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Large language model protein set generation for interpretable serum proteomics in localized prostate cancer.

5110 Background: High-plex serum proteomics can track prostate cancer biology and treatment response beyond PSA, but interpretation is limited by high dimensionality. Pathway analysis can help, but incomplete overlap between legacy pathway libraries and assay panels can yield hard-to-interpret enrichments dominated by a few measured proteins. We evaluated an automated large language model (LLM) workflow using protein annotations to build protein sets containing only measured proteins. Methods: Serum from 88 individuals was profiled with an aptamer-based ~7,000-protein assay (SomaScan 7K; SomaLogic, USA). The cohort included localized prostate cancer treated with radiotherapy (RT) with or without androgen-deprivation therapy (ADT) with serial sampling (pre-RT n = 76, end-RT n = 72, ~1-month follow-up n = 76), plus metastatic (n = 4) and normal controls (n = 8). Assay fidelity was assessed by correlating PSA aptamers with clinical PSA. Protein-level analyses tested ADT effects and paired within-patient changes across RT. For program-level analysis, UniProt annotations for each measured protein were processed with an LLM to generate structured summaries, converted to embeddings, and clustered into protein sets restricted to SomaScan proteins. Set coherence and assay coverage were compared to Gene Ontology (GO) and Reactome mappings. Protein-set enrichment comparing ADT vs no ADT identified candidate programs and were evaluated for association with biochemical recurrence among high-risk ADT-treated patients (n = 50; 20 events) using Cox models adjusted for pre-treatment PSA. Results: PSA aptamers correlated with clinical PSA (Spearman r = 0.66–0.77). ADT suppressed reproductive-axis proteins (LH, FSH, hCG) and prostate-lineage proteins (PSA, PAP, TGM4); RT contrasts captured acute epithelial injury/lymphoid suppression followed by remodeling and stress responses. LLM protein sets showed higher set name/protein description coherence (median cosine similarity 0.59) than GO (0.30) or Reactome (0.36) and covered all measured proteins; GO/Reactome sets averaged ~50% member coverage. Pre-RT ADT enrichment identified histone programs (NES 2.13–2.18; FDR < 0.01), summarized as a Histone H2 score. Histone H2 score increased across no ADT, ADT, and metastatic samples (Kruskal–Wallis p = 0.003; all pairwise FDR < 0.05). In high-risk ADT-treated patients, pre-RT Histone H2 score was associated with recurrence (HR 0.53, FDR = 0.024), and remained significant in a bivariate model with pre-treatment PSA (Histone H2 HR 0.49, FDR = 0.013; PSA HR 2.78, FDR < 0.001). Non-H2 histone score (H1/H3) showed no ADT-associated shift (Wilcoxon p = 0.70), supporting specificity of the Histone H2 signal. Conclusions: LLM-derived protein sets restricted to measured proteins improved interpretability of serum proteomics and revealed an ADT-associated Histone H2 program complementary to PSA.

Reproductive outcomes after chemotherapy in young women with non-Hodgkin lymphoma: A systematic review and meta-analysis.

e19098 Background: With improving survival in young women with non-Hodgkin lymphoma (NHL), fertility outcomes have become an important survivorship concern. Chemotherapy related gonadotoxicity varies by regimen, yet pregnancy outcomes after modern NHL treatments remain incompletely characterized. We performed a systematic review and meta analysis to evaluate post treatment pregnancy rates in young female NHL survivors across chemotherapy regimens and to assess the impact of fertility preservation strategies. Methods: A systematic literature search of PubMed, Embase, and Cochrane Library from inception through December 2024 was conducted following PRISMA guidelines. Eligible studies included reproductive aged women with NHL treated with systemic chemotherapy and reporting post treatment pregnancy outcomes. The primary endpoint was post treatment pregnancy rate. Secondary analyses included chemotherapy regimen type and use of fertility preservation strategies. Random effects meta analysis was used to pool pregnancy rates. Heterogeneity was assessed using I² statistics. Results: Twelve observational studies comprising approximately 350 young female NHL survivors met inclusion criteria. The pooled post treatment pregnancy rate was 45% (95% CI, 38–52), with moderate heterogeneity (I² = 46%). CHOP and R CHOP based regimens demonstrated the highest pregnancy rates, ranging from 45% to 55%. More intensive regimens, including R CHOEP, dose adjusted EPOCH R, and Hyper CVAD, were associated with slightly lower but still favorable pregnancy rates (30–45%), particularly in women under 35 years of age. Increasing age at treatment and higher cumulative cyclophosphamide dose were consistently associated with reduced pregnancy rates. Use of gonadotropin releasing hormone agonists during chemotherapy was not associated with a statistically significant improvement in pregnancy outcomes. Most reported pregnancies occurred without assisted reproductive technologies, although successful pregnancies following oocyte or embryo cryopreservation were described in selected patients. Conclusions: Nearly half of young women treated for NHL are able to achieve pregnancy after chemotherapy, particularly following standard CHOP based regimens. While intensified regimens may carry increased gonadotoxic risk, meaningful fertility potential remains in younger patients. Routine use of ovarian suppression alone does not appear to improve pregnancy outcomes. These findings support individualized fertility counseling and early referral for fertility preservation in higher risk patients while reassuring many young women with NHL regarding post treatment reproductive potential.

