distension was computed. Maximum localized diametric distension was 2.4±1.0%, 4.2±1.7%, and 5.5±1.6%, and axial deformation was 0.0±0.1%, -0.1±0.3%, and 1.1±0.6% in the endografts of TAA, TAD, and BTAI cohorts, respectively. Diametric distension damping from pre- to post-TEVAR was ~50%. Diametric and bending deformations were localized at certain axial positions on the endograft, and the inner curve bends more than the centerline, especially adjacent to overlapping regions. The presented techniques support investigation of multi-axial endograft deformations between disease causes and geometric locations on the device. Discretized quantification of deformation is needed to define device fatigue testing conditions and predict device durability in patients. This study demonstrates analytic techniques to quantify discretized deformation of thoracic endografts. Cardiac-resolved computed tomography is sometimes acquired for surgical planning and follow-up, however, the dynamic data are not typically used to quantify pulsatile deformations. Our analytic techniques extract the centerline and surface geometry of the stented thoracic aorta during the cardiac cycle, which are used to quantify diametric, axial, and bending deformations to provide better understanding of device durability and impact on the native anatomy.

Triplex ELISA for Assessing Durability of Taenia solium Seropositivity after Neurocysticercosis Cure.

Neurocysticercosis prevalence estimates often are based on serosurveys. However, assessments of Taenia solium seropositivity durability in patients with various neurocysticercosis types are lacking. We optimized a triplex serologic ELISA by using synthetic GP50, T24H, and Ts18var3 antigens for T. solium. We used that assay to test sequential serologic responses over several years after neurocysticercosis cure in 46 patients, 9 each with parenchymal or ventricular neurocysticercosis and 28 with subarachnoid disease. Triplex results were concordant with 98% of positive and 100% of negative enzyme-linked immunoelectrotransfer blots. Eight years after neurocysticercosis cure, 11.1% of patients with parenchymal, 47.3% with subarachnoid, and 41.7% with ventricular disease were still seropositive. Median time to seroreversion after cure in this cohort in a T. solium nonendemic area was 2 years for parenchymal disease, 4 years for ventricular disease, and 8 years for subarachnoid disease. Our findings can inform epidemiologic models that rely on serosurveys to estimate disease burden.

FEVAR Is Durable, Now Let’s Focus On the Patient’s Durability

FEVAR Is Durable, Now Let’s Focus On the Patient’s Durability

Ross versus Repair for Treatment of the Unicuspid Aortic Valve in Adults.

Aortic stenosis or regurgitation in patients with a unicuspid valve morphology require interventions early in life. We have performed either primary valve repair or the Ross procedure. The aim of this study was to compare the mid-term results of repair and pulmonary autograft replacement. Between 12/1998 and 04/2022, 345 patients (77% male; mean age 34±9.7 years) underwent treatment of a unicuspid aortic valve. Patients were excluded if they were <18 years (n = 84) or > 54 years (n = 3) at the time of the operation. The remaining cohort was divided into 2 groups: 167 (64%) patients underwent valve repair, 91 (36%) patients underwent pulmonary autograft replacement.The indications for surgery were aortic regurgitation (n = 104), aortic stenosis (n = 45), combined disease (n = 103), and endocarditis (n = 6). Fifty-one patients had root dilatation (>43mm) with aortic regurgitation (repair n = 23; Ross n = 28). Mean follow-up was 5.9 (SD: 5 years) [range 0.1 to 22.3 years]. There was 1 early, 3 late deaths, and 47 patients required reintervention. Survival at 10 years was 95% in the Ross group and 97% after valve repair (p = 0.769). Freedom from reintervention at 10 years was 98% in the Ross group and 80% after valve repair (p = 0.012). A ROC curve analysis showed a trend towards better durability in patients < 26 years. The ideal treatment of the unicuspid aortic valve remains debatable. Repair of a unicuspid valve can be considered a bridge to pulmonary autograft replacement, at least in younger patients. The appropriate time when to replace and when to repair requires further investigation.

