Citations

e21521 Background: Outcomes following tumor-infiltrating lymphocyte (TIL) therapy vary in real-world practice, and accessible predictors are needed to inform patient selection and timing of referral. We evaluated whether baseline disease burden, metastatic distribution, and treatment delivery factors are associated with outcomes following TIL therapy. Methods: We retrospectively analyzed patients with metastatic melanoma treated with TIL therapy across Mayo Clinic sites (N = 27 infused). Baseline disease burden was characterized using AJCC metastatic stage and organ-specific involvement. A composite high visceral burden variable was defined as the presence of M1d disease and/or liver metastases. Bridging therapy use prior to infusion was recorded. Post-infusion IL-2 exposure was categorized as low (0-2 doses) vs. high (3-6 doses). Best overall response (BOR) was summarized using RECIST-based standard criteria. Overall survival (OS) and progression-free survival (PFS) were measured from TIL infusion and estimated using Kaplan–Meier methods with univariable Cox regression. Results: Median age at infusion was 62.0 years; 59.3% were male. Melanoma subtypes included cutaneous (81.5%) and mucosal (18.5%). Bridging therapy was used in 48.1%. Baseline metastatic stage was M1a/M1b in 18.5%, M1c in 63.0%, and M1d in 18.5%. Median follow up was 8.3 months. BOR included complete response (18.5%), partial response (37.0%), stable disease (22.2%), and progressive disease (22.2%), yielding an objective response rate of 55.6% and disease control rate of 77.8%. Patients with high visceral disease burden experienced inferior OS vs. those without high visceral burden (median 5.2 vs 13.4 months; HR 4.77, 95% CI 1.22–18.63; p = 0.014). Bridging therapy was not associated with OS or PFS. Higher post-infusion IL-2 exposure (seen in 77.8% of patients) was associated with improved OS (median 9.0 vs 3.7 months; HR 0.16, 95% CI 0.04–0.67, p = 0.005), likely reflecting early post-infusion clinical tolerance rather than a causal treatment effect. Median PFS for the cohort was 3.6 months and did not differ by IL-2 exposure ( p = 0.3), metastatic stage ( p = 0.8), bridging therapy ( p = 0.7), liver metastases ( p = 0.2), or LDH above upper limit of normal ( p = 0.1). Conclusions: The above findings are hypothesis generating and will support evaluation in larger cohort. In this real-world cohort of patients treated with TIL therapy, baseline visceral disease burden was strongly associated with survival outcomes, while bridging therapy did not compromise post-infusion efficacy among patients proceeding to infusion. Post-infusion IL-2 exposure correlated with OS and likely reflects early treatment tolerance. These readily available clinical features may inform patient counseling, referral timing, and sequencing decisions as TIL therapy enters broader clinical use.

e18607 Background: Progression to myelofibrosis (MF) is associated with worse survival and influences treatment decisions, yet predictors of fibrotic progression in polycythemia vera (PV) and essential thrombocythemia (ET) remain poorly characterized. Methods: Patients with pathologically confirmed PV or ET were identified from a retrospective chart review. Demographics (age, sex, race, ethnicity), clinical features (thrombosis and bleeding history, performance status, symptom burden, organomegaly), bone marrow pathology (cellularity, trilineage hematopoiesis, megakaryocyte proliferation and atypia, fibrosis grade), molecular markers ( JAK2 , CALR , MPL , ASXL1 , EZH2 , TET2 , SRSF2 , IDH1/2 , SF3B1 , TP53 ), cytogenetics, laboratory values, and treatment history (phlebotomy, hydroxyurea, interferon, ruxolitinib) at first bone marrow biopsy were recorded. MF progression was defined as hematologist-confirmed transformation to MF. Kaplan-Meier analyses estimated median MF-free survival (MFS), defined as time to MF progression or death. Univariable followed by multivariable Cox proportional regression were performed to identify candidate MFS predictors. The proportional hazards assumption was assessed using Schoenfeld residuals. Hazard ratios (HR) with 95% confidence