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Abstract Background Single-agent R is a common 1st-line therapy for patients (pts) with FL, especially those with low-tumor burden advanced stage disease or comorbidities. EO is a therapeutic vaccine generated from non-self-protein sequences from gut bacteria, including 4 HLA-A2 CD8 T cell epitopes that mimic B cell-specific markers: CD20, CD22, CD37 and BAFF-receptor. EO also contains a CD4 helper epitope UCP2. EO expands pre-existing memory CD8 T cells recognizing non-self-protein sequences from gut bacteria which can cross-react with B cell antigens on tumor cells. The aim adding EO to R is to safely increase the depth and duration of responses. Methods Cohort 3 (C3) of trial EONHL1-20/SIDNEY includes pts with HLA-A2 and previously untreated low-tumor burden (GELF) FL grade 1-3A in need of treatment (per pt/treating physician). Pts receive EO (300μg/peptide) SC with adjuvant Montanide, q2 weeks (w) x 4, then q4w for a total of 12 doses, combined with R starting at w7 (375 mg/m2 IV q1w x4, then q8w x4). For immune responses blood mononuclear cells were assayed by flow cytometry and EO-mimic or B cell peptide specific tetramers without in vitro stimulation. The primary objective is to assess safety; secondary objectives include EO immunogenicity and preliminary efficacy. Results As of July 2025, the 6 planned pts had started EO. Median age was 66 years (range 46-73); 5 ECOG 0/1 ECOG 1; 1 Ann Arbor stage III/5 stage IV; FLIPI low risk 2/intermediate 2/high 2; FLIPI-2 low risk 2/intermediate 4. At median follow-up 10.6 months (mo) 4 pts completed and 2 are ongoing on EO. Median treatment duration was 43 w (range 2-43). Best response by Lugano in the 6 pts included 4 complete (CR) and 2 partial responses (PR). Median time to PR/CR was 17.1 w (range 6.0-18.0). Currently there is only 1 (not yet confirmed) progression at 20.5 mo. All 5 immune response evaluable pts had expansion of CD8 T cells specific for EO mimic and B cell target peptides during treatment; 4 of 5 had detectable expansions at w5 (1st testing time). Currently, the longest tested immune response is at w65 and positive for both EO mimic and B cell target peptides. Expanded specific CD8 T cells had a memory phenotype predominantly composed of effector memory (TEM) cells but also including central memory (TCM) and terminally differentiated effector memory CD8 T (TEMRA) cells. Across the 5 pts, the medians of max % (sum of specific CD8 T cells targeting either the 4 EO mimic peptides or the 4 B cell antigen epitopes at a specific timepoint) among all peripheral CD8 T cells were 0.71% (range 0.19-3.97) for EO mimic and 0.33% (0.20-1.30) for B cell target peptides. The most common EO-related adverse events (AEs) were local administration site reactions (erythema, pain, induration). These included Gr (Grade) 1 reactions in 3 pts, Gr 2 in 1 pt, and Gr 3 in 1 pt; latter being ulceration with EO-interruption at w10.1, and in context of a strong immune response against EO mimic [3.97% of all peripheral CD8 T cells at w5] and B cell target [1.30%] peptides, and CR from w16.7. Other EO related AEs were Gr 1 lymph node pain (1 pt), and related to both EO and R were Gr 2 urticaria (1 pt) and Gr 1 fatigue (1 pt). Only R related were Gr 2 infusion related reaction (3 pts), Gr 2 enterocolitis infection (1 pt), and in 1 pt each Gr 1 flushing, anemia, headache and diarrhea. There were no further Gr 3-4 AE and no death on treatment/follow-up. Complete B cell depletion was seen in 5 pts tested at w18 (R added w7); no recovery in the range of w30-65. Only 3 infections were reported, per above enterocolitis, and 2 cases of COVID-19 both resolved without sequalae. ConclusionsThe combination of EO with R has a predictable and manageable safety profile, with EO only adding local administration site reactions to the well-known R safety profile. In this feasibility cohort all evaluable pts developed a specific immune response against EO and B cell targets, and a Lugano objective response. The combination of EO and R is feasible and can be evaluated in further trials. Updated results will be presented at the meeting.

