Citations

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

7501 Background: AL amyloidosis is a plasma cell dyscrasia (PCD) characterized by κ or λ Ig light chain amyloid fibrils that deposit in vital organs. Anselamimab is an investigational mAb designed to complement anti-PCD therapy through accelerated removal of amyloid fibrils. Cardiac Amyloid Reaching for Extended Survival (CARES) studies (NCT04512235 and NCT04504825) investigated the efficacy and safety of anselamimab compared with placebo, in addition to anti-PCD therapy. Methods: Alongside anti-PCD therapy with CyBorD (daratumumab was permitted) newly diagnosed patients with European modification of Mayo stage IIIa or IIIb AL amyloidosis were randomized 2:1 to receive anselamimab (1000 mg/m 2 ) or placebo (normal saline) IV every 7 days for 4 weeks followed by every 14 days for the remainder of the blinded study (18 months after the last participant enrolled). The primary endpoint was a hierarchical combination of time to all-cause mortality (ACM) and frequency of adjudicated cardiovascular hospitalizations (CVH) using the Finkelstein-Schoenfeld test and win-ratio in the combined study population. Subgroup analysis by involved κ or λ free light chain (iFLC) was prespecified. Results: 271 patients were randomized to receive anselamimab and 135 placebo. Baseline characteristics were similar between treatment arms. The median duration of treatment was 21.4 months and 21.1 in the anselamimab and placebo arms, respectively. Daratumumab was used in 79.3% and 83.7% of the anselamimab and placebo arms, respectively. Results of the primary efficacy analyses are shown in the table. Anselamimab-treated patients with κ iFLC had a 62% reduction in ACM (HR = 0.38; 95% CI, 0.17, 0.86; nominal P = 0.012) and a 71% reduction in risk for CVH (estimated CVH rate ratio = 0.29; 95% CI, 0.10, 0.87; nominal P = 0.028). Patients with λ iFLC had a 10% reduction in risk for CVH; none in ACM. Safety data were comparable between both treatment arms. In anselamimab-treated patients, safety findings were similar between κ subgroup and full population. Conclusions: Anselamimab, a κ light chain–directed anti-fibril monoclonal antibody used alongside standard of care chemotherapy, offers a first-in-class, new therapeutic option for patients with newly diagnosed κ AL amyloidosis. Clinical trial information: NCT04512235 and NCT04504825 . Summary of primary efficacy endpoints. Endpoint Overall κ Isotype λ Isotype Anselamimab (N=271) Placebo (N=135) P -value Anselamimab (N=48) Placebo (N=24) P -value Anselamimab (N=219) Placebo (N=109) P -value ACM and CVH win ratio (95% CI) 1.1 (0.8, 1.5) 0.332 2.06 (0.98, 4.31) 0.100 0.9 (0.6, 1.3) 0.848 ACM n (%) 90 (33.2) 52 (38.5) 15 (31.3) 14 (58.3) 73 (33.3) 37 (33.9) HR (95% CI) 0.8 (0.6, 1.1) 0.290 0.38 (0.2, 0.9) 0.012 1.0 (0.7, 1.5) 0.647 CVH Frequency/year (95% CI) 0.6 (0.4, 0.8) 0.9 (0.6, 1.4) 0.145 0.41 (0.2, 0.8) 1.4 (0.6, 3.4) 0.028 0.7 (0.4, 1.0) 0.8 (0.4, 1.3) 0.664 Incidence risk ratio (95% CI) 0.7 (0.4, 1.2) 0.29 (0.1, 0.9) 0.9 (0.5, 1.7)