intervals (CI) were computed, with p<0.05 indicating statistical significance. Results: A total of 505 PV and 198 ET patients were identified. The majority were White (PV: 92%; ET: 86%). PV patients were predominantly male (54%) whereas ET patients were predominantly female (66%). MF progression occurred in 160 (32%) PV and 32 (16%) ET patients. Death was observed in 139 (28%) PV and 10 (5%) ET patients. Median MFS was 158.5 months (95% CI: 143.0-183.0) for PV and 308.0 months (95% CI: 175.0-NR) for ET. In PV, older age at diagnosis (HR 1.04; 95% CI: 1.02-1.07; p<0.001) and shorter time since PV or ET diagnosis to biopsy (HR 0.995; 95% CI: 0.990-0.999; p=0.048) independently predicted worse MFS. In ET, bone marrow hypercellularity (HR 5.67, 95% CI: 1.40-23.0, p=0.015) independently predicted worse MFS. Conclusions: PV patients demonstrated shorter MFS compared to ET. Older age at diagnosis in PV, whereas bone marrow hypercellularity in ET was significantly associated with fibrotic progression or death. Active surveillance of at-risk patients may facilitate early detection and timely treatment initiation. Disease Variable HR (95%CI) P-value PV Age at diagnosis 1.04 (1.02-1.07) <0.001 Time since PV or ET diagnosis to biopsy 0.995 (0.990-0.999) 0.048 ET Bone marrow hypercellularity 5.67 (1.40-23.0) 0.015

e18524 Background: Venetoclax (Ven) in combination with hypomethylating agents (HMA) is FDA-approved front-line therapy for elderly or unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML); however, majority relapse or are refractory ( Pratz AJH 2024 ). We examined survival outcomes in the setting of frontline Ven-HMA failure. Methods: ND-AML patients with failure to achieve complete remission (CR/CRi) or loss of CR/CRi after front-line Ven+HMA, excluding post-transplant relapse were retrospectively studied. Response was evaluated per European Leukemia Net 2022 criteria ( Dohner Blood 2022 ). Results: 356 patients with ND-AML (median age 75 years; 65% males; 55% secondary) receiving frontline Ven+HMA (median; 3 cycles (1-26), had refractory [n=219 (62%)], or relapsed disease [137 (38%)]. At diagnosis, karyotype was complex in 142/347 (41%). Mutations involved TP53 (29)%, ASXL1 (19%), RUNX1 (17%), SRSF2 (15%), KRAS/NRAS (13%), IDH2 (7%), FLT3-ITD (7%), NPM1 (6%) and IDH1 (5%). At treatment failure, complex karyotype was present in 72/180 (40%), including 55 from baseline. In 137 patients with paired NGS, mutations persisted in TP53 (88%), IDH1 (86%), IDH2 (78%), NPM1 (75%), K/NRAS (73%), RUNX1 (70%), FLT3-ITD (65%) mutations. Mutations were acquired in a minority [ IDH1 / IDH2 (2% each) TP53 (3%), NPM1 (4%), FLT3-ITD (5%) K/NRAS (6%)]. Clearance of mutations were infrequent for TP53 (12%) and IDH1 (14%). At median follow-up of 4 months (mo) (0-80) from the time of relapse/refractory disease, 320 (90%) patients have died, with median survival of 4 mo (1-2-3 yr survival 19%/8%/5%). On multivariate analysis, peripheral blasts >20%, complex karyotype, and wild-type IDH1 were independent predictors of inferior survival, while allogeneic stem cell transplant (ASCT) was associated with improved survival. A 3-point prediction model based on peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 stratified patients into low-, intermediate-, and high-risk groups, with median survival of 7, 3, 2 months, respectively (p<0.01). 13 patients underwent ASCT (median survival; 22.5 mo; 3-yr survival 33%), from low (n=10) or intermediate-risk groups (n=3). Salvage therapy (n=170, 48%) yielded CR/CRi of 31% for Ven+HMA (n=36), 54% intensive chemotherapy (n=26), 50% FLT3 inhibitors (i) (n=22), 37% IDH1/2i (n=19), 25% other regimens (n=69). Median survival was similar: Ven+HMA 8 mo, intensive chemotherapy 10 mo, FLT3i 6.5 mo, IDH1/2i 14 mo, other regimens 6 mo, but inferior with supportive care (2 mo; p<0.01). Conclusions: The current study identifies peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 as predictors of inferior survival in ND-AML relapsed/refractory to front-line Ven+HMA and underlines that while no specific salvage therapy conferred superior outcomes, ASCT was indispensable for long-term survival.

