Citations

Abstract Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms “nonalcoholic” and “fatty” were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

Abstract Funding Acknowledgements Type of funding sources: None. Background The impact of capacitance and blood volume redistribution on outcomes of patients with chronic heart failure is incompletely understood. Quantitative plasma volume (PV) measurements together with echocardiographic evaluation allow a comprehensive assessment of the interplay between volumetric overload, cardiac chamber remodelling and myocardial function. Purpose We hypothesize that PV expansion is associated with myocardial and renal dysfunction, right ventricular-pulmonary arterial uncoupling and unfavorable outcomes in HF patients with reduced ejection fraction (HFrEF). Methods Patients hospitalized at Mayo Clinic with decompensated HF and who had PV by the indicator-dilution nuclear methodology (Daxor BVA100) were included. Patients were considered hypervolemic if BV was ≥25% over expected. The primary endpoint was the composite of all-cause mortality or heart transplantation. The closest TTE to the time of PV was used to measure various indexes of myocardial performance (standard echo parameters and global chamber-specific strain parameters). Event-free survival was estimated using the Kaplan-Meier method. The relationship between PV and various parameters was evaluated with correlation coefficient (r²). Results A total of 65 patients were enrolled in the study. Reduced LVEF was present in 53 (81.6%) patients. There were 44 events (32 deaths, 12 heart transplants) after a median follow-up of 43 months (IQR 14–65). Results in patients with HFrEF are presented in the Table. Our main findings were: 1) PV expansion was associated with an increased risk of adverse events (Figure 1); 2) Volume redistribution correlated with various indexes of cardiac chamber function, suggesting that volume overload and associated cardiac remodeling may be responsible for altered myocardial mechanics in patients with HFrEF (Figure 2); 3) right ventricular-pulmonary arterial uncoupling was triggered by the plasma volume expansion, that causes postcapillary pulmonary hypertension; 4) PV redistribution was also associated with renal dysfunction and increasing the level of the protein catabolism (Table 1). Conclusion Expansion of plasma volume in HFrEF patients is associated with left atrium dilatation, abnormal filling of both atria and right ventricular dilatation / dysfunction. Plasma volume redistributions apparently became a trigger of right ventricular-pulmonary arterial uncoupling and stimulated postcapillary pulmonary hypertension, renal dysfunction with increasing the level of protein catabolism and unfavorable outcomes.

Background: There is a paucity of data regarding the temporal trends and outcomes of transcatheter aortic valve replacement (TAVR) among patients with prior coronary artery bypass graft (CABG) surgery. Methods: We queried the Nationwide Readmissions Database (2016-2019) for hospitalized patients who underwent TAVR using ICD-10 codes. We evaluated the trends and outcomes of TAVR among patients with versus without a history of prior CABG. Multivariable regression analysis was used to adjust for patients’ and hospitals' characteristics when comparing the study groups. The primary outcome was in-hospital mortality. Results: The final analysis included 173,274 admissions who underwent TAVR of whom 31,271 (18.3%) had a history of prior CABG. During the study years, there was a decrease in the proportion of patients with prior CABG among those undergoing TAVR (22.0% in 2016 vs. 16.2%, Ptrend=0.01), while there was no change in their in-hospital mortality rate (1.08% in 2016 vs. 1.25% in 2019, Ptrend= 0.43). Patients with prior CABG were younger and less likely to be women compared with those without prior CABG. On multivariable adjustment, In-hospital mortality was lower among the group with versus without prior CABG (adjusted odds ratio [aOR] 0.77; 95% confidence interval [CI] 0.65-0.91, p<0.01). Adjusted analysis showed lower rate of 90-day readmission (OR 0.95; 95%CI 0.90-0.98, p=0.01), and similar rate of ischemic stroke (aOR 0.89; 95%CI 0.76-1.03, p=0.89), permanent pacemaker (PPM) implantation (aOR 0.99; 95%CI 0.93-1.05, p=0.99). Among those with prior CABG, female gender, and chronic kidney disease ≥3 were independently associated with higher in-hospital mortality, and obesity was associated with lower in-hospital mortality. Conclusion: In this analysis, there was a decrease in the proportion of patients with prior CABG among those undergoing TAVR. TAVR among those with prior CABG was not associated with increased short-term mortality or PPM implantation.