Clinical burden and downstream consequences of severe fluoropyrimidine-associated toxicity in a single-center study.

e24176 Background: Fluoropyrimidines are widely used in the treatment of gastrointestinal and other solid tumors but are associated with potentially life-threatening toxicities. While fluoropyrimidine-associated toxicity has been well described in European cohorts, real-world data on severe toxicity and downstream clinical consequences in U.S. practice remain limited. Methods: We conducted a retrospective observational study of adult patients treated with systemic fluoropyrimidine-based chemotherapy within a single health system serving a predominantly rural population in Southwest Virginia. Between 2015 and 2025, 299 patients received systemic fluoropyrimidine therapy, of whom 21 met inclusion criteria for grade ≥3 chemotherapy-induced toxicity (7%). Toxicities were graded according to CTCAE v6. Toxicities and downstream acute care utilization events were included if they occurred within 90 days of treatment initiation. Time to toxicity was defined as days from treatment initiation to the first documented event. Descriptive statistics were used. Results: Of patients with severe fluoropyrimidine-associated toxicity, median age was 64 years, and 52.4% of patients were female. Most patients had an ECOG performance status 0–1. Colorectal cancer was the most common malignancy. Regimens included FOLFOX (42.9%), single-agent oral fluoropyrimidine therapy (38.1%), FOLFIRINOX (14.3%), and XELOX (4.8%); treatment intent was palliative in 66.7% and curative or adjuvant in 33.3%. Maximum toxicity grade was 3 in 66.7% and 4 in 33.3% of patients. Median time to toxicity was 22 days (IQR, 15–30), with 85.7% developing grade ≥3 toxicity within 30 days and 23.8% within 14 days. Common grade ≥3 toxicities included neutropenia (42.9%), thrombocytopenia (33.3%), hand-foot syndrome (28.6%), diarrhea (23.8%), and mucositis (14.3%). Within 90 days, 52.4% required emergency care, 61.9% were hospitalized, and 23.8% required ICU admission; overall, 66.7% experienced a high-acuity clinical event. Permanent fluoropyrimidine discontinuation occurred in 57.1% of patients. Compared with patients with grade 3 toxicity, those with grade 4 toxicity experienced higher rates of hospitalization (85.7% vs 50.0%), ICU admission (42.9% vs 7.1%), and treatment discontinuation (85.7% vs 42.9%). Grade ≥3 hand-foot syndrome was more common with oral capecitabine, whereas hematologic toxicities were more frequent with IV 5-FU–based regimens. Conclusions: Severe fluoropyrimidine-associated toxicity occurred early and was associated with substantial acute care utilization and frequent treatment discontinuation in this U.S. population, highlighting the need for improved upfront risk stratification strategies.

Improving germline genetic testing rates among newly diagnosed breast cancer patients.

e22645 Background: Germline genetic testing is important for newly diagnosed breast cancer (BC) patients (pts) as results drive treatment decisions and identification of hereditary cancer risk. In 2023, the National Cancer Institute reported testing rates for people with cancer were still low and a major concern, as testing results can change recommended screening and treatment. In January 2024, ASCO updated guidelines recommending germline testing for all pts 65 years or younger and selected older individuals. At Sylvester Comprehensive Cancer Center (SCCC), part of University of Miami Health System, 45% of newly diagnosed BC pts received genetic testing in 2023. To ensure compliance with updated guidelines, SCCC implemented a targeted initiative to increase germline testing rates by 5% by the end of 2024. Methods: A quality improvement initiative (QII) using a Plan–Do–Study–Act framework was implemented. During the Plan phase breast surgical and medical oncologists were surveyed to identify preferred testing methods and existing testing barriers. The barriers identified included a lack of pre- and post-test counseling patient education materials, guideline awareness, and availability of genetic counselors (GCs). During the Do phase, educational videos and flyers were developed in English and Spanish by a geneticist and GCs. If pts had additional questions, they could schedule an appointment with a GC. A Best Practice Alert (BPA) was also created in the EMR to remind providers to order testing or refer to cancer genetics clinic. Flyers were distributed to all breast surgical and medical oncology clinics. During the Study phase we tracked testing rates and provider feedback. Adjustments to the BPA were made to increase efficacy and decrease burden on providers. During the Act phase, we analyzed testing rates. Results: After implementation of the QII, germline testing completion rose from 45% to 67% in 2024, a 22% increase that exceeded our 5% target. Testing rates were reassessed for the first half of 2025 and found to have increased an additional 14%, a total of 81% of BC pts were now undergoing germline genetic testing. We continue to monitor rates bi-annually to ensure continued adoption and optimization of interventions. Conclusions: This initiative substantially improved genetic testing rates at SCCC, demonstrating the effectiveness of a multifaceted approach, reflective of the needs and workflow of providers. Provider education, patient-facing resources, and electronic decision-support tools worked collectively to reduce barriers, standardize test selection, and enhance adherence to guidelines. The continued increase in testing highlights the sustainability of this approach in routine oncology practice, ultimately leading to more personalized care for pts and families. We hope to apply this strategy to increase rates of genetic testing across all cancer subtypes and improve on rates of cascade testing as well.

A phase II trial of tagraxofusp, hyper-CVAD, and venetoclax for patients with newly diagnosed or relapsed/refractory BPDCN.