Abstract Introduction Short diagnosis-to-treatment interval (DTI) is associated with aggressive disease biology and inferior outcomes in diffuse large B-cell lymphoma (DLBCL), and is recognized as a potential source of selection bias in clinical trials if not properly addressed. However, its prognostic significance in follicular lymphoma (FL) remains poorly characterized. We aimed to evaluate the prognostic significance of DTI in newly diagnosed FL patients who received frontline (1L) immunochemotherapy (IC), using a large international dataset and an independent external validation cohort. Methods For the discovery dataset, we evaluated patients diagnosed between 2002 and 2018 from ten observational cohorts as part of the FLIPI24 Consortium. External validation was conducted using data from patients enrolled in the Lymphoma Epidemiology of Outcomes (LEO) Cohort between 2010 and 2015. All patients had FL grade 1–3A and received 1L IC within 100 days of diagnosis. Patients with a concurrent DLBCL were excluded. Missing baseline laboratory values were addressed via multiple imputation. The primary endpoint was event-free survival at 24 months (EFS24); secondary endpoint was 5-year overall survival (OS), both calculated from treatment initiation. DTI was analyzed as continuous (via splines) and dichotomized variable (≤14 vs >14 days; as defined in DLBCL). Results In the discovery cohort (n=3,907), median age was 61 years (IQR 53–69), and 50% were male; 49% of patients were high-risk according to FLIPI, 26% according to PRIMA-PI, and 38% according to FLIPI24. Included patients received R-CHOP (54%), R-CVP (26%), or B-R (20%) as 1L treatment, followed by anti-CD20 maintenance in 60%. The median DTI was 30 days (IQR 17–48). Using the 14-day cut-off, 851 patients (22%) had short DTI. These patients had more adverse baseline characteristics, including B symptoms (42% vs 32%, P<0.01), ECOG performance status ≥2 (15% vs 8%, P<0.01), elevated LDH (51% vs 40%, P<0.01), hemoglobin <12 g/dL (30% vs 17%, P<0.01), and elevated β2-microglobulin (56% vs 44%, P<0.01). Prognostic indices (PIs) were also more frequently high-risk in the short-DTI group: FLIPI (56% vs 47%), PRIMA-PI (36% vs 24%), and FLIPI24 (51% vs 34%, all P<0.01). Spline modeling showed a decreasing EFS24 rate with increasing DTI, reaching a plateau at 30–40 days. In logistic regression model, each additional week of DTI improved EFS24 (OR 0.92, P<0.01). DTI attenuated but remained prognostic after adjusting for PIs (OR 0.93 for FLIPI, 0.95 for PRIMA-PI, 0.96 for FLIPI24, all P<0.01). When analyzed as a dichotomized variable, short DTI was associated with inferior EFS24: OR 1.74 adjusted for FLIPI, 1.63 for PRIMA-PI, and 1.53 for FLIPI24 (all P<0.01). The 2-year EFS of short vs long DTI groups was 71% vs 82% (HR 1.50, 95% CI 1.34–1.67, P<0.01), 5-year OS was 80% vs 86% (HR 1.38, 95% CI 1.21–1.56, P<0.01), and the 5-year cumulative risk of histologic transformation was 7.7% vs. 5.4% (P<0.01). In the validation cohort (n=516), median age was 61 years (IQR 52–69 years), 55% were male; 36% of patients were high-risk according to FLIPI; 29% according to PRIMA-PI, and 33% according to FLIPI24. Patients received B-R (59%) or R-CHOP (41%) as 1L treatment. The median DTI was 31 days (IQR 19–48), 84 patients (16%) had DTI ≤14 days. Similar patterns were observed; patients with short DTI had adverse baseline characteristics, PIs, and shorter 2-year EFS (72% vs 84%, HR 1.69, 95% CI 1.13–2.55, P=0.01). DTI remained associated with EFS24 when analyzed as a continuous variable (per week: OR 0.88 unadjusted, 0.90 with FLIPI, 0.89 with PRIMA-PI, and 0.89 with FLIPI24), and dichotomized (≤14 vs >14 days: OR 1.83 adjusted for FLIPI, 1.88 for PRIMA-PI, and 1.73 for FLIPI24). Conclusion Short DTI, defined as ≤14 days (observed in 22% of FL patients vs 46% in DLBCL), is a strong and independent predictor of inferior outcomes in newly diagnosed FL patients treated with IC. While DTI correlates with adverse baseline features and established PIs, it retains independent prognostic value. Although a 14-day threshold is reasonable for risk modeling, DTI contains greater informational value when modeled as a continuous variable. Among PIs, FLIPI24 most strongly attenuated the DTI effect, underscoring its superior discriminative power over FLIPI and PRIMA-PI. Clinical trials designs should mitigate any potential barriers to enrollment of FL patients requiring urgent therapy.