Long-Term Valve Durability in Patients Undergoing Transcatheter Aortic Valve Implantation.

To evaluate the long-term incidence of structural valve deterioration (SVD) in patients who underwent transcatheter aortic valve implantation (TAVI). Between 2008 and 2018, 693 underwent TAVI at two centres. Four hundred and twenty-one (421) patients (mean age 83.6±6.0 yrs) survived for ≥2 years post TAVI and had at least two consecutive transthoracic echocardiographies (TTEs) with the latest TTE no less than 2 years after TAVI, and were therefore included in the analysis for SVD. Median follow-up was 4.7 (3.6-6.0) years and median echocardiography follow-up 3 (3.0-4.0) years. All-cause mortality was 30.9% (130) with a median time to death of 4.1 (3.0-5.6) years. The cumulative incidence of SVD increased from 1.7% (95% CI, 0.4-2.9) at 3 years to 3.5% (95% CI, 1.5-5.8) at 5 years and 4.7% (95% CI, 1.6-7.9) at 10 years. The overall median time to SVD was 3 (2-4) years. Twelve (12) patients demonstrated SVD stage 2, and 1 patient stage 3. No SVD required re-intervention. All other patients showed no significant changes in valve parameters over time. Structural valve deterioration is an uncommon event, occurring in 5% over a total follow-up of 10 years. Most patients show stable valve parameters. However, the analysis is limited by the loss of follow-up (owing to patient mortality), which renders extrapolation of the data to a younger patient population difficult.

Coaptation Length as Predictor of Recurrent Mitral Regurgitation After Surgical Repair for Degenerative Mitral Valve Disease: Meta-Analysis of Reconstructed Time-to-Event Data

Coaptation Length as Predictor of Recurrent Mitral Regurgitation After Surgical Repair for Degenerative Mitral Valve Disease: Meta-Analysis of Reconstructed Time-to-Event Data

A Phase 1 Study of ADI-001: Anti-CD20 CAR-Engineered Allogeneic Gamma Delta1 (γδ) T Cells in Adults with B-Cell Malignancies

Introduction: ADI-001 is a first-in-class allogeneic gamma delta (γδ) CAR T cell therapy targeting the B-cell antigen CD20. ADI-001 has both adaptive and innate cytotoxic effector functions to complement CAR targeting, potentially enhancing efficacy and reducing the possibility of tumor escape due to antigen loss. ADI-001 expresses MHC-independent γδ T cell receptors, thus lowering the risk of graft-versus-host disease (GvHD) without the need for gene editing. Methods: This multicenter phase 1 clinical trial is evaluating ADI-001 in adults with relapsed / refractory B-cell lymphoma. Eligibility criteria included the presence of measurable lesions, expression of CD20 on tumor cells and ≥ 2 prior systemic therapies. All patients received conditioning therapy with fludarabine and cyclophosphamide. ADI-001 can be administered at four dose levels (DL) (DL1:3E7, DL2:1E8, DL3:3E8 and DL4:1E9 CAR+ cells) in a 3+3 dose-escalation scheme. Patients who completed the 28-day DLT period were considered evaluable. In DL3, patients could receive a second course of conditioning therapy and be re-dosed with ADI-001 if there was no DLT during the first 28 days, no progressive disease on PET/CT assessment on Day 28, and have recovered from cytopenias. Treatment-emergent adverse events were graded by CTCAE v5.0, and Immune Effector Cell Associated Neurologic Syndrome (ICANS) and Cytokine Release Syndrome (CRS) assessments were performed per ASTCT criteria. Objective response rates (ORR) were evaluated by independent radiographic review per Lugano 2014 criteria. Results: As of 15 July 2022, 11 patients were enrolled and nine were evaluable. Of these nine patients, six (67%) were male and the median age was 62 years (range 45-75). Eight patients had large B-cell lymphoma (LBCL) and one had mantle cell lymphoma (MCL). Of the eight patients with LBCL, five had diffuse-large B-cell lymphoma (DLBCL), two had high-grade B-cell lymphoma (HGBCL) with double/triple hit, and one had HGBCL not otherwise specified. At baseline, the median IPI score was four (range 2-4); the median tumor burden was 2,974 (150-7,919) mm2, and 89% (8/9) had stage III/IV disease. The median number of prior therapies was four (range 2-5). Four patients had prior anti-CD19 CAR T cell therapy (two Liso-cel and two Axi-cel). Among nine evaluable patients, three patients were treated at each of DL1, DL2, and DL3. Two patients at DL3 were re-dosed with a second course of ADI-001. Two patients developed CRS: one Grade 1 and one Grade 2. One patient developed a Grade 1 ICANS which resolved within 24 hours. There were no ≥ Grade 3 CRS or ICANS. The only related SAEs were Grade 2 CRS, Grade 1 ICANS and Grade 3 adenoviraemia. There was no reported GvHD or protocol-defined DLT events. The best ORR was 78% (7/9), and the complete response (CR) rate was 78% (7/9). For the four patients who had prior CD19 CAR T therapies, the ORR was 100% (4/4) and CR rate was also 100%. As of the data cut-off date, of the seven patients who had achieved CR, two patients progressed, one died while in complete remission and four were still in CR and in active follow-up, with a range of follow-up time between 1.2 and 8.8 months. CAR+ γδ T cell kinetics improved in a dose-dependent manner with peak cell expansion occurring between Days 7 and 10 at DL3 based on flow cytometry. Conclusions: ADI-001 γδ CAR T cells maintained a favorable safety profile. Preliminary efficacy showed encouraging CR rate and sustained durability in patients, including those previously exposed to CAR T therapy. Additional data will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MM-087 Early, Deep, and Durable Responses, and Low Rates of Cytokine Release Syndrome With REGN5458, a BCMAxCD3 Bispecific Antibody, in a Phase 1/2 First-In-Human Study in Patients With Relapsed/Refractory Multiple Myeloma