6502 Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with (w/) historically dismal outcomes, including median (med) overall survival (OS) of 8 – 12 months (mos) and frequent central nervous system (CNS) involvement (Martin-Martin Oncotarget 2016, Pemmaraju Blood 2021). Tagraxofusp (TAG; first CD123-targeted therapy approved for BPDCN) improves responses (Pemmaraju JCO 2022), but relapse remains common. Venetoclax (VEN) demonstrates activity in BPDCN (Montero Cancer Disc 2017), and intensified chemotherapy may improve outcomes. We report the results of a phase II investigator-initiated trial (NCT04216524) of TAG, Hyper-CVAD, and VEN in newly diagnosed (ND) or relapsed/refractory (R/R) BPDCN. Methods: Adults (≥18 years [yrs]) w/ ND or R/R BPDCN received: Cycle [C] 1: TAG days [d] 1-5; C2, 4, 6, 8: TAG d1 – 5 w/ VEN d2 – 14 (C2) and d1 – 7 (C4, 6, 8); C3, 7: VEN d1 – 7 w/ Hyper-CVAD or mini-hyper-CVD; C5: VEN d1 – 7 w/ high-dose methotrexate/cytarabine or mini-methotrexate/cytarabine. Cycles were 28 days for up to 8 cycles, followed by POMP, VEN, and TAG maintenance. Pts received ≥8 intrathecals. Results: Nineteen pts were enrolled (14 ND; 5 R/R). Med age was 61 yrs (range, 20 – 79); 79% male. Disease sites included 84% skin, 63% bone marrow, 16% CNS, 16% extramedullary. Co-occurring mutations were TET2 (60%), ASXL1 (33%), DNMT3A (20%), NRAS (13%), KRAS (13%). Two pts had prior/concomitant MDS. For ND, overall response rate (ORR; complete remission [CR] plus CR w/ incomplete count recovery [CRi] plus partial response [PR]) was 93% (13/14, all CR/CRi). Pts received a med of 2 (1 – 6) cycles w/ 2 (1 – 3) cycles to best response. The 30- and 60-day mortality was 0%. After a 55-mos med follow-up, (19.5 – NR), med OS was 15 mos w/ 24-month OS of 42%. Med EFS was 14.6 mos w/ 24-month EFS of 42%. Nine pts (65%) went to stem cell transplant (SCT) (2 died in CR, 6 remain alive in CR; of these, 3 remain alive in CR almost 5 yrs; with only 1 post-SCT relapse). In the 4 responding pts who did not go to SCT, 3 relapsed, 1 died in CR. For R/R, ORR was 100%; CR/CRi of 50%. Pts received a med of 2 (2 – 4) prior lines; 3 (60%) had prior SCT. Pts received a med of 3 (1 – 7) cycles w/ 3 (1 – 3) to best response. Two pts went to SCT (1 auto, 1 allo); 1 pt is alive on active treatment. The 30- and 60-day mortality was 0% and 20%. With f/u ranging 1.4 – 21.8 mos, med OS and EFS is 8.9 mos; 12-month OS and EFS was 30%. In responding pts, causes of death were progression n = 4; died in CR n = 5 (3 ND, 2 R/R, 1 post SCT, 1 unknown, 3 sepsis). The most common any grade adverse events (AE) were edema (n = 13) and fatigue (n = 11). There were 2 grade 5 AE (progression, respiratory failure). Two grade 3 capillary leak events were observed. Conclusions: As frontline therapy, TAG with Hyper-CVAD, and VEN shows promising safety with no early mortality or high-grade CLS, with high response rates enabling frequent SCT consolidation and no CNS relapse. Clinical trial information: NCT04216524 .

Randomized multicenter phase II trial of radioimmunotherapy versus chemoimmunotherapy followed by surgery for c-stage IB-III NSCLC (RICHIS trial).

TPS8132 Background: Chemotherapy combined with PD-1 or PD-L1 blockade (chemo-immunotherapy, ChemoIO), administered in the neoadjuvant, adjuvant, or perioperative setting, has become standard of care for surgically resectable non-small cell lung cancer (NSCLC). However, ChemoIO may be associated with significant toxicity that may limit treatment delivery and compromise surgical fitness. Preclinical data demonstrate that non-ablative stereotactic body radiotherapy (SBRT) can synergize with immunotherapy by enhancing tumor antigen release, interferon signaling, T-cell priming, and systemic antitumor immunity. We previously completed a phase II trial comparing neoadjuvant non-ablative SBRT (24 Gy) plus immunotherapy (SBRT-IO) versus immunotherapy alone, demonstrating favorable tolerability and higher rates of major and complete pathological response (MPR, pCR) in the SBRT-IO arm. SBRT-IO may therefore represent a neoadjuvant alternative for selected patients, with the potential to reduce treatment-related toxicity. Methods: RICHIS (NCT06623656) is an open-label, multicenter, randomized phase II trial enrolling approximately 112 patients with histologically confirmed, surgically resectable clinical stage IB-III (N2) NSCLC. Eligible patients are ≥18 years old, have ECOG performance status 0-1, and lack EGFR mutations or ALK fusions. Participants are randomized 1:1 to receive neoadjuvant SBRT-IO (SBRT 8 Gy × 3 fractions plus up to three cycles of cemiplimab) or standard ChemoIO (platinum-based doublet chemotherapy plus up to three cycles of cemiplimab). Randomization is stratified by tumor PD-L1 expression ( < 1% vs. ≥1%) and clinical stage (IB/II vs. III). Following neoadjuvant therapy, all patients undergo surgical resection and receive adjuvant cemiplimab for up to 12 months; patients in the SBRT-IO arm may additionally receive adjuvant chemotherapy. The primary endpoint is pCR. Key secondary endpoints include grade 3-5 adverse events (neoadjuvant and postoperative), event-free survival, MPR, and postoperative length of stay. Correlative immune and molecular biomarker studies are planned. Trial enrollment began on 2/4/2025 and is currently enrolling across 2 sites, with planned enrollment at 5 US sites. 19 of 112 patients are currently accrued. Clinical trial information: 24-02027124 .

Efficacy of Perioperative Pembrolizumab in Mismatch Repair Deficient/Microsatellite Unstable Localized Colorectal Cancers: Results of the Phase II Trial IMHOTEP

PURPOSE Mismatch repair deficiency (dMMR) or microsatellite instability (MSI) represents a distinct phenotype among solid tumors resulting in the generation of highly immunogenic neoantigens. Pembrolizumab has been approved in first-line unresectable or metastatic dMMR/MSI colorectal cancers (CRC). We aimed to assess efficacy and tolerance of perioperative pembrolizumab in dMMR/MSI CRC. PATIENTS AND METHODS The prospective multicenter phase II trial IMHOTEP enrolled patients with localized resectable dMMR/MSI CRC to receive one or two cycles of IV pembrolizumab 400 mg once every 6 weeks before surgery and 1-year total duration thereafter. The primary end point was pathologic complete response (pCR) rate (ypT0N0). Secondary objectives included safety, event-free survival, and overall survival. RESULTS IMHOTEP enrolled 81 patients with dMMR/MSI CRC who received at least one cycle of pembrolizumab from November 26, 2021, to February 22, 2023: median age was 66 (21-89) years, 46 (52%) were women, and 63 (71%) had clinical stage III disease at baseline. Out of the 72 patients included in the efficacy population, 38 patients (52.7% [95% CI, 41.4 to 63.9]) achieved a pCR. The exploratory post hoc analysis showed a pCR rate increased from 46% (23/50) after one cycle to 68.2% (15/22) after two cycles of neoadjuvant pembrolizumab ( P = .0125). With a median follow-up of 24.5 (95% CI, 23.3 to 25.6) months, three disease recurrences occurred. Grade ≥3 immune-related toxicities were reported in 14 (15.7%) patients including one grade 5 (myasthenia). CONCLUSION The IMHOTEP trial showed promising results, with pCR achieved after one or two cycles of neoadjuvant pembrolizumab in 53% of patients with dMMR/MSI CRC. To our knowledge, this prospective study is the first to demonstrate the feasibility and the safety of perioperative pembrolizumab.