Abstract Background: Higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) and secondary acute myeloid leukemia (sAML) share overlapping molecular features but both remain clinically diverse with poor prognosis. Machine learning (ML)-based genomic clustering offers an opportunity to redefine disease subgroups beyond traditional clinical prognostic schemes or pathologic classifications. Prognostic scoring systems emphasize outcomes while pathologic classifications morphology resulting in inclusion of patients (pts) with different genetic background into same outcome or morphologic subgroup. We compared our ML-unsupervised clustering (UC) model named molecular nosology1 with the taxonomy model2 to evaluate differences in cluster architecture and clinical relevance in HR-MDS and sAML. Methods We analyzed HR-MDS (≥10% blasts) and sAML pts with available molecular data at diagnosis from a well-annotated cohort. Our molecular nosology model used UC via a binary latent-factor model to generate molecular clusters (MCs). The taxonomy model assigned pts to predefined genomic classes. We compared MC size, genomic enrichment, and overall survival (OS) across diagnostic categories. Concordance was assessed using Adjusted Rand Index (ARI) and Normalized Mutual Information (NMI). Purity and entropy were calculated to assess how concentrated (purity) or dispersed (entropy) each taxonomy group was across MCs. Results Among 898 pts, 367 (41%) had HR-MDS and 531 (59%) had sAML. Median age was 71 (IQR 65–77) years. Compared to sAML, HR-MDS pts had similar age (71 vs. 72, p=0.556) but higher hemoglobin (9.9 vs. 9.3, p<0.001) and platelet counts (91 vs. 50, p<0.001). Normal karyotype was more common in HR-MDS (55% vs. 42%, p<0.001). TET2 (24%), ASXL1 (24%), RUNX1 (23%), and SRSF2 (22%) were the most frequently mutated genes. Using our nosology model, we identified 14 MCs.1 The most frequent were MC2 (normal karyotype) at 22% and MC13 (TP53-complex) at 17%, followed by MC1 (+8/ASXL1/TET2/RUNX1, 12%), MC6 (SRSF2/RAS-pathway, 9%), and MC9 and MC14 (each 8%). Less common clusters included MC12 (5%) and MC3–MC5 (2–3%). For comparison, the taxonomy model included 18 genomic groups: TP53-complex (20%), mNOS (13%), bi-TET2, IDH-STAG2, and no event (each 10%), CCUS-like, SETBP1/-7, and AML-like (each 6%), SRSF2 (4%), del(5q), BCOR/L1, EZH2-ASXL1, and SF3B1 (each 3%), and five rare subgroups (DDX41, der(1;7), U2AF1157, U2AF134, ZRSR2; all <1%). Our MCs aligned closely with several taxonomy groups: 82% of TP53-complex cases were assigned to MC13, 99% of no event cases mapped to MC2, and 97% of del(5q) cases mapped to MC8. Bi-TET2 cases were distributed across MC6 and MC12 (both TET2-enriched); SETBP1/-7 to MC11; and EZH2-ASXL1 cases to MC1 and MC12. In contrast, mNOS, AML-like, and CCUS-like groups were genomically heterogeneous and spanned multiple MCs. ARI and NMI values were 0.391 and 0.458, indicating moderate concordance. Purity was highest in no event (0.989), del(5q) (0.967), and TP53-complex (0.823), and lowest in IDH-STAG2 (0.247), CCUS-like (0.241), and AML-like (0.347), all with high entropy (>2.5), reflecting genomic diversity not captured by taxonomy groups alone. Median OS for the entire cohort was 17 mo (95%CI: 14–20). HR-MDS pts had longer OS vs. sAML (26 vs. 12 mo, p<0.001). OS did not differ significantly between HR-MDS and sAML within most taxonomy groups or MCs, except for MC3 (NA vs. 11 mo, p=0.014), MC6 (111 vs. 15 mo, p<0.001), and MC9 (18 vs. 9 mo, p=0.027) for the nosology model and SF3B1 (129 vs. 23 mo, p=0.033), del(5q) (33 vs. 6 mo, p=0.022), bi-TET2 (25 vs. 8 mo, p=0.019), mNOS (34 vs. 9 mo, p<0.001) for taxonomy. Conclusions Some molecular taxonomy groups showed strong concordance with our nosology-defined clusters, which served as the gold standard for genomically distinct subsets (e.g., TP53-complex, del(5q), and no event), irrespective of diagnosis or blast percentage which may present the stage of the disease. In contrast, taxonomy-defined categories such as CCUS-like, AML-like, and mNOS were more genetically diverse and less aligned with specific clusters in the nosology model. Median OS within most clusters was not significantly influenced by blast count, underscoring the potential of molecular-driven clustering to reveal underlying disease biology not captured by morphology and to refine classification in MDS/AML and sAML with few exceptions (SF3B1 or biTET2). Ref 1.Kewan, Durmaz et al.Nat Commun 2023 2.Bernard, et al.Blood 2024

