Citations

Abstract Isolated cardiac sarcoidosis (iCS), defined by granulomatous inflammation limited to the myocardium, represents the most diagnostically challenging and prognostically adverse form of sarcoidosis. As it is fundamentally a diagnosis of exclusion, iCS diagnosis relies on the absence of extracardiac sarcoid and the integration of multimodality imaging, endomyocardial biopsy, and molecular testing, each with inherent limitations. Cardiac magnetic resonance and positron emission tomography provide complementary assessment of inflammation, fibrosis, and ventricular function, enhancing diagnostic confidence. Electroanatomic mapping-guided biopsy may improve histologic yield, whereas genetic testing helps exclude phenocopies such as arrhythmogenic, hypertrophic, or dilated cardiomyopathies. Circulating biomarkers remain non-specific but may complement imaging-based algorithms. Future research should focus on harmonized imaging protocols, non-FDG radiotracers, and molecular tissue profiling to refine activity assessment and guide therapy. Multimodal, probability-based frameworks represent the most promising approach for earlier, more accurate diagnosis and risk stratification in iCS.

PURPOSE Cholangiocarcinoma is a rare cancer associated with poor prognosis. Pemigatinib was the first FGFR1-3 inhibitor approved for second-line therapy and beyond, on the basis of the phase II FIGHT-202 trial. Here, we assess efficacy and safety of first-line pemigatinib. METHODS FIGHT-302 is a phase III, randomized, global trial evaluating pemigatinib as first-line therapy (ClinicalTrials.gov identifier: NCT03656536 ). Adults with advanced cholangiocarcinoma with FGFR2 rearrangement were randomized 1:1 to receive pemigatinib (13.5 mg once daily) or chemotherapy (1,000 mg/m 2 gemcitabine plus 25 mg/m 2 cisplatin once per day on days 1 and 8 of every 3-week cycle for ≤8 cycles) and were stratified by prior receipt of chemotherapy, geographic region, and tumor burden. Pemigatinib crossover was allowed for patients progressing on chemotherapy. The primary end point was progression-free survival (PFS). Secondary efficacy, safety, and exploratory end points were also analyzed. RESULTS Overall, 4,563 patients were prescreened, 196 were screened, and 167 randomly assigned to receive pemigatinib (n = 83) or chemotherapy (n = 84) before early closure of the study because of a change in standard of care. The median PFS was 8.3 months in the pemigatinib group versus 6.8 months in the chemotherapy group (hazard ratio, 0.58 [95% CI, 0.39 to 0.87]; nominal P = .0078); objective response rate was 47% versus 15%, and the median duration of response was 14.2 versus 6.3 months. Median overall survival was similar (24.4 v 25.0 months, respectively). In the crossover group (n = 42, second-line pemigatinib), the median PFS was 8.1 months. Safety was consistent with the known profile of pemigatinib. CONCLUSION To our knowledge, this was the largest, first-line, randomized, phase III trial of a targeted therapy for advanced FGFR2- rearranged cholangiocarcinoma. Pemigatinib demonstrated prolonged median PFS compared with chemotherapy, with no new safety findings.

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.

Abstract Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45–74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45–74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen’s d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen’s d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P < 0.00001) and an earlier age of first exposure to tackle football (P < 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P < 0.04) and rotational force (P < 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

Donation after circulatory death (DCD) livers increasingly use machine perfusion (MP). This study evaluates MP’s impact on older DCD livers based on data from the United Network for Data Sharing, covering all first adult DCD liver transplants (2016–2025). The cohort, divided into pre-MP and MP eras (separated by the FDA approval of the first normothermic MP platform in 2021), showed accelerated growth in DCD liver transplants during the MP era. Donors ≥60 rose 7.8-fold, including donors ≥70 (a USA first). By 2025, DCD livers accounted for 43.2%, with 61.35% from donors ≥50. Normothermic regional perfusion (NRP) (3.0%–21.7%), NMP (2.3%–35.6%), and sequential NRP-NMP (0.1%–19.2%) increased significantly (p < 0.001). The MP era was associated with a decrease in median waitlist time from 112 to 62 days (p < 0.001). Early graft survival was similar across ages. For ages 50–59, 1- and 3-year survivals were 87.9%/78.4% pre-MP and 90.1%/78.8% in the MP era. For 60–69, survival was 85.0%/80.6% pre-MP and 90.0%/71.3% in the MP era. DCD LTs for ≥70 were limited to the MP era with 87.8% 1-year survival. Multivariable Cox regression showed that static cold storage (HR = 1.19), donor age 50–69 versus 18–49, and recipient age (HR = 1.04) increased the risk of graft loss after adjustment. MP is associated with an increased number of older DCD liver transplants and acceptable early graft survival.

