Citations

Abstract Introduction: Standardized reporting of clinical trials results for MDS is essential to improve clinical interpretation and cross-study comparison. However, reporting of patient characteristics, response criteria, and endpoints in publications is often inconsistent; there is no systemic analysis of MDS trial reporting available. We conducted a systematic review of published MDS trial manuscripts on behalf of the international consortium for MDS (icMDS) to assess variability in reporting practices. Methods We searched ClinicalTrials.gov to identify all clinical trials registered for adults (≥18 years) with MDS that reported results between 2015-2024. Clinical trials that included acute myeloid leukemia (AML) or MDS/myeloproliferative neoplasms (MPN) were included if they enrolled ≥5 MDS patients. We excluded trials without an MDS cohort; non-therapeutic trials; trials focused on transplant interventions; or those which enrolled solid malignancies or other hematologic malignancies (chronic myeloid leukemia or lymphoid diseases). Finally, trials were required to have a manuscript available on Larvol, PubMed, or Google Scholar. Trials were categorized by disease risk (lower-risk [LR] vs. higher-risk [HR]) and trial phase (early phase [EP] vs. late phase [LP]). Results We identified 502 MDS trials on ClinicalTrials.gov, of which 351 did not meet inclusion criteria and 79 lacked a manuscript. A total of 72 trials (32 EP, 40 LP) with 80 publications (34 EP, 46 LP) were analyzed. Frequently reported baseline characteristics included age (100% EP, 100% LP), disease risk (74% EP, 74% LP), Eastern Cooperative Oncology Group performance status (85% EP, 72% LP), prior treatments (71% EP, 67% LP), and RBC transfusion dependency (32% EP, 70% LP). Less frequently reported characteristics included blood counts (hemoglobin [Hb; 38% EP, 54% LP], platelet count [38% EP, 54% LP], neutrophil count [24% EP and LP]) and bone marrow blasts (29% EP, 43% LP). Although disease risk was widely reported, definitions varied: IPSS and IPSS-R were each reported in 54% of manuscripts, while IPSS-M appeared in only 3%. Cytogenetic risk was separately reported in 39% of manuscripts (38% EP, 39% LP), and mutational data in 45% (47% EP, 43% LP). Responses per IWG 2006 criteria were reported in 84% of manuscripts. The primary endpoint involved safety/tolerability in 85% of EP manuscripts, though definitions were variable; recommended phase 2 dose was the most common (26% of EP manuscripts). In LP trials, primary endpoints were risk-specific: transfusion independence (TI) in 77% of LR, overall response rate (ORR) in 28% of HR, and complete remission (CR) or overall survival (OS) in 22% of HR. In HR manuscripts, CR was reported in 100%, ORR in 73%, hematologic improvement (HI) in 48%, RBC-TI in 23%, and OS in 80%. However, seven different definitions were used for ORR: CR + marrow CR + partial remission + HI per IWG 2006 was most common (35%). Event-free survival was reported in 25%; progression-free survival and relapse-free survival in 13%; and leukemia-free survival in 5%. Early mortality rate was reported in 35% (18% EP, 56% LP) and transplant rate in 58% (50% EP, 67% LP). Only 47% of HR and 90% of LR manuscripts identified HI-eligible patients. In LR-MDS, RBC-TI was reported in 72% of manuscripts but used six definitions. The most common were RBC-TI ≥8 weeks at any time during treatment (24%), ≥8 weeks within 28 weeks of treatment (13%), ≥8 weeks with Hb increase ≥1.0 (4%), ≥12 weeks with Hb increase ≥1.5 (4%), and ≥16 weeks within 24 weeks of treatment (12%). The remainder did not report RBC-TI, did not define it, or used a custom definition not used in another trial. HI was reported in 80% of LR papers with most of those reporting HI using IWG 2006 criteria (90%). Conclusion Reporting of baseline characteristics, response criteria, and outcomes is inconsistent in MDS clinical trials, with wide variability in response definitions, including ORR and TI. This heterogeneity limits interpretability, hampers historical comparisons and may obscure efficacy signals. Our findings highlight the need for standardized reporting guidelines to ensure clarity and consistency in MDS trial publications. As a next phase of this effort, we will conduct a formal Delphi process among icMDS experts to establish consensus recommendations for minimal and optimal MDS clinical trial reporting in manuscripts by disease risk (LR/HR) and trial phase (EP/LP).

