Citations

Abstract The use of chimeric antigen receptor (CAR) T-cell therapy is increasing for adult B-cell acute lymphoblastic leukemia (B-ALL), with 3 CD19 CAR T-cell products commercially available. Several key clinical questions related to best practices for CAR T-cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T-cell therapy for adults with B-ALL. Consensus panelists (n = 9) included principal investigators (PIs) from Real World Outcomes Collaborative of CAR T-Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T-cell center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n = 27). Consensus topics included patient selection, bridging and pre–CAR T-cell leukemia staging, lymphodepletion, and CAR T-cell treatment setting, specific toxicity prevention and management, post–CAR T-cell response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies after CAR T-cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After 2 panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but 1 recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T-cell therapy in adult B-ALL.

Abstract Background Several bispecific antibodies (BsAbs), including mosunetuzumab, glofitamab, and epcoritamab, are approved for non-Hodgkin lymphoma (NHL). However, real-world patient-centered data evaluating treatment-related time burden and preferences are lacking. Methods We conducted an online survey of 120 patients with relapsed/refractory follicular lymphoma (FL; N = 60) and diffuse large B-cell lymphoma (DLBCL; N = 60) receiving BsAbs. Participants reported all-cause healthcare visits and time spent on cancer-related healthcare resource utilization over the past 30 days, including travel, treatment administration, recovery, and impact on daily activities. Participants also evaluated two hypothetical treatment profiles to assess preference for fixed-duration versus treat-to-progression therapy. Results Participants with FL reported a mean of 2.5 healthcare visits in the past 30 days, with significantly fewer visits for mosunetuzumab versus epcoritamab (1.7 vs 3.3, respectively; P < .01). In DLBCL, the mean was 2.6 visits, with fewer visits for glofitamab versus epcoritamab (2.2 vs 3.0; P =.01). Although epcoritamab visits were shorter in FL, more frequent visits and longer recovery time resulted in significantly lower monthly time burden with mosunetuzumab versus epcoritamab (31.2 vs 61.9 hours; P < .05). Similarly, monthly time burden was also lower with glofitamab than epcoritamab in DLBCL (43.0 vs 87.7 hours; P < .05). Most participants reported little to moderate impact on daily activities. Across treatment groups, ≥92% preferred a hypothetical fixed-duration regimen over a treat-to-progression therapy. Conclusion Our real-world data, including novel aspects of time toxicity, demonstrate clinically meaningful differences in time burden associated with BsAbs and emphasize the importance of incorporating patient convenience and preference into shared decision-making in NHL.

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results All 20 SP participants (median age 57.5 (range 42–75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration https://clinicaltrials.gov/study/ , identifier NCT05419011.

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Most malignant effusions are mononuclear predominant, with only 16-20% being neutrophilic. Neutrophilic predominance should raise suspicion for secondary inflammatory process, particularly empyema. In absence of infection, elevated neutrophils can be a sign of tumor necrosis or tumor lysis. In malignant pleural effusions, markers such as low glucose, low pH, and high LDH may indicate a high tumor burden and are markers of poor outcomes. 64-year-old male with past medical history of metastatic mucinous lung adenocarcinoma status post diagnostic right lower lobe wedge resection and recurrent bilateral malignant pleural effusions, presented to outpatient clinic for therapeutic right-sided thoracentesis. 900 mL of viscus green-brown pleural fluid was removed, and initial fluid studies revealed a neutrophil-predominant exudate with 45,045 total nucleated cells (TNCs) and pH of 7.01. Given concern for infection the patient was admitted, and a right-sided 14 French pigtail pleural catheter was placed. Left-sided thoracentesis was also performed, with pleural fluid studies consistent with a lymphocytic exudate. Vitals on admission were all within normal limits and white blood cell count was 8.9. Chest computed tomography (CT) scan showed extensive bilateral lymphangitic metastases scattered throughout both lungs and bilateral hydropneumothoraces with evidence of a left-sided pleural rind. Infectious workup, including pleural fluid cultures and broad-range bacterial polymerase chain reaction (PCR) were all negative. Cytology of both left and right pleural fluid revealed malignant adenocarcinoma with a substantial amount of necrosis. Patient was discharged home on oral antibiotics with plan to follow up as outpatient for possible tunneled pleural catheter placement. Post-discharge, patient continued to receive intermittent therapeutic thoracenteses. Subsequently readmitted, again with concerns for empyema, bilateral tunneled pleural catheters were placed after infectious workup was again unrevealing. At one month follow up, he reported drainage of 300-500 mL of pleural fluid with alternating daily drainages without complication. Differentiating neutrophilic malignant pleural effusions from empyema is clinically difficult and can lead to delay in definitive pleural treatments. Although it is important to rule out infection, malignancy should remain on one’s differential diagnosis, particularly if the remainder of the patient’s history and presentation are inconsistent with an infectious etiology. This abstract is funded by: None