TPS7101 Background: Patients with high-risk CLL/SLL not achieving a complete response (CR) after ≥ 12 months of BTK inhibitor (BTKi) monotherapy remain at risk for early progression due to residual disease and BTKi resistance. A BCL-2 inhibitor (BCL-2i) introduces a complementary, BCR-independent apoptotic mechanism that may deepen responses and prolong progression-free survival (PFS). Lisaftoclax, a selective oral BCL-2i with a short half-life (4-6 h), enables once-daily dosing and is approved in China as second-line CLL therapy. Lisaftoclax monotherapy has demonstrated overall response rates (ORRs) of 67% in relapsed/refractory CLL and 62.5% in BTKi-refractory disease, including del(17p)/ TP53 -mutated cases. Lisaftoclax combined with acalabrutinib achieved ORRs >97% with favorable tolerability. This study evaluates whether lisaftoclax plus BTKi (acalabrutinib, zanubrutinib, or ibrutinib) improves PFS and/or overall survival (OS) (vs continued BTKi monotherapy) in patients with CLL/SLL and residual disease after prolonged BTKi treatment. Methods: This study will enroll approximately 440 patients randomly allocated to receive lisaftoclax plus BTKi or BTKi alone. Eligible patients have CLL/SLL and, after ≥12 months of BTKi monotherapy (lines 1-3), have achieved neither CR nor progressive disease (PD). Randomization is stratified by del(17p)/ TP53 status. Key inclusion criteria include age ≥18 years, ECOG PS 0-2, and residual disease with either high-risk features (del(17p)/ TP53 mutation, unmutated IGHV , or complex karyotype [≥5 abnormalities]), or measurable residual disease with lymph nodes ≥2.5 cm in the absence of high-risk features. Exclusion criteria include prior BCL-2i therapy or Richter transformation. Patients in the investigational arm will undergo a 5-day oral lisaftoclax ramp-up to 400 mg once daily plus physician's choice of BTKi in 28-day cycles until progression or toxicity. Control patients continue their current BTKi monotherapy. Safety and disease assessments (CT/MRI) will occur regularly. The primary endpoint is PFS by independent review committee (iwCLL 2018); key secondary endpoint OS; and other secondary endpoints, PFS by investigator, ORR, duration of response, MRD negativity, and safety. Enrollment is ongoing across 126 sites in 18 countries (ClinicalTrials.gov ID: NCT06104566). Clinical trial information: NCT06104566 .

TPS5632 Background: Concurrent chemoradiation therapy (CCRT) is the standard of care for locally advanced cervical cancer (LACC); however, outcomes remain suboptimal in patients with high-risk disease. Recent studies suggest that integration of immunotherapy (IO) with definitive chemoradiation, or induction chemotherapy prior to CCRT improves outcomes. Whether treatment intensification with induction systemic therapy and IO prior to CCRT and IO further improves disease control remains unknown. Induction chemotherapy may reduce tumor burden, eradicate micrometastatic disease, and improve tumor immunogenicity prior to definitive CCRT. Preclinical and clinical data support synergy between systemic therapy or radiotherapy and immune checkpoint blockade, providing the rationale for evaluating an induction strategy incorporating chemotherapy and immunotherapy before standard CCRT with immunotherapy, followed by maintenance immunotherapy. Optional tumor tissue and blood samples will be collected for exploratory correlative analyses, including immune and molecular biomarkers associated with response, resistance, and patterns of failure. Methods: NRG-GY037 is a prospective, multi-institutional phase III randomized trial conducted through NRG Oncology. A total of 336 patients will be enrolled (168 per arm). Patients will be stratified by FIGO stage (III vs. IVA) and presence or absence of para-aortic lymph nodes (N2). The primary endpoint is progression free survival (PFS). The study has 90% power to detect PFS hazard ratio of 0.65 in the experimental arm. Treatment: Patients with previously untreated, high-risk LACC are randomized to receive either induction chemotherapy with pembrolizumab for 6 weeks followed by CCRT with pembrolizumab and pembrolizumab maintenance, or standard CCRT with pembrolizumab followed by pembrolizumab maintenance. Major Eligibility Criteria: Eligible patients have histologically confirmed cervical carcinoma (squamous, adenocarcinoma, or adenosquamous), TNM T3 and T4 disease, N0-2, ECOG performance status 0–1, and no prior definitive therapy for cervical cancer. Current Enrollment Status: The trial is actively accruing patients. No efficacy or safety data are available at the time of submission. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT07061977. Clinical trial information: NCT07061977 .