Abstract Introduction Bronchiectasis is a chronic respiratory disease that increases fatigue, disability, and impairs quality of life. However, the impact of fatigue on patients with bronchiectasis, even in short-term follow-up, has not been sufficiently examined. We explored the association between fatigue and clinical outcomes among patients with bronchiectasis. Methods Adult bronchiectasis patients enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry were retrospectively analyzed. Patients with at least one annual follow-up visit in the 3-5 years post baseline and with fatigue data at both baseline and follow-up were included. Patients were grouped as experiencing fatigue versus not experiencing fatigue in the 2-years prior to baseline as reported at their baseline visit. We explored the relationship between baseline fatigue with patient demographics, co-existing conditions, components of the modified bronchiectasis severity index at baseline and follow-up. Wilcoxon, chi-square, and Fisher’s exact tests were used to assess the differences in continuous variables and associations between categorical variables, respectively. Stepwise multivariable logistic regression models explored the relationship of baseline fatigue with exacerbations and hospitalizations at follow-up. Model selection predictors were evaluated based on clinical relevance or p < 0.05 in univariable analyses. Results 1265 adults with bronchiectasis met the inclusion criteria. 563(45%) reported experiencing fatigue and 702 (55%) did not. The median age (interquartile range) was 70(62-78) years and patients were predominantly female (n = 1042, 83%). At baseline, patients experiencing fatigue had a higher proportion of co-existing diagnoses such as gastroesophageal reflux disease, chronic obstructive pulmonary disease, and rheumatologic disease, compared to those without fatigue (all p < 0.05). Furthermore, patients with fatigue had a higher prevalence of pulmonary-related hospitalizations (p < 0.001) at baseline and follow-up. Pseudomonas aeruginosa colonization and elevated dyspnea (modified Medical Research Council [mMRC] grade≥1) were more prevalent among those experiencing baseline fatigue compared to those without (all, p < 0.05). History of prior exacerbations (Odds Ratio [OR]:1.67, 95% CI:1.17-2.41) and baseline Pseudomonas aeruginosa colonization (OR:1.22, 95% CI:1.01-1.47) were significantly associated with increased odds of exacerbations at follow-up. In multivariable stepwise logistic regression, there was an increased odds of at least 1-hospitalization at follow-up among males (OR:2.23, 95% CI 1.12-4.42), patients with decreased Body Mass Index (OR:0.93, 95% CI: 0.87-1.0), and among patients with elevated dyspnea (mMRC grade ≥1) at baseline (OR:2.22, 95% CI: 1.16-4.24),[Table 1]. Conclusions Fatigue in bronchiectasis patients is associated with a more severe disease and greater healthcare utilization, although it may not independently predict future exacerbations or hospitalizations when accounting for other factors. This abstract is funded by: Bronchiectasis and NTM Association

Abstract Introduction Burkholderia, Achromobacter, and Stenotrophomonas species are associated with worse clinical outcomes in cystic fibrosis (CF),1 though little is known about their prevalence or pathogenicity in non-CF bronchiectasis (pwBE). Herein we describe the prevalence and clinical characteristics of pwBE who isolated each of these three organisms. Methods We conducted a retrospective cross-sectional analysis of baseline data from the US Bronchiectasis and Nontuberculous Mycobacteria (NTM) Research Registry (BRR). Adult bronchiectasis patients with known Achromobacter, Burkholderia cepacia complex (BCC), or Stenotrphomonas maltophilia culture results were included. Patients were stratified according to the presence of at least one positive culture among the gram-negative species. Demographics, clinical characteristics, and first annual follow-up culture results were summarized descriptively for the overall study population and between groups. No inferential analyses or hypothesis testing was performed. Results 5003 pwBE met the inclusion criteria, of which 39 (0.78%) isolated Achromobacter species, 11 isolated Burkholderia (0.22%), and 288 isolated Stenotrophomonas maltophilia (5.8%). Patients with Achromobacter were older, with a median age (interquartile range) of 76 (73.0-79.0) years, compared to the overall bronchiectasis cohort (69.0 years). Those with Burkholderia or Stenotrophomonas were younger, at 69.0 (53.0-75.0) and 71.0 (63.0-77.0) years, respectively. A high proportion of those with Achromobacter were male (31%) versus those with Burkholderia (9%) and Stenotrophomonas (24%), were current or former smokers (46%), were more likely to have had one or more exacerbations in the 2 years prior to enrollment (87%) than the overall BE cohort (57%), and were more likely to have had pulmonary-related hospitalization than those with either Burkholderia or Stenotrophomonas (46% vs. 27% and 19%, respectively). PwBE who isolated Burkholderia were less likely to have co-colonization with Pseudomonas aeruginosa or NTM species (9% each). At first annual follow-up, no patients with baseline Burkholderia isolated them at follow-up, and only 31% with baseline Stenotrophomonas isolated it at follow-up. Conclusion Overall prevalence of Achromobacter, Burkholderia, and Stenotrophomonas species in the BE cohort was low. Patients who isolated Achromobacter species were older, more likely to be current or former smokers, and more likely to experience pulmonary exacerbation and hospitalization. 15 patients who had not previously isolated Achromobacter, and 3 patients who had not previously isolated Burkholderia did so at annual follow-up. Interestingly, no patients with baseline Burkholderia isolates went on to isolate it at annual follow-up, which contradicts earlier studies in pwCF.2 The number of patients isolating Burkholderia in the U.S. BRR is very low, thereby limiting interpretation. This abstract is funded by: None