Introduction: Cardiac resynchronization therapy (CRT) has known benefit for heart failure (HF) with reduced left ventricular ejection fraction (LVEF) and dyssynchrony. However, very little is known about its benefit in infiltrative cardiomyopathies such as cardiac amyloidosis (CA) due to relative rarity of these conditions. Methods: This retrospective case series (2003-2021) comprised patients with HF due to transthyretin wild-type CA with (case) or without (control) CRT implant. Only controls with an indication for CRT or LVEF <40% were included. To further match disease severity, cases were 1:1 matched (propensity score tolerance 0.04) to controls for age, NYHA class, and CA stage (UK Staging). Primary outcome was MACE (major adverse cardiac events) which included stroke, myocardial infarction, HF hospitalization and cardiac mortality during a 3-year follow-up. Loss to follow-up was censored as per last visit date. LVEF and NYHA were noted closest to 1-year follow-up. Survival analysis for MACE was performed with Kaplan-Meier (KM) and multivariable cox regression models. Results: Study Cohort (n=160) had a mean age of 75.5 (SD 7.8) years and 97.5% were males. A majority had NYHA class 2 or 3 (92.3%) and CA stage 2 (42.2.%). Notably, median LVEF at baseline was lower in controls (33.5 vs 36.5; P = .001) and 77.5% of controls had an indication for CRT device. A total of 79 MACE events occurred, most frequent being HF hospitalization (n=45). KM curves were comparable for MACE events in the two groups (log-rank test; P = .059). Even after adjusting, as in table, CRT device was not associated with MACE events (adjusted HR 0.66; 95% CI 0.40-1.09; P = .106). Lastly, change in LVEF ( P = .84) and NYHA ( P = .86) at follow-up was similar in cases vs controls. Conclusions: The findings of this largest yet observational study to examine this question suggest that CRT in patients with transthyretin wild-type CA does not favorably impact outcomes for MACE events, improve LVEF or NYHA functional class.

Abstract Meningiomas are the most common primary intracranial tumor. They are slow growing and often incidentally found tumors that arise from the arachnoid villi. As they grow, they have a greater likelihood of becoming symptomatic with seizures being one of the most clinically significant symptoms. Seizures are more likely to present as a symptom of larger meningiomas and meningiomas that compress cortical areas particularly those in non-skull base locations. These seizures are often managed medically, utilizing the same anti-seizure medications that are used to treat other causes of epilepsy. We discuss common anti-seizure medications used including valproate, phenobarbital, carbamazepine, phenytoin, lacosamide, lamotrigine, levetiracetam and topiramate and their common adverse effects. The goal of pharmacotherapy for seizure control is to maximize seizure control while minimizing the adverse effects of the medication. The decision to provide medical management is dependent on individual seizure history and plans for surgical treatment. Patients who did not require seizure prophylaxis before surgery are commonly prescribed seizure prophylaxis postoperatively. Symptomatic meningiomas not controlled by medical management alone are commonly evaluated for surgical resection. The efficacy of surgical resection in providing seizure freedom is dependent on several features of the tumor including tumor size, the extent of the peritumoral edema, the number of tumors, sinus infiltration and the degree of resection.