Abstract Introduction Sedation is routinely administered to facilitate comfort and tolerance of life support for critically ill adults dependent on invasive mechanical ventilation. Isoflurane, a widely used anesthetic during surgery, has properties that may also benefit ICU patients requiring continuous sedation. However, efficacy as a sedative and safety in this population is not well established. Methods We conducted two identically designed multicenter randomized trials, INSPIRE ICU1 and INSPIRE ICU2, at hospitals across the US. Ventilator-dependent adults were randomly assigned in a 1.5:1 ratio to receive either inhaled isoflurane or intravenous propofol as the first-line sedative for up to 48 ± 6 hours, targeting a sedation depth between Richmond agitation-sedation scale (RASS) -1 (drowsy) to -4 (responsive only to physical stimuli). Isoflurane was administered via an anesthetic conserving device (Sedaconda ACD-S). In both arms, opioids were permitted at the lowest dose required to achieve freedom from pain. The primary outcome was the percentage of time at target sedation level, assessed as a noninferiority outcome with pre-specified margin of 15%. Secondary outcomes included opioid exposure, wake-up time after end of treatment, time to extubation, and proportion of time with spontaneous breathing effort. Results A total of 470 combined participants were included in the two trials. In each trial, 142 patients were randomly assigned to isoflurane and 93 to propofol. In INSPIRE ICU1, percentage of time within target sedation depth was 77.1 [53.2, 89.9] % with isoflurane and 80.9 [58.2, 96.4] % with propofol (difference -1.5 [-8.9, >99] %; p < 0.01 for noninferiority). In INSPIRE ICU2, percentage of time within target sedation depth was 72.6 [66.4, 78.9] % with isoflurane and 74.5 [67.5, 81.5] % with propofol (difference -1.9 [-9.4, >99] %; p < 0.01 for noninferiority). In both trials, patients assigned to isoflurane received significantly less opioid, measured as fentanyl equivalents, during the treatment period. In INSPIRE ICU2, participants receiving isoflurane were significantly likelier to exhibit spontaneous breathing efforts, but this finding was not replicated in INSPIRE ICU1. There were no significant differences in time to wake-up or time to extubation between groups in either trial. No episodes of malignant hyperthermia or propofol infusion syndrome were reported. Adverse events were comparable in type and frequency between groups. Conclusions In two US multicenter trials, isoflurane was noninferior to propofol for maintaining target sedation depth in adults undergoing invasive ventilation, and was associated with significantly lower opioid exposure. (NCT05327296, NCT05312385) This abstract is funded by: Sedana Medical

Abstract Rationale American Indians and Alaska Native (AI/AN) people have the highest prevalence of tobacco use of any US racial or ethnic minoritized group, though this varies regionally. Smoking, and smoking-related cancers including lung cancer are more common in AI/AN people than non-Hispanic whites in the Pacific Northwest. Lung cancer screening (LCS) is effective but broadly under-utilized in AI/AN eligible adults. This study’s objective was to evaluate a AI/AN community co-designed patient navigation intervention to bridge community healthcare settings to a LDCT-capable LCS program. Methods We conducted a single-arm pilot study of the patient navigation intervention, grounded in community-based participatory research principles. The intervention was formalized in a living handbook, co-created with input from patients and providers at an AI/AN Urban Indian Organization and primary care clinic, Seattle Indian Health Board. Two community health workers served as navigators to deliver culturally sensitive support, link to shared decision-making with a nurse practitioner at the academic LCS program, coordinate transportation, interface with insurance and provide other barrier-directed activities. Patients eligible for LCS (n = 44) were recruited from the AI/AN clinic setting through on-site outreach. Enrolled participants completed pre-navigation surveys which assessed baseline knowledge, attitudes, experiences and barriers. Those who engaged with the central program completed an additional post-navigation survey (n = 15). Electronic health records were reviewed for all navigation and LCS-related data. Results Between July 2023 - November 2024, 44 participants were enrolled in the study. The median age of the participants was 65 (IQR 58-70), 66% reported current smoking, and 76% reported an annual household income <$30,000. All participants reported at least one barrier that delayed care in the past 12 months. On review, two participants were up-to-date on LCS prior to enrollment. Within 6 months, 13 participants completed a shared decision-making appointment and 11 went forward with LDCT. On post-intervention surveys, barriers most commonly addressed were: scheduling (100%), transportation (80%), explaining LCS (80%) and cost/insurance (73%). Participants reported high acceptability, measured by Acceptability of Intervention Measure (AIM median 5.0, IQR 5-5) and patient satisfaction measured by Patient Navigation Satisfaction Measured-Instrument (PNS-I median 45, IQR 42-45). Conclusion A culturally tailored patient navigation program for LCS was feasible and highly acceptable among urban AI/AN adults. Navigation addressed multiple barriers and successfully connected some patient participants from a community clinic to tertiary screening centers for shared decision-making and/or screening. These findings support the effectiveness of academic-community partnered navigation to increase LCS uptake in AI/AN clinic settings. This abstract is funded by: ATS/ALA/Chest Foundation: Respiratory Health Equity Research Award (Triplette)