Abstract Background: Multiple myeloma patients face complex barriers to diagnosis, care access, support, and navigation. This study analyzes patient-reported experiences to identify structural gaps and cluster patients into meaningful segments based on their needs and perceptions. Methods: We administered a 48-item anonymous survey to adult myeloma patients at the Medical College of Wisconsin and through national platforms, including the International Myeloma Foundation, Leukemia & Lymphoma Society, and Facebook groups. The survey assessed demographics, treatment experiences, delays, perceived personalization, and barriers to care. We used JMP 17 for analysis and Julius.AI for visualization. Rule based segmentation of structured responses was used to identify distinct patient personas. Chi-square tests assessed associations, with p < 0.05 considered significant. The study was IRB-approved. Results : A total of 320 participants responded between April 25 and June 5, 2025; 289 (90.3%) completed the survey in full. The cohort was predominantly older (55.7%, n=170/305 between 60- 75), White (79.3%, n=241/304), female (58.9%, n=179/304), highly educated (89.5%, n=272/304), and suburban (52.5%, n=159/303). Modal insurance types were Medicare (37.8%) or private insurance (30.9%); 11.2% both. Most (69.7%) reported a smooth treatment start; delays were primarily due to insurance/cost (4%). Using rule-based segmentation of structured responses, we identified three distinct patient personas: (1) Empowered but Unsupported (n=56; 17.5%) who indicated no emotional support barriers, less interest in navigators, but frequent reports of unmet needs such as poor communication. (2) Engaged and Informed (n=105; 32.8%): Highly motivated patients who requested personalized care, clinical trial transparency, or insurance navigation and (3) Delayed and Discouraged (n=35; 10.9%) who reported lower support, diagnostic delays, and a strong perception of race-related disparities. Unclassifiable personas (n=124) were due to missing or neutral responses There was no difference in self identified race across the personas (p = 0.08), but 100% of the Delayed/ Discouraged group believed race played a role in care, compared with 44% of the Engaged/Informed and 21.4% of the Empowered/Unsupported (p < 0.001). Minoritized patients (86.7% Black, 100% other minoritized) were more likely to perceive race as a factor (p = 0.0024). Empowered/Unsupported patients were significantly more likely to request better communication (100%) and empathy (53.6%), while Engaged and Informed patients prioritized clinical trial access (61%). None of the Delayed and Discouraged patients made this request (p < 0.0001). Black respondents most frequently expressed the need for greater empathy (53.7%; p = 0.0012). Those <60 (40.2%, n=33) were more likely to express interest in clinical trials (p=0.03), this interest did not vary by race (p=0.36). Interest in patient navigation did not significantly differ by education level (p = 0.3), suggesting that even highly educated patients may struggle with treatment complexity. Most patients felt their care was personalized (71.1% 207/291), with no differences by race (p = 0.55), but perceptions varied by persona with only 39.1% of Engaged/Informed patients felt their treatment was always tailored, vs. 61.8% of Empowered/Unsupported and 88.6% of Delayed/Discouraged (p < 0.0001), contrasting patients' expectations with the actual delivery of care. Conclusion: Patient-reported experiences reveal distinct personas with differing needs, perceptions and expectations of care. While most patients reported smooth treatment transitions and felt their care was personalized, gaps persist particularly among highly engaged patients who report unmet expectations around communication, personalization, and trial access. Perceptions of racial disparities persist, especially among minoritized groups illuminating the unequal experiences of patients within the myeloma care landscape. These findings stress the importance of segmenting care approaches to align with patient identity, complexity, and support needs in multiple myeloma.