Uncontrolled systemic inflammatory responses are a critical pathological feature of fatal Ebola virus (EBOV) infection. While some inflammatory responses may originate from mononuclear phagocytes (MNPs), nonimmune cells vastly outnumber MNPs and may be an important source of inflammation. Here, we demonstrated that highly virulent EBOV induced a high and sustained pro-inflammatory response compared to less virulent ebolaviruses in non-MNPs through TLR4-independent NF-κB activation. We identified the EBOV matrix protein VP40 as a potent activator of NF-κB in non-MNPs, whose intrinsic inflammatory activation ability is higher than VP40 proteins from less virulent ebolaviruses. This suggests that VP40 is a virulence determinant inducing distinct degrees of pro-inflammatory responses among ebolaviruses. Mechanistically, VP40 activated the NF-κB signaling pathway, primarily via TNFR1 using a ligand-independent mechanism. These findings reveal mechanisms that may drive systemic inflammation and promote EBOV pathogenesis, suggesting potential therapeutic strategies to mitigate immune dysregulation in severe EBOV infections.

ABSTRACT Thogotoviruses are arthropod-borne viruses belonging to the genus Thogotovirus within the family Orthomyxoviridae . Like other orthomyxoviruses, such as the influenza A viruses (IAV), thogotoviruses replicate in the nucleus. As a result, progeny viral ribonucleoprotein complexes (vRNPs) must be exported to the cytoplasm prior to virion assembly and budding at the plasma membrane. In IAV, this export depends on binding of the viral nuclear export protein (NEP) to the cellular exportin chromosomal maintenance 1 (CRM1). In contrast, the mechanism of vRNP nuclear export, including identification of a protein with NEP functionality, has not been characterized for any thogotoviruses. Here, we characterized vRNP nuclear export in Dhori virus (DHOV), a prototypic member of the Thogotovirus genus. DHOV replication and nuclear export of the viral nucleoprotein were inhibited by the canonical CRM1 inhibitor leptomycin B (LMB), suggesting that DHOV vRNP export also utilizes CRM1. Interestingly, LMB treatment led to nuclear retention of the DHOV matrix (M) protein in both infected and transfected cells. Using a mammalian two-hybrid system, we found that DHOV M interacts with CRM1 through a nuclear export sequence (NES) located between amino acids 111 and 128. Mutation of hydrophobic residues within this NES reduced M-CRM1 interaction, abolished the NES phenotype when fused to a fluorescent protein, and impaired rescue of recombinant DHOV by reverse genetics. Together, our results reveal that DHOV vRNP nuclear export is CRM1-dependent and mediated by the M protein rather than a dedicated NEP-like protein, providing the first mechanistic insight into vRNP egress in the genus Thogotovirus . IMPORTANCE Dhori virus (DHOV) is a pathogenic tick-borne virus in the genus Thogotovirus , in the family Orthomyxoviridae. Despite evidence of DHOV exposure in various mammals, including humans, its basic biology is not well understood. We investigated how DHOV’s progeny genome and protein complexes—viral ribonucleoprotein complexes (vRNPs)—are transported out of the nucleus. Our findings show that DHOV, like the influenza viruses, uses the cellular protein chromosomal maintenance protein 1 (CRM1) for vRNP export. We found that chemically inhibiting CRM1 completely blocked DHOV vRNP export, preventing the production of progeny viruses from infected cells. Screening of all known DHOV proteins revealed that the matrix protein, which forms the virus’ scaffold, interacted with CRM1, suggesting it may link CRM1 to the vRNPs. These results advance our understanding of DHOV replication and suggest that chemically inhibiting vRNP export could be a way to treat thogotovirus infections.

Abstract Rural health disparities in the United States remain poorly understood, in part due to inconsistent definitions of “rurality” and the failure to integrate both geographic and socially constructed dimensions of place. This commentary draws from insights shared during the panel “Addressing Diversity in Cancer Prevention, Control, and Survivorship Within Rural Communities” at the 2024 Transforming Community and Rural Healthcare (TCRH) conference. Panelists emphasized the limitations of current rural-urban classification systems, which often overlook the intersectional identities, cultural heterogeneity, and lived experiences of rural populations. They advocated for integrating community-based participatory research (CBPR) and identity-based approaches to define rurality more holistically. Such methods prioritize self-identification, social determinants of health (SDOH), and localized knowledge, allowing for a more accurate assessment of cancer disparities and the development of equitable interventions. The commentary outlines how geophysical and census-based metrics, although convenient, can misrepresent rural communities and inadvertently perpetuate disparities in cancer care access, outcomes, and policy. The authors argue for an identity- and community-centered conceptualization of rurality that is dynamic, inclusive, and responsive to the complexity of rural life.