e13656 Background: Effective multidisciplinary cancer care is bottlenecked by the cognitive burden of synthesizing fragmented electronic health records across different specialties. Current AI tools often function as isolated chatbots rather than integrated workflow assistants. We developed and validated "OncoSphere AI," an Agentic AI multidisciplinary clinical workflow support tool designed to autonomously orchestrate the multidisciplinary review process by deconstructing complex cases into domain-specific insights. Methods: OncoSphere AI is a novel, multi-agent large language model–driven platform that simulates a multidisciplinary tumor board for cancer care. The architecture uses a parallel reasoning framework in which eight virtual specialty agents—Medical Oncology, Radiation Oncology, Surgical Oncology, Pathology, Radiology, Pharmacy, Clinical Research, and Nurse Navigation—independently analyze structured and unstructured patient data against specialty specific guidelines and contemporary peer-reviewed literature. System performance was assessed via built-in telemetry (task completion, latency, inter-agent agreement) and blinded review by eight expert oncologists using a structured survey to rate data extraction fidelity, guideline concordance, safety, and clinical utility compared with standard manual review. Results: The study cohort (n=20, median age 59.5 years; 55% female) had a median of 2.5 (range 0-7) prior lines of therapy and multiorgan metastatic disease (median: 2, range 1–4), including lung, breast, gastrointestinal (CRC, pancreatic, hepatobiliary), and genitourinary (prostate, renal) malignancies. OncoSphere AI demonstrated high workflow utility (mean rating: 4/5) and strong extraction fidelity, with more than 90% of biomarker extractions rated as a “perfect match” by expert reviewers. Operational efficiency gains were substantial with AI processing averaged 4.7 minutes per case versus 29.3 minutes for manual review, corresponding to an 84% reduction in time (p<0.001). System telemetry revealed adaptive compute behavior, with the platform autonomously allocating 1.73-fold more reasoning tokens to complex, refractory cases than to standard scenarios. Safety review identified only one critical contraindication issue in a heavily pretreated, multi-line setting. Conclusions: OncoSphere AI effectively automates the clinical “perception layer,” consistently transforming heterogeneous longitudinal data into decision-grade insights with high fidelity and marked time savings. By operating as a coordinated ensemble of domain-specialized AI agents rather than a single generic model, it offers a scalable approach to reduce physician cognitive burden and to standardize guideline-concordant care planning in diverse, heavily pretreated oncology populations.

Objectives To evaluate whether extracellular volume (ECV) fraction derived from contrast‐enhanced computed tomography (CT) is associated with recurrence risk in patients with treatment‐naïve high‐risk non‐muscle‐invasive bladder cancer (HR‐NMIBC) receiving intravesical gemcitabine/docetaxel (Gem/Doce) therapy. Patients and Methods This retrospective cohort study, conducted at a tertiary referral centre, included 103 patients with HR‐NMIBC treated with intravesical Gem/Doce between 2012 and 2024. All patients underwent pre‐resection contrast‐enhanced CT with an equilibrium phase (~3 min post‐injection). Tumour ECV fraction (%) was calculated using the formula: ECV = (ΔHUtumour/ΔHUaorta) × (1 − haematocrit) × 100, where Δ Hounsfield units (HU) represents the change in attenuation between non‐contrast and equilibrium phases. Regions of interest were manually placed in the tumour and abdominal aorta, and haematocrit values obtained within ±10 days were used. Associations between clinical variables, ECV, and recurrence were evaluated using Cox proportional hazards models, with discrimination assessed by Uno's C‐statistic. Results The median (interquartile range) follow‐up was 17 (10–25) months. High‐grade recurrence‐free survival (HG‐RFS) was 76% at 12 months and 69% at 24 months. CT‐derived ECV was the only variable significantly associated with HG‐RFS (hazard ratio 1.05, 95% confidence interval 1.03–1.08), demonstrating strong discrimination (C‐statistic, 0.81; P < 0.01). A 15% threshold offered the best sensitivity–specificity trade‐off (~70% each) for predicting HG‐RFS at 12 and 24 months. Patients with ECV ≤15% had markedly better HG‐RFS than those with ECV >15% at 24 months (88% vs 41%). Conclusions The CT‐derived ECV is a practical, first‐of‐its‐kind imaging biomarker associated with recurrence risk and useful for risk stratification in patients with HR‐NMIBC treated with intravesical Gem/Doce, a regimen increasingly used in the setting of global Bacillus Calmette‐Guérin shortages and intolerance. ECV can be rapidly quantified from routine contrast‐enhanced CT using standard picture archiving and communication system (PACS) tools, without additional imaging or proprietary software, making it a feasible metric for integration into risk‐adapted management pending large‐scale validation with extended follow‐up.