Abstract Introduction We sought to determine what type of treatment reengagement after smoking relapse would increase long-term cessation. Aims and Methods Participants were military personnel, retirees, and family members (TRICARE beneficiaries) recruited across the United States from August 2015 through June 2020. At baseline, consented participants (n = 614) received a validated, four-session, telephonic tobacco-cessation intervention with free nicotine replacement therapy. At the 3-month follow-up, 264 participants who failed to quit or relapsed were offered the opportunity to reengage in cessation. Of these, 134 were randomized into three reengagement conditions: (1) repeat initial intervention (“recycle”), (2) Smoking reduction with eventual cessation goal (“rate reduction”), or (3) Choose #1 or #2 (“choice”). Prolonged abstinence and 7-day point prevalence abstinence were measured at 12 months. Results Despite being in a clinical trial advertised as having the opportunity for reengagement, only 51% (134 of the 264) of participants who still smoked at 3-month follow-up were willing to reengage. Overall, participants randomized to recycle had higher prolonged cessation rates at 12 months than rate reduction conditions (OR = 16.43, 95% CI: 2.52 to 107.09, Bonferroni adjusted p = .011). When participants who randomly received recycle or rate reduction were pooled, respectively, with participants who chose recycle or rate reduction in the Choice group, recycle had higher prolonged cessation rates at 12 months than rate reduction (OR = 6.50, 95% CI: 1.49 to 28.42, p = .013). Conclusions Our findings suggest service members and their family members who fail to quit smoking but are willing to reengage in a cessation program are more likely to benefit from repeating the same treatment. Implications Finding methods that are both successful and acceptable to reengage people who smoke who want to quit can have a significant impact on improving the health of the public by reducing the portion of the population who smoke. This study suggests that repeating established cessation programs will result in more people ready to quit successfully achieving their goal.

Abstract Purpose A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used. Materials and Methods A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 ­olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%. Results A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist. Conclusion This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).

8009 Background: Heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with standard of care therapy have median overall survival (OS) of ~12 months (mo). In the single-arm, phase 1b/2 CARTITUDE-1 study (NCT03548207), pts received a single infusion of ciltacabtagene autoleucel (cilta-cel), a CAR-T cell therapy targeting BCMA. At the final protocol-specified analysis (27.7-mo median follow-up [MFU]), overall response rate (ORR) was 98%, with 83% stringent complete response (CR); 27-mo rates of progression-free survival (PFS) and OS were 55% and 70%, respectively. Here, we report study closeout results. Methods: Eligible pts received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD); and had received prior PI, IMiD, and anti-CD38 antibody therapy. Primary endpoint was ORR and safety; secondary endpoints included PFS, OS, and minimal residual disease (MRD) negativity at 10-5. Results: 97 pts received cilta-cel (median age 61 years [y]; median 6 prior LOT; 42% penta-drug refractory; 88% triple-class refractory; 99% refractory to last LOT). As of October 14, 2022, MFU was 33.4 mo (range, 1.5-45.2). Median (m) duration of response was 33.9 mo (95% CI, 25.5–not estimable [NE]). mPFS was 34.9 mo (95% CI, 25.2–NE), with an estimated 47.5% progression free and alive at 36 mo. mOS was not reached (NR), with an estimated 62.9% survival at 36 mo. Of 49 MRD-evaluable pts, 26 had MRD negativity sustained for ≥12 mo, of which 20 had sustained MRD-negative ≥CR. mPFS was NR in these subgroups (Table). 18 pts were MRD negative with ≥CR at 24 mo post infusion. No new safety signals and no new neurotoxicity events were reported since the 27.7-mo MFU. 6 new cases of second primary malignancy were reported, including 2 cases of basal cell carcinoma and 1 case each of myelodysplastic syndrome, B-cell lymphoma, melanoma, and prostate cancer. 5 additional deaths occurred (progressive disease [PD], n=3; pneumonia and sepsis, n=1 each [both unrelated to cilta-cel]), for a total of 35 (PD, n=17; unrelated to cilta-cel, n=12; related, n=6). Conclusions: Longer mPFS was observed after a single infusion of cilta-cel than any previously reported therapy in heavily pretreated pts with RRMM. Achieving CR and/or sustained MRD negativity was associated with prolonged PFS. Pts continue to be followed for safety and survival in the 15-y CARTINUE long-term study (NCT05201781; MMY4002). Clinical trial information: NCT03548207 . [Table: see text]