Abstract Background: BCMA- and GPRC5D-targeting immunotherapies including CART cell therapy and Bispecific antibodies are currently approved for the treatment of multiple myeloma. However, clinical outcomes after dual antigenic exposure remain undefined. Herein we report the first report of BCMA-GPRC5D dual targeted multiple myeloma (DEMM). Methods: We conducted a retrospective multi-center study of RRMM patients treated with both BCMA- and GPRC5D-targeted treatments (TT) (CAR T, bispecific antibodies, ADCs) between November 1, 2022, and July 1, 2025. Outcomes included PFS1 (post-dual exposure), and overall survival (OS). Kaplan-Meier estimates and event-free probabilities were calculated. Results: One hundred and fifty patients who underwent TCE treatments were included and 49 patients met the criteria for inclusion. Median age was 65 years, 22.4% had creatinine clearance <=30 and ECOG 2 or greater was present in 22.2%; 57% had high-risk cytogenetics (IMWG 2016), and 60.5% were penta-refractory. Patients received a median of 6 prior lines of therapy (LOT) before 1st TCE and 9 prior LOT before DEMM. 65.3% received 1 TCE, 30.6% received 2 TCE and 4.1% received 3 TCE before DEMM. Similarly, 67.3% received 1 BCMA, 24.5% received 2 BCMA TT and 4.1% received 3 BCMA TT before DEMM. Prior TT included- BCMA CART (57.1%), BCMA Bispecific (57.1%), BCMA ADC (18.4%), other TCE (10.2%). The last dual exposure was GPRC5D Bispecific in 91.8%, BCMA Bispecific in 6.1% and BCMA CART in 2%. The median followup post relapse was 3.4 months (range 0.0-16 mos). The median PFS during the last dual exposure TT was 3.98 months (95% CI: 2.96–6.70). 32.7% did not receive any subsequent LOT and died due to progressive disease. 67.3% of patients had progressive MM and received next LOT. Median PFS1 was 1.77 months (95% CI: 1.28–6.21) with 3-, 6-, and 12-month event-free probabilities of 44%%, 19% and 0% respectively. Median OS was 5.7 months (95% CI: 2.53-12.16) for DEMM from the time of refractoriness to dual antigenic targets. Conclusions: Patients dual-exposed to BCMA- and GPRC5D-directed therapies have a poor prognosis, 32.7% had not received further treatment and in those who received treatment the PFS1 was less than 2 months and an OS of 5.7 months from progression. This reflects an area of high unmet need for the patients that are dual-exposed to BCMA- and GPRC5D-directed therapies. Further data on the cohort will be updated at the meeting. Acknowledgements include, the International Myeloma Foundation, IMWG.

Abstract Background: Clonal cytopenia of undetermined significance (CCUS) is defined as clonal hematopoiesis in the absence of a hematologic neoplasm, along with unexplained cytopenia. While several studies have identified risk factors and developed scores to predict progression to overt myeloid neoplasms, the clinical and molecular features during the progression process remain poorly understood. Aim: Evaluate the clinical and clonal characteristics of patients with CCUS, with a focus on the longitudinal evolution of clonal and clinical parameters over time. Methods: After IRB approval, we retrospectively reviewed charts of patients with unexplained cytopenia (2015-2024), recording data at the time of CCUS diagnosis (WHO 2022 diagnostic criteria) and at time of follow-up bone marrow biopsy after diagnosis. Follow-up CBC and karyotype data were recorded for patients who had repeat bone marrow biopsies (n= 111), while follow-up clonal parameters and risk scores were calculated for those who underwent repeat NGS (n= 74). A reduction or expansion in clone size was defined as a change exceeding 5% (CE5%), or change exceeding 10% (CE10%) from the baseline value. Overall survival (OS) was calculated from diagnosis to last follow-up. For statistical analysis, we used BlueSky Statistics V10.3.1. Results: 214 CCUS patients (median age 73, 68% males) were included. At baseline, 30% of patients had abnormal cytogenetics, with del (20q) being the most common one (8%; n= 18), followed by trisomy 8 (6%; n= 13), and loss of chromosome Y (5%; n= 10). The median number of mutations was 2 (range, 1-5), with the most common mutations TET2 (38%), SRSF2 (21.5%), ASXL1 (21%), ZRSR2 (18.5%), DNMT3A (9.5%), and U2AF1 (9%). Most patients had high risk CHRS (60%), followed by intermediate (30%), and low risk (10%). On the other hand, 41% had high risk CCRS, 29% had intermediate risk, and 30% had low risk. After a median