9510 Background: Although acute toxicities associated with adoptive cellular therapy using lifileucel are well described and largely occur within the first 2 weeks of treatment, adverse events beyond this early window remain incompletely characterized. We sought to characterize treatment-related adverse events (AEs) with emphasis on those starting or persisting ≥2 weeks after lifileucel infusion. Methods: We conducted a retrospective multicenter study across three centers (Moffitt Cancer Center, Massachusetts General Hospital, and Mayo Clinic). Patients with advanced melanoma treated with lifileucel were included. The primary endpoint was incidence and characterization of AEs occurring or persisting ≥2 weeks after standard of care lifileucel infusion. Results: Among 79 patients (median follow-up 11 months [95% CI, 9.6–15]), median age was 63 years (range 30–79), 59% were male (n = 47), 41% were female (n = 32), and ECOG PS was 0–1 in 98%. Patients received a median of 5 IL-2 doses (range 0–6). Of 79 patients, 78 experienced treatment-related adverse events that either persisted or occurred >2 weeks after cell infusion. A total of 308 delayed treatment-related adverse events were identified; 96 were new events (31%) and 212 (69%) were continued toxicities that started < 2 weeks after cell infusion. Lymphopenia was the most common delayed or persistent toxicity, occurring in a majority of patients (n = 68/79, 86%). Treatment-associated anemia (n = 59/79, 75%), fatigue (n = 56/79, 71%) and thrombocytopenia (n = 24/79, 30%) were also common. Viral infections occurred in 9.0% (n = 7), including CMV/EBV viremia (n = 1) and respiratory or gastrointestinal viral infections (metapneumovirus, parainfluenza, SARS-CoV-2, and norovirus). Hemophagocytic lymphohistiocytosis (HLH) occurred in 2 patients (n = 2/79, 3%) and was fatal in both cases. No other toxicity related deaths were noted. Autoimmune toxicities directly attributable to TIL included vitiligo in 9% (n = 7; median onset 41 days), uveitis in 5% (n = 4; median onset 26 days), and sensorineural hearing loss in 1% (n = 1; onset 28 days). All patients underwent TIL infusion in the inpatient setting; a total of 14 of 79 patients (18%) were re-admitted after discharge due to treatment-related toxicity (median time from infusion 19 days). Conclusions: In this multicenter real-world cohort, toxicities persisting beyond two weeks were largely driven by lymphodepleting chemotherapy–associated immunosuppression and cytopenias. These findings highlight the importance of structured post-discharge monitoring and support ongoing efforts to de-intensify lymphodepleting chemotherapy to improve safety while maintaining clinical benefit.