Vididencel, an active immunotherapy in high-grade serous ovarian carcinoma patients: Analysis of tumor-directed immune responses post-primary treatment.

5597 Background: Ovarian cancer (OC) remains the most common cause of mortality in gynecologic cancers, with advanced-stage high-grade serous carcinoma (HGSOC) accounting for most cases. PARP inhibitors have provided significant benefits and notable progression-free survival for patients with BRCAmut and HRD+, but survival benefits following primary treatment remains a major clinical challenge. We have conducted a phase 1 trial (NCT04739527) assessing the role of an active immunotherapy, vididencel, in patients with HGSOC post-primary treatment. Vididencel expresses multiple tumor-associated antigens (TAA), including WT1 and PRAME, which are frequently upregulated in HGSOC. Methods: Following primary treatment, patients received 8 doses of vididencel intradermally administered every 14 days, followed by 2 booster injections at week 14 and 18. Peripheral blood mononuclear cells (PBMC) were obtained at week 0, 4, 10, 14, 18 and 22. Disease status was evaluated at week 22 using clinical assessment and CA125 levels. Patients were followed for disease status for 2 years. IFNγ ELISpot was performed on PBMC for WT1, PRAME, MAGEA3/4 and NY-ESO1. Vididencel induced T-cell responses were calculated as ≥2-fold increase of the mock-corrected baseline response. Results: All 17 patients completed treatment phase (up to week 22 or end of treatment). Patient demographics are outlined in table I. 11 out of 17 patients completed predefined 2-year follow-up. With median follow-up of 26.4 months 8 out of 11 patients remain alive. 12 out of 17 patients (71%) showed improved tumor-directed vididencel-induced immune responses (VIR) and are associated with improved progression-free survival. 5 of 12 patients (42%) with VIR still had stable disease, with 2 patients beyond 3.5 years of follow-up. Conclusions: Long-term follow-up of HGSOC patients treated with vididencel confirms safety, tolerability and feasibility resulting in strong T cell response against TAA. The improved tumor-directed responses were associated with better progression-free survival. These data confirm that vididencel is a safe immunotherapy and provides strong basis for novel combination treatments for ovarian cancer patients. Clinical trial information: NCT04739527 . Patient demographics. Demographics Total patients 17 Age(in years) Mean Median Range 61.66443-75 Stage n(%) III IIV 12(70.6) 5(29.4) Primary treatment n(%) PDS IDS 2(11.8)15(88.2) Surgery outcome n(%) Complete Optimal 15(88.2) 2(11.8) CA125 at screening Mean Median Range 21.8207-55 Molecular subtype n(%) BRCAm BRCAwt 13(76.5) 4(23.5) PDS, primary debulking surgery IDS, interval debulking surgery; BRCAm, BRCA mutation; BRCAwt, BRCA wild type.

An external validation of the IMmotion151 molecular subtypes in patients with advanced renal cell carcinoma using the ORIEN database.

4529 Background: There is a major unmet need for novel biomarkers in advanced renal cell carcinoma (RCC). A promising candidate biomarker is the classification of advanced RCC into 7 distinct molecular subtypes identified in an exploratory analysis of the IMmotion151 trial (Motzer et al., Cancer Cell 2020). These transcriptomic clusters were predictive of treatment outcomes with atezolizumab + bevacizumab vs sunitinib. However, a recent validation study reported that while these clusters were able to be replicated in an external cohort, they failed to stratify survival between avelumab + axitinib vs sunitinib (Saliby et al., Cancer Cell 2024). Given these mixed results, there is a need for further validation of the IMmotion151 molecular clusters. We used a multi-institutional cohort from the Oncology Research Information Exchange Network (ORIEN), an alliance of cancer centers, to replicate these clusters and assess if they were prognostic for 5-year overall survival (OS) in patients with advanced RCC. Methods: Patients with RCC metastatic to lymph nodes or a distant site were identified in the ORIEN database. Included patients had mRNA sequencing data available from a metastatic tumor sample. We used methods similar to those used in the IMmotion151 exploratory analysis to attempt to replicate the molecular clusters. Using an unsupervised clustering algorithm called non-negative matrix factorization (NMF) on the top 10% most variable genes in each sample, we derived 7 distinct molecular clusters. To compare our clusters with those identified in IMmotion151, we constructed a heatmap of expression (using z-scores) for pre-specified gene sets across each cluster. We then conducted Kaplan-Meier analysis to assess if our clusters were able to stratify 5-year OS in our patient cohort for a significance level of p ≤ 0.05. OS was measured from the time of diagnosis with metastatic RCC. Results: 155 eligible patients were included in our analysis. We successfully replicated clusters 2 (angiogenic), 3 (complement/Ω-oxidation), 4 (T-effector/proliferative), and 6 (stromal/proliferative). Cluster 7 (snoRNA) was not possible to replicate as our transcriptomic data only included mRNA. Kaplan-Meier analysis did not show any statistically significant difference (p = 0.85) in 5-year OS between our 7 clusters. Cluster 2 had a median OS of 47.5 months, cluster 3 had a median OS of 43.6 months, median OS was not reached for cluster 6, and there were insufficient patients in cluster 4 to be included in the survival analysis. Conclusions: While our results show that the IMmotion151 molecular subtypes are robust and replicable even in smaller datasets, the lack of any association between subtypes and survival outcomes casts further doubt on the clinical utility of these biomarkers. Our results may also be influenced by our smaller sample size compared to the IMmotion151 analysis (n = 823).

Brentuximab vedotin plus cyclophosphamide, doxorubicin, etoposide, and prednisone (CHEPA) in newly diagnosed CD30-positive peripheral T-cell lymphomas with integrated ctDNA analysis: Results of the phase 2 CHEPA trial.