Abstract Introduction Superior vena cava (SVC) syndrome results from the obstruction or occlusion of the SVC, leading to a range of complications depending on severity, location, and chronicity with the development of collateral circulation. We present a case of a patient with prior facial edema and subsequent development of bilateral pleural effusions whose evaluation led to discovery of SVC stenosis and occlusion of bilateral brachiocephalic veins, likely related to chronic indwelling pacemaker leads. Case Report A 73-year-old woman with bileaflet mitral valve prolapse with mild-to-moderate regurgitation, sinus node dysfunction status post pacemaker placement in 2014, atrial fibrillation and an unprovoked extensive right upper extremity deep venous thrombosis (DVT) managed on chronic apixaban therapy presented to clinic for evaluation of bilateral pleural effusions. One year prior to presentation, she developed facial and supraclavicular edema with positional dyspnea. A CT head and neck did not explain her abrupt facial edema though showed a left-sided pleural effusion, which was addressed locally with serial thoracenteses followed by tunneled pleural catheter placement. This ultimately led to discomfort without improvement in dyspnea, prompting catheter removal. She later developed a right-sided pleural effusion and underwent thoracentesis with the fluid analysis shown in Table 1. Physical exam was notable for collateral vessels along the chest wall and abdomen. The collateral vessels, unexplained pleural effusions, prior extensive right upper extremity DVT, and history of now resolved facial edema prompted CT venogram; this revealed occlusion of the right and left brachiocephalic veins and severe narrowing of the SVC with venous collaterals noted. PET-CT showed no evidence of malignancy. Electrophysiology consultation attributed the SVC stenosis to the indwelling pacemaker leads. The patient underwent SVC cavogram with successful angioplasty across right internal jugular vein down to the SVC with improvement in pressure gradient. After recanalization, there was no significant reaccumulation of pleural effusions on follow up and patient’s dyspnea improved. Discussion Pleural effusions in the setting of SVC syndrome have been described, most commonly due to thrombosis, device-related complications, or malignancy. This case highlights the importance of considering device-related vascular complications in patients with unexplained pleural effusions, particularly those with a history of intrathoracic devices or procedures. Management should target the underlying cause of the effusion; however long-term data on outcomes and optimal management strategies for pacemaker-related SVC syndrome remain limited. This abstract is funded by: None

PURPOSE We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], P < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.

ABSTRACT Disease Overview Plasmablastic lymphoma (PBL) is a rare CD20‐negative aggressive lymphoma with poor prognosis when treated with standard treatment options. Although PBL is associated with HIV infection and other immunosuppressed states, it can also affect immunocompetent individuals. Diagnosis The diagnosis of PBL requires a high clinical suspicion and pathological confirmation. EBV‐encoded RNA (EBER) expression and MYC gene rearrangements are frequently detected in the malignant cells. The differential diagnosis includes EBV+ diffuse large B‐cell lymphoma (DLBCL), extracavitary primary effusion lymphoma, ALK+ DLBCL, and HHV8+ large B‐cell lymphoma, among others. Risk Stratification Age ≥ 60 years, advanced clinical stage, and high International Prognostic Index scores are associated with worse survival. Management Combination chemotherapy regimens, such as infusional EPOCH, are recommended. The addition of bortezomib or daratumumab might improve outcomes. B‐cell maturation antigen‐targeted therapies have shown early efficacy. The participation of patients with PBL in prospective clinical trials is warranted.