9551 Background: Lymphodepleting (LD) chemotherapy is required prior to tumor-infiltrating lymphocyte (TIL) therapy, yet the depth, kinetics, and completeness of peripheral T-cell recovery in practice remain poorly defined. Using a pooled, multi-institution cohort, we characterized longitudinal CD4 and CD8 T-cell reconstitution and the prevalence of CD4 lymphopenia following TIL therapy. Methods: We conducted a retrospective multicenter study across Mayo Clinic, Moffitt Cancer Center, and Massachusetts General Hospital of patients with metastatic melanoma treated with TIL (N = 41, median follow-up 7.6 months). Absolute CD4 and CD8 T-cell counts and CD4:CD8 ratios were assessed at baseline (pre-LD), week 4, month 3, and month 6 post-TIL. Clinically significant CD4 lymphopenia was defined as CD4 < 200 cells/µL. All patients received Pneumocystis jirovecii and antiviral prophylaxis, with antibacterial and antifungal prophylaxis administered per institutional protocols. Post-TIL infections were recorded. Paired changes from baseline were evaluated using Wilcoxon signed-rank testing. Results: Median age was 65 years (range 35-79), and 68% were male. At baseline, 16 patients (39%) had CD4 counts below the institutional lower limit of normal prior to LD. Eighteen patients (44%) received bridging therapy prior to TIL and had lower baseline CD4 and CD8 counts compared with those who did not ( p < 0.05 for both); however, post-TIL CD4 and CD8 recovery trajectories did not differ between groups. CD4 counts declined sharply following LD and demonstrated incomplete and heterogeneous recovery. Median CD4 decreased from 490 cells/µL at baseline to 250 at week 4, 290 at month 3, and 220 at month 6, remaining significantly below baseline at all post-TIL timepoints ( p < 0.05). Clinically significant CD4 lymphopenia was observed in 45% (10/22) of evaluable patients at month 3 and in 50% (44%, 7/16) at month 6. In contrast, CD8 counts increased early after TIL (median 240 to 590 cells/µL at week 4; p = 0.004) and remained higher than baseline at month 6. The CD4:CD8 ratio inverted from a median of 2.02 at baseline to 0.46 at week 4 and remained below 1.0 through month 6, reflecting sustained CD4 suppression despite CD8 recovery. Post-TIL infections occurred despite widespread prophylaxis, including bacterial (13%), viral (10%), and fungal (4.9%) infections. Conclusions: In a multi-institution cohort, LD chemotherapy preceding TIL is associated with profound and prolonged CD4 T-cell suppression, persistent CD4:CD8 inversion, and a high prevalence of CD4 < 200 cells/µL through 6 months. These findings identify delayed immune reconstitution as a common and clinically relevant consequence of TIL therapy and support prospective optimization of antimicrobial prophylaxis duration, vaccination timing, and immune monitoring strategies.

8519 Background: Non-classical mutations (NCM) of epidermal growth factor receptor (EGFR) represent a broad group of oncogenic mutations in non-small cell lung cancer (NSCLC), often associated with resistance to osimertinib (e.g., P-loop and αC-helix compressing [PACC] mutations). Patients (pts) with NCM have inferior clinical outcomes with a high incidence of CNS metastases (CNSm). Silevertinib (BDTX-1535) is a fourth-generation, covalent EGFR TKI with high CNS penetrance targeting both EGFR classical mutations and NCM. The antitumor activity and safety of silevertinib in pts with advanced NSCLC were evaluated in a Phase 2 trial (NCT05256290). Methods: Pts with advanced EGFR NCM NSCLC who received no prior systemic therapy were enrolled (Cohort 3) based on a local molecular test. Silevertinib 200 mg was administered orally once daily. The primary endpoint of objective response rate (ORR) was assessed using RECIST v1.1. CNS ORR was assessed using Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) in pts with no prior CNS therapy. Secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), and safety. Results: From February 2024 to July 2025, 43 pts with 35 unique NCMs (including 25 pts with PACC mutations) were enrolled in Cohort 3: median age 70.0 years, 72% female, 74% white, and 42% never smoked cigarettes. As of November 3, 2025, median follow-up was 7.2 months. ORR