follow-up of 46 months, 62 patients died (median OS not reached). A decrease in the white blood cell (WBC) count from the time of diagnosis to follow-up was more frequently seen among CCUS patients who progressed to MN (70% vs 50%, p= 0.04), however, changes in hemoglobin and platelets did not differ between those who progressed and those who did not (p> 0.05). Although the frequency of abnormal karyotypes at diagnosis was similar between patients who eventually progressed (28%) and those who did not (31%) (p= 0.6), 4 (2%) patients with initially normal karyotypes acquired chromosomal abnormalities during follow-up, and all progressed to MDS. Among the 74 patients who had follow-up NGS, 31% acquired new mutations, clonal expansion of pre-existing mutations were seen in 54% using CE5% and 19% per CE10%, and 16% developed new variants of uncertain significance (VUS). Acquiring new pathogenic mutations was similar in patients who progressed to MN compared to those who did not progress (34% vs 28%, p= 0.6). On the other hand, clonal expansion was significantly more observed in patients who progressed compared to those who did not, using both CE5% (73% vs 31%, p = <0.001) and CE10% (27% vs 9%, p= 0.03). At follow-up, ASXL1 was the most commonly acquired mutation among patients who did not progress (4 cases), followed by TET2 (2 cases), and U2AF1, GATA2, DNMT3A, SF3B1, ZRSR2, TP53, and CBL (1 case each). On the other hand, SRSF2, SETBP1, CBL, JAK2, TET2, and RUNX1 were more frequently acquired among those who progressed to myeloid neoplasms (each appeared in 2 patients). When recalculating CCRS, CHRS, IPSS-M, and IPSS-R at follow-up for patients who had repeat NGS, there was no significant difference in score changes - either upward or downward - between those who progressed and those who did not (p> 0.05). Conclusion: In CCUS patients who progressed to myeloid neoplasms, WBC decline, clonal expansion (more frequent), and evolving chromosomal aberrations (less frequent) were observed, supporting the value of longitudinal genomic and clinical monitoring in CCUS.

Abstract Background In advanced-stage classical Hodgkin lymphoma (cHL), achieving a negative interim PET (iPET) after two cycles of ABVD is generally considered a favorable prognostic marker. Most patients with early metabolic response proceed to complete therapy without residual disease. However, a subset of patients experience discordant end-of-treatment (EOT) findings, with evidence of the disease despite an initial complete response. This study aimed to identify baseline clinical features that might help predict this unexpected outcome.Methods A retrospective review was conducted of 122 patients with stage III or IV cHL treated at our institution between 2016 and 2024. All patients achieved complete metabolic response (Deauville score ≤3) on iPET following two cycles of ABVD. Clinical and laboratory data, including IPS score, bone marrow, and extranodal involvement, were collected. The primary outcome was residual disease identified at EOT-PET. Logistic regression was used to identify predictive factors. Disease-free survival (DFS) was estimated using Kaplan-Meier analysis.Results Of the 122 patients with negative iPET scans, 21 (17.2%) were found to have residual uptake on EOT-PET. The median age was 28 years; 63% were male, and 70.5% had nodular sclerosis subtype. Most patients (69.7%) had stage IV disease. In univariate analysis, no baseline variable- including IPS score, bone marrow involvement, extranodal disease, or B symptoms- was significantly associated with residual PET positivity. However, in multivariate analysis, stage IV disease emerged as an independent predictor, with a statistically significant association with residual disease at EOT (OR 3.32; 95% CI, 0.97–11.37; p = 0.041). The median follow-up was 28.8 months. The median DFS was not reached, and the estimated two-year DFS was 83%.Conclusions While early metabolic remission on interim PET is reassuring, a notable proportion of patients still demonstrate residual disease by the end of therapy. Stage IV disease was independently associated with this outcome when adjusted for other variables. No significant associations were identified with IPS score, bone marrow, or extranodal involvement. These findings suggest that relying solely on interim PET may overlook residual risk in a subset of patients, particularly those with extensive disease burden at baseline.