55 Background: Prior authorization (PA) processes are known to create administrative burdens and delays in care, but little is known about how these challenges impact rural oncology patients and practice settings. Methods: To understand the broad impact of prior authorization on rural oncology patients and practices, we conducted this study across three community oncology practices serving majority rural patient populations with distinct geography, healthcare infrastructure, and models of care. Sites included one critical access hospital system located in a highly-rural community (Lakewood Health System; Staples, Minnesota), a community-based hub-and-spoke hospital system-based practice located in a mid-sized community (Mayo Clinic Health System – Northfield; Northfield, Minnesota), and a standalone referral level III trauma center serving a highly rural patient base (Self Regional Healthcare; Greenwood, South Carolina). This retrospective cohort study examined all intravenous and subcutaneous cancer-directed therapy plans (no oral therapy) that required PA submission at these locations over a three-month period from October 1, 2024 to December 31, 2024. Results: 129 PA submissions were required during the study period. 82 were due to cancer-directed therapy agents (of which 14 were immunotherapy agents), and 47 were due to adjunctive therapies (of which 22, 16, and 9 were due to granulocyte stimulation, bone preservation, and anti-emesis agents, respectively). All 129 PA submissions ultimately resulted in approval of the desired medication or formulary-approved biosimilar. Delays from PA submission to approval ranged from 0 to 18 days. A total of 209 patient-days were delayed due to PA during the study period, which did not ultimately result in change of care or denial of care in any instance. Conclusions: At all sites included in this study, all PA submissions were eventually authorized. The PA process was found to introduce inconsistent and potentially avoidable delays for hundreds of patients and their care teams. These findings highlight the inefficiency of current PA processes among rural cancer populations and the practices that care for them, underscoring the need for ongoing efforts directed at state and federal PA reform.

Although innovation in cancer treatment has improved cure rates and survival, the costs have escalated beyond societies' ability to pay. Cancer care costs in the United States are expected to rise to 245 billion by 2030. In this health policy session, we focused on three cost-containment strategies, and their potential impact on cancer care delivery. Site Neutrality: Curbing the Cost of Cancer Care, but at What Risk? , explores legislation that would introduce payment parity across differing sites of care: elimination of facility fees in hospital owned practices and shift of billing for oncology infusions away from hospital owned practices. Unintended consequences could reduce access to care for vulnerable populations, shift costs to patients, and reduce safety. Post-Pandemic Digital Health Reimbursement: Impact on Access to Care , explores how the emergency waivers, licensure flexibilities, and parity reimbursement necessitated by COVID-19 shepherded innovation that outpaced the regulatory framework needed for long-term sustainability. Today, telehealth services, hospital at home, remote patient monitoring, and decentralized clinical trial enrollment face reintroduction of regulatory and payment barriers. Will we live to see efficacy-based pricing for cancer drugs? Learning from international models , explores how lack of drug price negotiation has led to higher prices in the United States compared with Canada and Europe. Comparative clinical effectiveness pricing systems compare the value of each drug to standard treatments. Comparative cost-effectiveness programs look at the incremental cost per additional unit of health gained above the standard of care. The United States could learn from these approaches used in comparable countries.

e13828 Background: Disparities in cancer outcomes between rural and urban populations are often linked to limited healthcare resources in rural areas. However, the impact of socioeconomic factors, particularly income inequality, requires further investigation. Methods: We analyzed cancer mortality rates using the Surveillance, Epidemiology, and End Results (SEER) database, focusing on rural-urban continuum codes and median county income, the proportions of patients with de novo metastatic disease at diagnosis, those aged 80 and older, and those experiencing a treatment delay of three months or more. Results: Our findings indicate that non-metropolitan counties (56.7%, 95% CI: 56.6%, 56.8%) and those with lower median incomes (54.9%, 95% CI: 54.8%, 55.1%) have significantly lower cancer survival rates than metropolitan counties (62.6%, 95% CI: 62.5%, 62.6%) and higher-income rural counties (62.6%, 95% CI: 62.6%, 62.7%), a trend consistent over the observation period. Higher proportions of de novo metastatic disease and increased treatment delays were observed in counties with lower income and greater rurality, with these counties also demonstrating higher annual percentage rates of change for both de novo metastatic disease (P < 0.05) and treatment delays (P < 0.05). Conclusions: Lower county-level median household income is associated with higher cancer mortality rates, increased de novo metastatic disease, and longer treatment delays. These results underscore the need to appreciate the role of income disparities in cancer outcomes and to improve access to oncology care in underserved rural populations.