by RECIST v1.1 is shown in the table. Sixteen pts (37%) had CNSm, including 7 pts (16%) with measurable CNS disease. RANO-BM CNS response was 86% (n=6/7). Complete clearance of EGFR VAF ctDNA was observed in 21/26 (81%) evaluable pts. Serious treatment-related adverse events (TRAEs) were reported in 5 pts (12%), and 4 pts (9%) discontinued treatment due to TRAEs. The most common TRAEs included rash (19%, grade 3), diarrhea (19%, grade 3), stomatitis (9%, grade 3), and paronychia (5%, grade 3). While 77% of pts had a dose reduction, 19/22 (86%) patients with a radiographic response maintained or deepened their response after dose reduction, including all patients with CNS response. Conclusions: Silevertinib demonstrated robust antitumor activity in treatment-naïve pts with a broad spectrum of NCM EGFR driver mutations with high intracranial activity in pts with brain metastases. The safety profile was consistent with the known AEs of the EGFR TKI class. Clinical trial information: NCT05256290 . Data as of November 3, 2025 N ORR n (%) 95% CI DCR n (%) 95% CI ITT Population * 43 26 (60) (44.4, 75.0) 39 (91) (77.9, 97.4) PACC mutations 25 14 (56) (34.9, 75.6) 22 (88) (68.8, 97.5) Compound mutations † 16 11 (69) (41.3, 89.0) 15 (94) (69.8, 99.8) *No pts with classical (E746_A750del or L858R) mutations were enrolled. † Presence of ≥ 2 NCMs. As of December 27, 2025, the 6-month PFS rate was 86% overall and 80% in pts with CNSm; available PFS and DOR data will be presented.

7533 Background: Ciltacabtagene autoleucel (cilta-cel) shows benefit for patients (pts) with relapsed/refractory multiple myeloma (RRMM). A recently recognized uncommon adverse reaction, IEC-EC is characterized by severe/persistent diarrhea typically 1–3 months post CAR-T cell infusion. Here we summarize incidence and features of IEC-EC in clinical trials of cilta-cel for RRMM. Methods: 483 pts across RRMM studies (CARTITUDE-1, -2, -4, and CARTIFAN-1) were evaluated for evidence of IEC-EC. The clinical picture and nomenclature for IEC-EC were described in the real-world setting after infusion of most pts. As such, retrospective analysis was performed to identify cases consistent with IEC-EC, defined as prolonged (≥3 weeks) and severe (≥grade 3) diarrhea after cilta-cel infusion, without clear infectious etiology. Correlative biomarker analyses included peripheral CAR-T cell expansion/persistence, immune cell composition, and cytokines/inflammatory markers. Centralized pathomorphological review and immunohistochemical analysis of available biopsies was conducted. Results: Across RRMM studies, 6/483 (1.2%) pts demonstrated the clinical picture of IEC-EC, presenting 12–214 days after receiving cilta-cel (median onset 67 days post infusion). Best response was CR/sCR for all subjects. Pts received therapies including steroids (4/6). Four pts experienced symptom resolution within 123–227 days; 2 had persistent symptoms until death (causes: multiorgan failure and COVID19). Pts with IEC-EC had lower levels of B cells and higher levels of CAR+ T cells and inflammatory cytokines (eg, IL-6) at onset compared to a GI symptom-free control group at comparable time; while all cilta-cel–treated pts experienced B cell depletion, pts with IEC-EC had more prolonged deficiency. Histological analyses of GI biopsies from 5 pts with IEC-EC revealed plasma cells, normally present in the GI tract, were absent. CAR-T cells were detected and localized to the lamina propria and were not observed juxtaposed with epithelia, making it unlikely direct damage to epithelia was caused by CAR-T cells. Histologic damage was greater in the small intestine (predominantly duodenum) than the colon. Conclusions: Retrospective analysis of cilta-cel trials identified a low IEC-EC incidence (1.2%). Findings support a reactive mechanism involving plasma cell depletion and immune dysregulation rather than direct CAR-T cell cytotoxicity and highlight the importance of upper endoscopy to identify injury patterns in the small intestine that may be less pronounced in the colon. Although the pathophysiology is not fully defined, increased awareness and earlier diagnosis may improve understanding of management and enhance likelihood of IEC-EC reversibility.