Abstract Introduction Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is the most common subtype of peripheral T-cell lymphoma. It is characterized by aggressive clinical behavior and poor prognosis and treatment often includes chemotherapy, but the benefit of hematopoietic stem cell transplantation (HSCT) remains an area of ongoing investigation. Using the National Cancer Database, we analyzed the impact of HSCT on survival in a large cohort of patients with PTCL-NOS. Materials and Methods We queried the National Cancer Database (NCDB) for patients aged 18 or older diagnosed with PTCL-NOS between 2004 and 2019. Patients who lost to follow-up were excluded. We analyzed the impact of HSCT on overall survival (OS) using Kaplan-Meier estimates and multivariate Cox regression to identify factors associated with OS. Results A total of 14,301 patients with PTCL-NOS were included in this analysis. Among them, 60.1% were male, 65.7% were Caucasian, 17.1% were black and 7.4% were Hispanic. Early-stage disease (stage I or II) was present in 24.1%, while 49.3% patients had advanced-stage disease (stage III or IV). The median age at diagnosis was 65 years (range 18-90, 23.6% were above age 75), and the median overall survival (mOS) was 15.3 months (95%CI 14.6-16), with a median follow-up of 82.8 months (95%CI 80.4-85.2). Regarding first-line treatment, 11.7% received radiation therapy, 68.9% received chemotherapy, and 6.6% underwent HSCT. The percentage of patients receiving HSCT increased from 3.3% in 2004 to 9.9% in 2019, tripling over the 16-year period. Transplant utilization varied by race/ethnicity: 7.3% of white patients underwent HSCT, compared to 6.4% of Hispanic and 4.3% of Black patients (P < 0.001). Socioeconomic disparities were also observed: patients with insurance were more likely to receive HSCT (6.8%) compared to those without insurance (2.1%); HSCT rates increased with income, from 3.9% in the lowest quartile to 8.1% in the highest; and patients from areas with higher education levels had nearly double the HSCT rate (8.4%) compared to those from the lowest-education areas (4.5%) with P<0.001 for all. In patients with advanced-stage disease, the mOS was 10.5 months (95%CI 9.8-11.1). Patients who received HSCT had significantly improved survival compared to those who did not (mOS 110.9 vs. 11.1 months; P < 0.001). Among those who underwent HSCT, there was no significant difference in survival between auto (N=207) and allo (N=47) mOS 118.9 vs. 95.7 months; P = 0.128. A similar trend of improved survival with HSCT and no significant difference between autologous and allogeneic HSCT was observed across all racial/ethnic groups: in Hispanic patients mOS in HSCT (N=31) vs. no HSCT (N=456) 106.2 vs. 8.8 months; P < 0.001. comparison between auto and allo was not performed due to the low number of allogeneic transplants (N=2). In Black patients mOS inHSCT (N=47) vs. no HSCT (N=1,215) 69.7 vs. 8.8 months; P < 0.001 and mOS in auto vs. allo NR in both groups; P = 0.764. InCaucasian patients mOS in HSCT (N=419) vs. no HSCT (N=4,111) 111.8 vs. 8.8 months; P < 0.001 and mOS in Auto vs. allo 118.9 vs. 99.4 months; P = 0.263. On multivariate analysis, older age, male gender, black race, presence of B-symptoms at diagnosis, HIV positive status, higher comorbidity score and receiving allogeneic (vs. autologous) HSCT were associated with worse survival. In contrast, having medical insurance, receiving radiation therapy, chemotherapy, and undergoing HSCT (vs. no HSCT) were associated with improved survival. Conclusion HSCT was associated with significantly improved overall survival in patients with PTCL-NOS, especially in those with advanced-stage disease. This survival benefit was consistently observed across racial and ethnic groups. These findings might be related to transplant eligibility. However, allogeneic HSCT was linked to worse outcomes compared to autologous HSCT, likely due to higher transplant-related mortality or selection bias of more aggressive diseases to undergo allogeneic transplant. Even though the trend reflects a growing adoption of HSCT as part of treatment strategies in advanced-stage PTCL-NOS over time, transplant utilization varied significantly by sociodemographic factors (insurance, education and income level), highlighting potential disparities in access to this potentially life-prolonging therapy. Further prospective studies are needed to refine transplant strategies and improve patient selection.