7081 Background: Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies associated with poor outcomes. While adding brentuximab vedotin (BV) to CHP has improved results in CD30+ PTCL, relapses remain common. Given the suggested benefit of etoposide (CHOEP) in younger patients, the prospective multicenter single-arm Phase 2 CHEPA study (NCT05006664) was conducted to evaluate the efficacy and safety of CHEPA (BV-CHEP) induction combined with circulating tumor DNA (ctDNA) analysis. Methods: Patients with previously untreated CD30+ PTCL eligible for autologous stem cell transplantation (ASCT) were enrolled. Treatment consisted of 6 cycles of CHEPA (D1: BV 1.8 mg/kg, cyclophosphamide 750 mg/m², doxorubicin 50 mg/m²; D1–3: etoposide 100 mg/m²; D1–5: prednisone 100 mg/d) every 21 days. The primary endpoint was the complete metabolic response (CMR) rate at the end of treatment (EOT). Secondary endpoints included safety, PFS, OS, ORR, and exploratory ctDNA analysis. Plasma cfDNA was profiled using CAPP-Seq (259 genes) and clonotypic VDJ sequencing at all TCR loci via SABER. Results: Between 05/2022 and 09/2025, 40 patients were screened; 33 met eligibility criteria and initiated therapy. The cohort included 14 (42%) ALCL and 19 (58%) non-ALCL cases (median age 57 years, range 26–69). Baseline characteristics showed a predominance of males (67%), advanced-stage disease (79%), elevated LDH (58%), and bone marrow involvement (30%); all pts had an ECOG PS of 0–1. All 33 pts completed 6 cycles of CHEPA. At EOT, 25/33 (76%) achieved CMR, meeting the primary endpoint. The ORR was 91% for the entire cohort (CMR: 86% for ALCL, 68% for non-ALCL). ASCT was preplanned in 21/33 pts and has been performed to date in 14 pts. At a median follow-up of 19 months, the 18-month PFS and OS probabilities were 75% and 92%, resp. Specifically, PFS was 100% for ALCL vs. 59% for non-ALCL, while OS was 100% vs. 87%. Age and bone marrow involvement were the only baseline variables significantly associated with CMR. Baseline ctDNA burden was significantly correlated with total metabolic tumor volume (r=0.68, p<0.001), LDH level (r=0.48, p=0.03), and PIT (p<0.05). Grade 3–4 adverse events occurred in 82% of pts, primarily hematological: neutropenia (79%), thrombocytopenia (18%), febrile neutropenia (15%), and anemia (15%). No grade 3–4 peripheral neuropathy or grade 5 events were reported. Conclusions: The CHEPA study met its primary endpoint with a 76% CMR rate. Despite limited follow-up and high non-ALCL prevalence of our cohort, PFS and OS results are promising. Toxicity was manageable with no treatment-related deaths even though 33% of patients were >60 years old, supporting the safety of adding etoposide to the BV-CHP backbone. Further investigation of outcomes based on EOT MRD by ctDNA is ongoing. Clinical trial information: NCT05006664 .

Efficacy of neoadjuvant TCHP with primary empegfilgrastim (E) prophylaxis in HER2-positive early breast cancer (HER2+ eBC): Final results of the DEFENDOR SPECIAL study.

e12651 Background: Neoadjuvant therapy (NAT) is the current standard of care for treating HER2-positive breast cancer. Achieving a pathological Complete Response (pCR) – is a strong predictor of betteroutcomes. Dose reductions and delays may impair NAT efficacy in early breast cancer. Strategies to enhance pCR are needed. This prospective observational study assessed primary empegfilgrastim (G-CSF) prophylaxis impact on pCR in HER2+ early BC treated with neoadjuvant TCHP regimen. Methods: From April 2020 to September 2023, 105 patients (pts) with HER2+ eBC received NAТ: 6 docetaxel/carboplatin/trastuzumab + pertuzumab + empegfilrastim (TCHP+E). E was administered 24h post each NAT cycle. The primary endpoint was relative dose-intensity (RDI), pCR (ypT0/is ypN0) in the intention-to-treat (ITT) population was one of the main secondary endpoint (NCT04905329). Results: Median age was 52.4 years. Clinical stages II and III were present in 58.1% and 41% of patients, respectively; 59% had nodal involvement at baseline. Mean RDI of TCHP+E regimen was 96%. pCR was achieved in 72.3% of patients. RCB-I and RCB-II were observed in 6.6% and 15.2%, respectively. The highest pCR rate (87.8%) was in pts with HR-/HER2+ (3+) tumors (n = 33). Not a single case of febrile neutropenia was recorded; neutropenia Gr.4 – in 2 (1.9%) pts, Gr.3 – in 1 (1%) pts; thrombocytopenia Gr. 3, 2, 1 – in 1 (1%), 4 (3.8%), 32 (30.5%) pts respectively. Conclusions: The use of empegfilgrastim allows to provide 96% RDI. TCHP with empegfilgrastim shows high efficacy in HER2+ breast cancer across HR status and tumor stage. HER2 expression level is a significant predictor of pCR. Clinical trial information: NCT04905329 . Pathological complete response. HR +3-8 Allred Score (n=69) HR +7-8 Allred Score (n=47) HR + low3-6 Allred Score (n=22) HR -0-2 Allred Score (n=36) HER2 2 + / FISH + (n=10) HER2 3 + (n=95) IIA-IIIA stages (n=72) IIIB-IIIC stages (n=32) pCR, ypT0/is ypN0 46 (66,6%) 27 (57,4%) 19 (86,4%) 29 (80,6%) 4 (40%) 72 (75,8%) 54 (75%) 21 (65,6%)

Prevalence of myelodysplastic syndrome and acute myeloid leukemia among hospitalizations with sickle cell disease: A National Inpatient Sample analysis.