Despite advances in treatment options, multiple myeloma remains incurable. REGN5458 is a BCMAxCD3 bispecific antibody under investigation in relapsed/refractory multiple myeloma (RRMM): ongoing Phase 1/2 trial (NCT03761108). To describe updated safety, overall response, and response durability in patients treated with REGN5458 in the Phase 1 part. The Phase 1 part follows a modified 3+3 dose-escalation design (4+3). Eligible patients with progressive RRMM, who were double- or triple-refractory, or intolerant to prior lines of systemic therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody, were included. Sixteen weekly infusions of REGN5458 monotherapy, then every two weeks until disease progression. Primary objectives were to assess safety, tolerability, and occurrence of dose-limiting toxicities of REGN5458, and to determine a recommended Phase 2 dose regimen. The objective response rate by modified International Myeloma Working Group criteria was a key secondary objective. At data cut-off (September 30, 2021), 73 patients were treated with REGN5458 in the dose-escalation cohort, with full doses ranging from 3-800 mg. The median age at enrollment was 64 years (range, 41-81). As per the Revised International Staging System, stages were 1, 2, or 3 in 15.0%, 57.5%, and 23.3% of patients, respectively. Patients had a median of five prior lines of systemic therapy (range, 2-17), with 89% of patients being triple-refractory. The median duration of follow-up was 3.0 months (range, 0.7-22.1). The most common treatment-emergent adverse events (TEAEs) were fatigue (45.2%), cytokine release syndrome (CRS) (38.4%), pyrexia (35.6%), and nausea (32.9%). There were no Grade ≥3 CRS or Grade ≥3 neurotoxicity events, and no treatment discontinuation due to CRS. Grade 3 and 4 TEAEs were reported in 31 (42.5%) and 24 patients (32.9%), respectively. The most common Grade 3/4 TEAEs were hematologic (39.0%). Responses were observed at all dose levels. Amongst patients treated at the 200-800 mg dose levels, the response rate was 75% (n=18/24). The median duration of response was not reached. REGN5458 shows early, deep, and durable responses with a manageable safety profile in triple or greater-refractory patients with RRMM. This study is funded by Regeneron.