e20761 Background: The prognostic role of serial circulating tumor DNA (ctDNA) dynamics during osimertinib treatment has been described mainly in Asian and European populations; however, it remains poorly defined in Hispanic patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC). Our aim was to determine whether serial plasma EGFR testing identifies patients at high risk of early mortality. Methods: This multicenter, retrospective study included 64 Hispanic patients with stage IIIB–IV EGFR-mutant NSCLC treated with first-line osimertinib between 2018 and 2023. Tumor tissue genotyping was performed using hybrid-capture next-generation sequencing. Plasma EGFR mutations were assessed at baseline, week 8, and week 24. Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox models adjusted for p53 status, RAF-pathway alterations, and metastatic burden. Results: The cohort had a median age of 61 years, with 65.6% of patients being female and 56.2% being never-smokers. Sensitizing EGFR mutations consisted mainly of exon 19 deletion (59.4%) and L858R (39.1%). Relevant co-mutations were identified in TP53 (29.7%) and RAF-pathway genes (6.2%). Plasma ctDNA remained positive in 42.2% of patients at week 8 and 22.0% at week 24. Week-8 ctDNA persistence was strongly associated with an inferior OS (HR 9.36, 95% CI 3.80–23.03, p < 0.001) after multivariable adjustment. Week-24 positivity also predicted worse OS (HR 3.34, 95% CI 1.13–9.89, p = 0.02). ctDNA status at week 8 or 24 was not significantly associated with PFS. Patients with TP53 or RAF pathway mutations demonstrated higher rates of molecular persistence. Conclusions: In Hispanic patients receiving Osimertinib, ctDNA positivity at 8-24 weeks is able to identify patients with poor survival outcomes. ctDNA monitoring may provide an early, non-invasive biomarker to guide treatment intensification and trial enrollment in EGFR-mutant NSCLC.

7011 Background: Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) will relapse or have refractory disease following 1L treatment (Tx) with SOC chemoimmunotherapy regimens R-CHOP or Pola-RCHP. High risk (HR) populations include those with International Prognostic Index (IPI) score 3–5 and IPI 1–2 with either ≥1 lesion ≥7 cm or baseline LDH >1.3×ULN. GOLCA is a potential, first-in-class, oral CELMoD designed for the Tx of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA induces rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing and immunomodulatory activity. GOLCA 0.4 mg + R-CHOP has shown promising safety, a ≥90% minimal residual disease (MRD) negativity rate, and durable efficacy (24-mo PFS, 79%) in 1L a-BCL (Nowakowski et al, ASH 2025, 476) and is being evaluated in the Phase (Ph) 3 study GOLSEEK-1 (NCT06356129). We report initial Ph1b results with GOLCA + Pola-RCHP in 1L a-BCL. Methods: Pts aged ≥18 y with ECOG PS ≤2, IPI 0–5 (Part 2A) or 2–5 (Part 2B), and newly diagnosed a-BCL with measurable tumorous disease were included. Pts were treated with GOLCA + Pola-RCHP for six 21-day (D) cycles or until disease progression/unacceptable toxicity/study withdrawal. In dose escalation, GOLCA was dosed at 0.2 and 0.4 mg D1–7. In dose expansion, pts were randomized 1:1 to Pola-RCHP + GOLCA 0.2 or 0.4 mg. Primary endpoint: safety; efficacy was a secondary endpoint. Results: At data cutoff, 57 pts were treated with GOLCA + Pola-RCHP (0.2 mg, n=28; 0.4 mg, n=29). Median age was 63 y. Most pts had HR disease (86%) and DLBCL not otherwise specified histology (84%). For known cell of origin (COO), 47% were germinal center B cell (GCB) and 39% non-GCB by Hans algorithm. Forty-seven pts (83%) completed Tx and 52 (91%) entered the follow-up (f/u) period. Grade 3/4 Tx-emergent adverse events occurred in 95% of pts, most frequently neutropenia (86%; an on-target side effect of GOLCA) and anemia (39%). Median relative dose intensity for GOLCA and Pola-RCHP components was >95%. At 15.5 mo median f/u, end of Tx (EOT) complete metabolic response (CMR) rate was 69% at 0.2 mg, 82% at 0.4 mg, and similar across COO subtypes. EOT CMR was consistent in HR pts (65% at 0.2 mg, 83% at 0.4 mg). The 12-mo DOR and PFS rates were 92% and 88% at 0.2 mg, and 96% and 96% at 0.4 mg. In pts with both pre-Tx and EOT ctDNA analysis, 65% and 83% at 0.2 and 0.4 mg achieved MRD negativity (PhasED-Seq) at EOT. Conclusions: GOLCA + Pola-RCHP demonstrated a predictable and manageable safety profile, and addition of GOLCA did not compromise median dose intensity of Pola-RCHP. GOLCA 0.4 mg + Pola-RCHP resulted in a high rate of durable CMRs, high rate of MRD negativity, and a promising 12-mo PFS rate. These data continue to show that GOLCA + SOC regimens R-CHOP and Pola-RCHP has potential to improve outcomes in 1L HR a-BCL. Clinical trial information: NCT04884035 .