e18545 Background: Sickle cell disease (SCD) is characterized by chronic bone marrow stress, inflammation, and high cellular turnover, which may predispose patients to clonal hematopoiesis and myeloid malignancies. However, population-level data comparing the burden of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) among SCD hospitalizations are limited. We evaluated the prevalence of MDS and AML among SCD hospitalizations. Methods: We conducted a retrospective cross-sectional study using the National Inpatient Sample (NIS) from 2016–2020. Adult hospitalizations (age ≥18 years) with SCD were identified using the ICD-10 diagnosis code D57 and excluding sickle cell trait (D57.3). Outcomes included MDS (D46) and AML (C92.0–C92.5). Survey-weighted analyses estimated hospitalization-level prevalence of MDS and AML among SCD versus non-SCD admissions. Multivariable survey-weighted logistic regression adjusted for age, sex, race, payer, ZIP-income quartile, hospital characteristics, and year. Adjusted prevalence estimates and absolute differences were derived using marginal effects. Results: Among an estimated 148.8 million adult hospitalizations, AML prevalence was lower among SCD hospitalizations than non-SCD hospitalizations (unadjusted: 0.11% vs 0.28%). After adjustment, SCD was associated with lower odds of AML (aOR 0.63, 95% CI 0.49–0.80; p<0.001), corresponding to an adjusted prevalence of 0.17% versus 0.28% and an absolute difference of −0.10%. In contrast, SCD was associated with higher odds of MDS (aOR 1.80, 95% CI 1.40–2.31; p<0.001), with adjusted prevalence of 0.48% versus 0.27% and an absolute increase of 0.21%. Conclusions: Among U.S. adult hospitalizations, SCD is associated with a higher adjusted prevalence of MDS but a lower adjusted prevalence of AML compared with non-SCD hospitalizations. These findings suggest differential myeloid disease patterns in SCD and underscore the need for further investigation into clonal hematopoiesis and bone marrow dysregulation in this population.

Inotuzumab ozogamicin versus blinatumomab in pediatric relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia: A systematic review and meta-analysis.

e18512 Background: Inotuzumab ozogamicin (InO, CD22-directed) and blinatumomab (blina, CD19-directed) are increasingly used for pediatric relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), but the available evidence is dispersed across early-phase trials, multicenter cohorts and a single randomized comparison. We synthesized efficacy outcomes, including Minimal Residual Disease (MRD)-negative remission, Complete Remission (CR) and Overall Response Rate (ORR), as well as survival and we also evaluated safety outcomes such as Cytokine Release Syndrome (CRS), neurotoxicity and Sinusoidal Obstruction Syndrome or Veno Occlusive Disease (SOS/VOD), to inform treatment selection. Methods: We included phase I-III trials and multicenter cohorts published between 2015-2025 that reported at least 10 CD22-positive pediatric or Adolescent and Young Adult (AYA) patients with R/R B-ALL treated with InO or blina. The primary outcome was MRD-negative complete remission among morphological responders. Secondary outcomes included CR or ORR, grade ≥3 neurotoxicity, grade ≥3 CRS, SOS/VOD of any grade including post hematopoietic stem cell transplantation (HSCT) and Event Free Survival (EFS) or Overall Survival (OS). Single arm proportions were pooled using random effects models. Sensitivity analyses used the Freeman–Tukey method, REML and leave-one-out influence procedures. Estimates from the RCT by Locatelli in 2021 were extracted as hazard ratios and two arm risk ratios. RoB was assessed and evidence certainty was evaluated with GRADE. Results: Across 6 studies and 239 patients, MRD negativity pooled to 64% (95%CI 40–83%), with substantial heterogeneity (I 2 =76%). CR/ORR pooled to 64% (95%CI 40–83%) across 285 patients. Severe toxicities were infrequent: CRS ≥3 occurred in 1.9% (95% CI 0–13%) of 234 patients; neurotoxicity ≥3 in 4.5% (95%CI 3.1–6.5%) of 340 patients. SOS/VOD any-grade pooled to 7% (95% CI 1–33%), while post-HSCT SOS occurred in 29% (95%CI 6–59%) of 54 patients, predominantly following InO exposure. In the randomized trial (n=158), blina improved EFS (HR 0.45, 95%CI 0.36–0.55) and trended toward improved OS (HR 0.43, 95%CI 0.18–1.01). Two-arm analyses showed higher MRD negativity (RR 2.16, 95%CI 1.52–3.05) and CR/ORR (RR 1.69, 95%CI 1.27–2.25) with blina vs chemotherapy. Sensitivity analyses were concordant. Conclusions: In pediatric R/R CD22-positive B-ALL, CD22- and CD19-directed immunotherapies achieve high MRD-negative remission rates and substantial overall responses with low rates of severe CRS and neurotoxicity. InO is associated with a significant risk of post-HSCT SOS. These findings support the use of immunotherapy to achieve deep remission before transplant and highlight the need for careful VOD mitigation, optimized treatment sequencing and future randomized comparisons.

High Schottky barrier formation in tilted-dipole PdCoO2/ <b> <i>β</i> </b> -Ga2O3 (001) interfaces

We report the growth and Schottky junction characteristics of metallic delafossite PdCoO2/β-Ga2O3 (001) heterostructures. The PdCoO2 thin films predominantly grow with the epitaxial relationship of PdCoO2 (006)//β-Ga2O3 (202), forming a high-quality oxide–oxide interface. Despite a 24° tilt between the PdCoO2 surface polarization axis and the β-Ga2O3 (001) surface normal, a large Schottky barrier height of ϕbJV &amp;gt; 1.7 eV was achieved. This value is comparable with that reported for PdCoO2/β-Ga2O3 (2¯01) where the PdCoO2 surface polarization axis is perpendicular to the interface. The PdCoO2/β-Ga2O3 (001) Schottky junctions showed a large on–off ratio of ∼108 at 573 K. These results demonstrate the feasibility of delafossite-type electrodes for β-Ga2O3 (001) heterostructures with high-quality homoepitaxial β-Ga2O3 layers.