Abstract Introduction: CD20xCD3 bispecific antibodies (BsAb) have been approved for use in relapsed/refractory (RR) large B-Cell lymphomas (LBCLs) with manageable toxicities. The main adverse events of clinical interest are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The risk factors for CRS and ICANS are not well understood. Knowledge of variables that contribute to increased risk may help clinicians identify and tailor management for high-risk patients (pts) and increase the comfort level for providers using these therapies in community practices. Methods: We performed a multicenter retrospective study at 21 US centers evaluating pts with RR LBCLs receiving commercially available epcoritamab (epco) or glofitamab (glofit) between 2023 and 2025. We obtained baseline characteristics, safety and efficacy outcomes. Univariate analysis was performed to identify associations between CRS, ICANS, and clinical variables of interest. Results: As of May 31, 2025, a total of 312 pts with RR LBCLs were treated with BsAb, Epco n=193 (62%), Glofit n= 119 (38%); median age 68; 63% male; 70% ECOG PS 0-1. Most common histologic type was diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) (n=239, 84%) followed by high-grade B-cell lymphoma (HGBL) (n=46, 16%). 179 pts (57%) were previously treated with chimeric antigen receptor T-cell (CAR-T) therapy, with 47% receiving CAR-T <6 months (mo) prior to BsAb. Among pts with prior CAR-T, CRS with CAR-T therapy of any grade occurred in 63%, with 26% ≥ grade 2. ICANS of any grade (G) occurred in 25% of pts (9.4% ≥ G3). Overall and complete response (ORR and CR) rates to BsAb were 51% and 29%, respectively. With a median follow up of 5 mo, median progression-free and overall survival (PFS and OS) were 2.3 and 7.3 mo, respectively. With BsAb treatment, CRS of any grade occurred in 117 (39%) patients: 24% G1, 8.7% G2, 4% G3, 1% G4 and 1% G5. The max grade CRS occurred most frequently after the third dose of epco (35%) and the first dose of glofit (23%). CRS was managed with additional steroids in 24% of pts and tocilizumab in 22%. 13% of pts experienced ICANS: 5.8% G1, 3.4% G2, 2% G3, 1% G4 and 0.3% G5. Factors that increased the risk for any grade CRS included: bulky disease ≥ 7.5 cm at time of BsAb treatment (OR 2.04, 95% CI 1.17 – 3.55, p = 0.012), elevated LDH (OR 2.56, 95% CI 1.45– 4.76, p = 0.002) and treatment with epco compared to glofit (OR 1.69, 95% CI 1.04- 2.77, p = 0.036). As G ≥2 CRS generally requires inpatient monitoring and management, we next compared the risk factors between pts with no CRS or G1 CRS and G ≥2 CRS. Factors associated with increased risk for high grade CRS included: bone marrow involvement by lymphoma (OR 3.47, 95% CI 0.97 – 11.3, p = 0.043), platelet count ≤ 75 (OR 2.46, 95% CI 1.21 – 4.87, p = 0.011), ≥ 2 extra nodal sites (OR 2.04, 95% CI 1.07 – 3.97, p = 0.032) and ≥G2 CRS with prior CAR-T (OR 3.35, 95% CI 1.13 – 9.97, p = 0.027). Factors that increased the risk for ICANS included: bulky disease (OR 2.67, 95% CI 1.28 – 5.49, p = 0.008), elevated Cr ≥ 1.5x ULN (OR 3.79, 95% CI 1.25 – 10.4, p = 0.012), elevated AST/ALT ≥ 3x ULN (OR 4.65, 95% CI 0.92 – 19.9, p = 0.042), low albumin (OR 2.85, 95% CI 1.49 - 5.5, p = 0.002), and co-occurrence of CRS with BsAb (OR 9.1, 95% CI 3.85- 25, p < 0.001). No other clinical variables including older age, histologic subtype, ECOG PS, B symptoms, IPI score, cell of origin or histologic subtype, baseline labs such as ALC, CRP, fibrinogen or D-dimer were significantly associated with CRS or ICANS risk. There was no difference in ORR or CR rates in patients who experienced CRS or ICANS. Conclusions: Our analysis of pts treated with commercial BsAb for LBCL shows an increased risk for CRS and ICANs based on clinical variables that are routinely obtained at baseline including tumor bulk, sites of disease, laboratory parameters, and history of prior CRS with CAR-T therapy. Differences in baseline populations receiving epco and glofit treatments in this real-world analysis have been previously reported (Brooks et al, Blood 2025) and the comparative risk for CRS between these treatments remains unclear. Future plans including multivariable analysis may allow for development of a predictive model to identify pts at high risk of CRS and ICANS with BsAb treatment, potentially leading to prospective clinical trials evaluating prophylactic interventions for high-risk pts.