5624 Background: Endometrial cancer (EC) is the most common gynecologic cancer and abnormal uterine bleeding (AUB) is the predominant presenting symptom. While <10% of AUB represents underlying EC, endometrial sampling is currently required to rule out EC. To develop an alternative, non-invasive rule-out strategy, we aimed to refine a previously reported EC-associated methylated DNA marker (MDM) panel in vaginal swabs. Methods: Patients ≥18 years old with AUB who met ACOG recommendations for endometrial sampling and those undergoing a hysterectomy for biopsy-proven EC or atypical hyperplasia (AH) were prospectively enrolled in a multicenter cohort study. A vaginal fluid specimen was collected via swab by a provider during a speculum exam. DNA was extracted from samples and bisulfite treated, followed by a target and signal amplification method to detect 8 previously identified MDMs. The cross-validated EC classification model used the mean of standardized MDMs. Clinical classification of benign endometrium (BE), EC, and AH was based on central pathology review. EC diagnoses were based on hysterectomy specimens. Endometrioid and mucinous constituted type 1 EC; serous, carcinosarcoma, clear cell, and mixed histology ECs were collectively analyzed as type 2. Results: Of 693 participants enrolled, 670 were evaluable with valid results: 524 in the AUB cohort and 146 in the suspected EC cohort. Within the AUB cohort, 16 had EC or AH. The final analysis cohort included 508 BE, 156 EC, and 6 AH. Of the evaluable participants 20% identified as Black, 3% Asian or Pacific Islander, 75% White, and 3% Other; 7% reported Hispanic ethnicity. Median age was 66 and 50 years for EC and BE AUB, respectively; 80% of those with EC and 43% with benign AUB reported being postmenopausal. Among participants with EC, 102 (65%), 17 (11%), 30 (19%), 6 (4%) were stage I, II, III, and IV, respectively; one EC was unstaged. Type 2 EC accounted for 42 (27%) of all EC cases. A 4-MDM panel yielded an AUC of 0.97 (0.96-0.99, 95% CI) for EC; models with 5-8 MDMs gave identical performance. All-stage EC sensitivity was 97, 97, 96, 95, and 92% at specificities ranging from 75, 80, 85, 90, and 95%, respectively. At the 85% (82-88%) specificity threshold, sensitivities across EC stage, type, and age were consistently high (Table). Sensitivity for AH was 33% (10-70%). Conclusions: An MDM panel demonstrated high sensitivity for EC across stage and EC type, supporting the potential for a non-invasive vaginal swab-based test to rule out EC. Future studies are necessary to finalize the panel and algorithm, prior to validating the test. Clinical trial information: NCT06294886 . EC Sensitivity (%, 95% CI) at 85% Specificity All Stages (n=156)* 96 (92-98) Stage I (n=102) 94 (88 - 97) II (n=17) 100 (82 - 100) III (n=30) 100 (89 - 100) IV (n=6) 100 (61 - 100) Type 1 (n=114) 95 (89 - 98) 2 (n=42) 100 (92 -100) Age ≤ 66 yrs (n=86) 95 (89 - 98) > 66 (n=70) 97 (90 - 99) *n=1 EC was un-staged.