Tailoring the physicochemical and electrochemical properties of Mg0.5+x(Zr1-xAlx)2(PO4)3 ceramic electrolytes

Biomimetic Janus Fabric with Ice Plant Bubble‐Like Cell Structure for Passive Daytime Radiative Cooling and Energy Conversion for Wearable Applications

ABSTRACT Smart textiles require advanced sensing capabilities, yet existing sensor‐integrated fabrics suffer from poor breathability, brittleness, and thermal vulnerability, restricting large‐scale deployment. Herein, inspired by the epidermal bubble‐like cell structure of ice plants, we developed an ultra‐lightweight Janus fabric, with a polyelectrolyte membrane as the key component—its inherent high stability, excellent ion conductivity, and good compatibility endow the fabric with superior structural flexibility and functional synergy. This design integrates passive daytime radiative cooling (PDRC) and sensing functions, retaining breathability and directional moisture transport. Notably, the polyelectrolyte membrane‐enhanced fabric achieves 9.86°C sub‐ambient cooling (101 W m − 2 net cooling power) under 1 sun intensity, 100% accurate motion monitoring, and stable triboelectric output (10 V stable output under 10 N constant force), along with exceptional durability (1000 folding cycles), recyclability, and antibacterial activity. Owing to the prominent advantages of structural innovation, excellent performance, and strong practicality, this study can not only be effectively extended to other inorganic particle systems (e.g., SiO 2 , boron nitride) but also holds broad application prospects in wearable electronic devices, flexible robots, and intelligent sensing systems.

Long-term outcomes of ¹⁸ F-fluoromisonidazole positron emission tomography (FMISO PET)–guided major radiation dose de-escalation in HPV-associated oropharyngeal cancer: The 30 ROC approach.

103 Background: We previously demonstrated favorable short-term outcomes in patients with human papillomavirus–associated oropharyngeal carcinoma (HPV+ OPC) treated with biologically selected major radiation dose de-escalation, guided by functional hypoxia imaging. We now report mature long-term outcomes from a substantially larger prospective cohort to evaluate the durability and long-term safety of this approach. Methods: We conducted a pre-specified integrated analysis of a series of three consecutive phase II trials, each trial representing a progressive refinement with the same therapeutic strategy, enrolling patients with T0–3/N1–2c HPV+ OPC from 10/1/2015 to 11/30/2023. 18 F-fluoromisonidazole positron emission tomography (FMISO PET) assessed intratumoral hypoxia to stratify treatment: patients without hypoxia received de-escalated chemoradiotherapy (CRT) to 30Gy, while those with intra-treatment hypoxia received standard CRT to 70Gy. The primary endpoint was 5-year overall survival (OS); secondary endpoints included local, regional, and distant failure, progression-free survival (PFS), treatment-related toxicities, and patient-reported outcomes (PROs). Time-to-event outcomes were analyzed using Kaplan-Meier method and cumulative incidence function. Results: A total of 430 patients were enrolled and received treatment. T, N stages were: T0/TX(51), T1(198), T2(173), T3(8); N1 (62), N2a (48), N2b (252), and N2c (68). 96 patients (22.3%) had &gt;10 pack-years of smoking history. There were 323 patients (75%) who had no hypoxia on FMISO PET and received 30Gy while 107 patients (25%) had evidence of intra-treatment tumor hypoxia and received 70Gy. With a median follow-up of 4.05 years (range 1.27–10.03 years), the 5-year OS was 97% in both the 30Gy and 70Gy cohorts. All oncologic endpoints were equivalent in the 30Gy vs 70Gy cohorts: 5-year local failure (2.2% vs 1.9%, p=0.7), regional failure (6.2% vs 3.9%, p=0.4), and PFS (91% vs 89%, p=0.5). Notably, patients with intra-treatment hypoxia, who received 70Gy had higher distant failure rates versus those without intra-treatment hypoxia and received 30Gy (7.5% vs 1.3%, p=0.004). Detailed acute/late toxicities and PROs will be presented at the meeting. Conclusions: FMISO PET–guided biological and personalized major radiation dose de-escalation results in durable long-term outcomes, benefiting ~75% of the patients. These findings establish a precision-based paradigm for definitive CRT in HPV+ OPC, currently being validated in an on-going randomized phase III trial (NCT06563479, &gt;1/3 randomized). Patients with intra-treatment hypoxia had a higher rate of distant metastasis where additional therapy can be considered in future trials. Clinical trial information: NCT03323463 , NCT05491512 .

First-in-human phase 1/2 study of ETX-19477, an oral, potent, and selective PARG inhibitor, in patients with advanced solid tumors (ERADIC8).

3109 Background: Poly(ADP-ribose) glycohydrolase (PARG) is an enzyme that catalyzes the removal of poly-ADP-ribose (PAR) chains from proteins during DNA damage repair. PARG inhibition leads to selective cell death in tumors with underlying replication fork defects, including BRCAm tumors, through a mechanism distinct from PARP inhibition. ETX-19477 is an oral, potent, and selective PARG inhibitor that shows robust preclinical activity in mouse models of ovarian, breast, and gastric cancers. Methods: ERADIC8 is an open-label, multicenter, Phase 1/2 study, consisting of two parts, dose escalation and dose expansion. A Bayesian Optimal Interval Design was used to enroll patients (pts) into dose escalation cohorts, with enrichment for pts with BRCAm high grade serous ovarian (HGSOC) and breast cancers. The primary objective is to assess safety/tolerability of ETX-19477 and define the maximum tolerated dose (MTD) and recommended Phase 2 dose(s). Secondary and exploratory objectives include pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity per RECIST v1.1. ETX-19477 is given orally once or twice daily in 21-day cycles. Results: As of Jan 6 2026, 45 pts were enrolled into the study across 11 dose levels (range: 80-750 mg QD, 190-350 mg BID). Tumor types included ovarian (n=24, BRCAm: 18), breast (n=8, BRCAm: 7), endometrial (n=6, BRCAm: 0), colorectal (CRC, n=3, BRCAm: 1), and other (n=4, BRCAm: 0) cancers. Treatment-related AEs (TRAEs; any grade) occurring in &gt;20% of pts were nausea (53%), vomiting (38%), and fatigue (24%). The only Gr3 TRAE occurring in &gt;5% of pts was neutropenia (16%). There was one Gr4 TRAE of neutropenia in 1 pt (2%) and no Gr5 TRAEs. ETX-19477 exposure is dose proportional, and the BID regimen achieves &gt;85% PARG inhibition throughout the dosing interval in a blood-based PAR accumulation pharmacodynamic assay. As of the data cutoff, dose escalation is ongoing at 350 mg BID (MTD has not been defined) and dose expansion is ongoing at 200-300 mg BID. Among BRCAm, HGSOC pts enrolled at BID dose levels, there were 7 evaluable pts with a median of 4 prior lines of therapy (range 2–11): 2 pts achieved a partial response (PR, 29%) and 3 pts achieved stable disease (SD, 43%). Both pts with PRs were platinum-resistant and received prior PARP inhibitor treatment. 1 pt with BRCAm CRC remains on active therapy (250 mg BID) with SD for 7 months. Conclusions: ETX-19477 was well tolerated and showed anti-tumor activity in heavily pretreated pts with BRCAm, platinum-resistant HGSOC during dose escalation. These findings provide the first clinical proof-of-concept of PARG inhibition in HGSOC. ETX-19477 is being further evaluated in the dose expansion phase of the study. Clinical trial information: NCT06395519 .

Bone marrow vascular architecture: Implications for targeting bone marrow cancers.

e18610 Background: Many hematologic cancers (HC) are localized in the bone marrow (BM). Drug therapies are often administered intravenously (IVT) and require doses that limit serious adverse side effects (SAE) but which also compromise tumor control. An underappreciated question is whether advances in therapy delivery modes could dispatch more to the BM target than IVT while limiting SAE. Methods: Academic sources on the anatomy/physiology of BM extra (EXO) and intraosseous (INO) blood flow (BF) were analyzed from medical textbooks + published literature from multiple specialties. The outcomes + SAEs of interventional techniques in high mortality diseases were also evaluated. Results: The BM of all bones are potential reservoirs for tumor cells. 5 L/Min cardiac output (CO) distributes unequally to all organs. Bone and BM receive 5% of CO divided among 206 bones by size. BM vascular density is robust/diffuse, hence only a few BM vessels deliver drugs primarily to the target. Anatomic/physiologic factors also affect EXO/ INO BF in normal/disease states: vasomotor tone, blood pressure, vascular resistance/permeability, intramedullary pressure, endothelial function, angiogenesis, microvascular anatomy/density. Understanding a detailed architecture of the EXO/INO BM blood supply (BS) may help conceptually. General categories of bones are: long, flat, irregular, short, sesamoid. EXO flow comes from local systemic arteries. INO arteries consist of nutrient, periosteal, metaphyseal and transcortical vessels which are distributed variably in the 5 bone classes. These vessels eventually lead to dense diffuse capillary systems which deliver drugs thoughout the BM, only small amounts directed to the more localized target, Venous drainage generally accompanies the arteries. Knowledge of the EXO/INO vascular layout addresses the feasibility of direct and regional arterial delivery (IADT) to the BM. Safety of arterial procedures is denoted by the SAE/efficacy of transcatheter aortic valve replacement (TAVR) in cancer patients including HC. 30 day mortality of cancer/noncancer classes is similar as are vascular complications. IADT to solid tumors (ST) retrospectively has inferred short term positive tumor responses + fewer SAE than IVT. The pharmacokinetics (PK) are more efficacious than IVT. Conclusions: IVT to tumors within BM is reduced by BM %CO, dispersal of BF to bones, dense BM vasculature and vascular physiologic factors. No matter how effective therapy is against tumors during testing, if only a small portion reaches the tumor niche effectiveness may be undermined. Interventionalists can offer short term direct and indirect regional IADT to major blood vessels supplying the BM as a conditioning protocol with improved local BM delivery, followed by IV therapy. The results of IADT in ST has been encouraging regarding benefits/SAE. It should also be evaluated for HC with PK studies, evolving from there based on the results.

Cancer treatment: Impact on metabolism.

e24140 Background: It is well-accepted that metabolic syndrome can drive cancer development through changes in insulin signaling and inflammation. Cancer therapy itself has been associated with adverse metabolic effects that persist beyond active therapy. Both increase cardiovascular risk and may increase cancer recurrence risk in survivorship. Systemic therapy has been linked to disruptions in glucose and lipid metabolism, increased insulin resistance, elevated fasting glucose and hemoglobin A1c (HgbA1c), and unfavorable lipid changes such as increased low-density lipoprotein (LDL). In the United States, approximately 0.33% of the total population are newly diagnosed with diabetes and 0.23% are newly diagnosed with hyperlipidemia annually. Methods: To assess these observations in a real-life setting, we retrospectively examined metabolic outcomes in persons undergoing systemic cancer therapy—chemotherapy or hormonal therapy—or local therapy for breast, colon, ovarian, or lung cancer between January 1, 2022, and December 31, 2025. Inclusion criteria were breast, colon, ovarian, or lung cancer diagnosis; normal HgbA1c or LDL level prior to cancer therapy; received chemotherapy, radiotherapy, or hormonal therapy within 12 months of lab studies, and repeat metabolic testing within 12 months of cancer treatment completion. The primary outcome was the proportion of patients who developed abnormal (elevated) HgbA1c or LDL levels following treatment. Results: A total of 685 persons received chemotherapy and underwent pre- and post-treatment metabolic testing. Of these, 152 (breast cancer (56), colon cancer (32), ovarian cancer (15), and lung cancer (49): 22.2%) demonstrated abnormal post-treatment Hgb A1c or LDL values. A total of 718 persons received radiotherapy with pre- and post-treatment metabolic testing; 93 (breast cancer (63), colon cancer (6), ovarian cancer (1), and lung cancer (23): 13.0%) developed abnormal findings. A total of 804 persons received hormonal therapy alone for breast cancer with pre- and post-treatment metabolic testing; 158 developed abnormal Hgb A1c or LDL values at follow-up. A breakdown by cancer type is shown in the table below. Conclusions: In this retrospective real-world analysis, cancer therapy whether local or systemic was associated with a higher incidence of developing abnormal post-treatment HgbA1c and LDL levels compared to population data. These findings demonstrate increased risk for cardiovascular disease and potentially cancer recurrence that arises from metabolic disruption due to cancer therapy. Our data highlight the importance of metabolic evaluation and risk-reduction strategies in survivorship care. Abnormal Post-Treatment HgbA1c or LDL Chemo (N= 685) Radiation (N= 718) Hormonal (N=804) Breast 56 63 158 Colon 32 6 NA Ovarian 15 1 NA Lung 49 23 NA Total 152 (22.2%) 93 (13.0%) 158 (19.7%)