Abstract BACKGROUND Ivosidenib is an oral inhibitor of mutant isocitrate dehydrogenase type I (IDH1) currently approved for the treatment of IDH1 mutated acute myeloid leukemia and myelodysplastic syndrome (MDS). Hematopoietic stem and progenitor cells carrying preleukemic mutations, referred to as clonal hematopoiesis (CH), are the origin of myeloid neoplasms (MN). Individuals who have cytopenias and CH, but do not meet diagnostic criteria for a hematologic malignancy, are classified as having Clonal Cytopenias of Undetermined Significance (CCUS), a condition associated with a high risk of progression to MN. While CCUS patients (pts) can have multiple mutations, they show lower mutational burden on average compared to MN. Thus, we hypothesized that treatment with ivosidenib would improve cytopenias in IDH1-mutant CCUS. METHODS; We performed a decentralized phase II single-arm study to characterize the safety and efficacy of ivosidenib in IDH1-mutant CCUS (NCT0503044). Drug was shipped to pts with local oncologists performing standard-of-care clinical exams supplemented by study team lead interviews for adverse event monitoring. Research labs were drawn by local providers or through Quest. QT corrected interval (QTc) was monitored through a mobile electrocardiogram device (AliveCor). Eligible patients were aged ≥ 18 years and had confirmed IDH1-mutant CCUS with at least 6 months of unexplained cytopenias (hemoglobin<10 g/dL, platelets<100 x109/L or absolute neutrophil count <1.8 x109/L). The primary endpoint was hematologic response of at least 8 weeks in duration based on the IWG 2006 criteria for MDS. RESULTS 20 pts with IDH1-mutant CCUS have been enrolled. Most were male (70%) with a median age of 66 (range 41-79). Overall, 74% had a self-reported race of non-Hispanic white, 11% of Hispanic white, 5% of Asian and 11% of black or African American. Most pts presented with neutropenia (95%) including some with co-occurring thrombocytopenia (21%). One pt presented with anemia and thrombocytopenia without neutropenia. Prior to treatment, the average number of co-mutations beyond IDH1 was 2 (range 0-3), with most pts (74%) harboring a co-occurring spliceosome gene mutation. The IDH1 variant allele fraction (VAF) was lower in the blood (mean=19%, range 3-35%) than in the bone marrow (mean=31%, range 18-43%) in most (93%) patients. Out of the 20 enrolled pts, 17 received at least 8 weeks of therapy at the time of our data cutoff (7/29/2025) and were included in the efficacy analysis. Grade ≥3 adverse events (AEs) occurred in five patients (26%) including two with grade ≥3 treatment-related adverse events (pancytopenia and sepsis in the first pt, rash in the second pt). The most common all-grade treatment-related adverse events were nausea (n=5, 26%), prolonged QTc (n=3, 16%), anemia (n=3, 16%), and diarrhea (n=3, 16%). There were no instances of reported differentiation syndrome. Overall, 82% of pts achieved a hematologic response (14/17) including improvement in neutropenia (88%) and thrombocytopenia (75%). With a median follow-up of 16 months (range 0.6-24 months), the median duration of hematologic response was not reached. Among responders, 86% had a continued response at one year. Two pts progressed to MDS after 4 and 17 months of treatment characterized by recurrence of cytopenias and the emergence of new clones. A surveillance bone marrow biopsy was performed at 18 cycles for the 8 pts who remained on treatment with none showing disease progression. Most pts (90%, N=9/10) treated for at least 12 months had a decrease in IDH1-mutant CH VAF over time and 40% (N=4/10) showed IDH1 mutation clearance (VAF <2%) with a median time to clearance of 9 months. Among those with decreasing IDH1 clonal burden, all had a corresponding decrease in other co-occurring mutations present at baseline with one responder showing emergence of a newly detectable CHEK2 mutation without disease progression. CONCLUSIONS Decentralized trials represent a feasible solution for the conduct of clinical trials in rare hematologic neoplasms and precursor conditions. Ivosidenib was well-tolerated and induced durable hematologic remissions in IDH1-mutant CCUS. Most pts showed a reduction in clonal burden with mutation clearance commonly seen with long-term treatment demonstrating that ivosidenib modifies the natural history of IDH1-mutant CCUS.

Abstract Background: Recent advances in computer vision have given rise to image foundation models (FMs), large-scale neural networks pre-trained on millions of unlabeled histopathology patches, which can learn generalizable representations of tissue morphology. In many cancers, these FMs have predicted genetic mutations and prognoses directly from histology, suggesting that morphology encodes “hidden” molecular information. In lymphoma, this field is nascent but growing.General-purpose histopathology FMs have limited representation of lymphoid morphology. We developed and evaluated LymphoVision, a lymphoma-specialized image foundation model pretrained with self-supervised learning, to extract clinically meaningful features from routine hematoxylin and eosin (H&E) histology. Methods: LymphoVision was pre-trained using knowledge distillation and consistency (DINOv2) on over 37 million multi-resolution patches (5x, 10x, 20x, 40x) sampled using a density-aware strategy from 31,211 H&E whole slide images (WSIs) from 9,155 archival lymphoma and reactive lymphoproliferative cases. To ensure diverse, representative samples, our patch sampling method uses an efficient graph-based clustering algorithm and prioritizes morphologically informative regions by clustering patch embeddings and performing density sampling within each cluster. The pretrained encoder was evaluated using a clustering-constrained attention multiple instance learning (MIL) framework on three diagnostic tasks: (1) cell-of-origin (COO) classification in diffuse large B-cell lymphoma (DLBCL), distinguishing germinal center B-cell (GCB) from non-GCB subtypes based on the Hans immunohistochemistry algorithm; (2) follicular lymphoma (FL) grading, differentiating low-grade (grades 1–2) from high-grade (grade 3); and (3) multiclass lymphoma subtype classification across six categories: DLBCL, FL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), classical Hodgkin lymphoma (CHL), and benign/reactive lymphoid conditions. WSI-level labels were derived from pathology reports, and none of the evaluation cases were included in pretraining. Models used a ViT-Giant LymphoVision backbone to generate 20x patch embeddings, followed by MIL using 50% training data and 2-fold cross-validation (25% validation, 25% test). Performance was assessed using area under the receiver operating characteristic curve (AUC), accuracy, recall (sensitivity) and F1 score. Results: For DLBCL COO classification (total n=358 cases), LymphoVision achieved a mean test AUC of 0.93 (range 0.92–0.94), accuracy of 84.5% and F1 of 0.85 across two independent test folds (n=91 per fold, 50% GCB). These results outperformed general-purpose FMs on the same task and cases, including Virchow-v2 (AUC 0.85) and UNI-v2 (AUC 0.88), despite those models being pretrained on 10–100 times more images. For FL grading (total n=660 cases), the test set in each fold included 166 cases (18% grade 3), yielding a mean test AUC of 0.88 (range 0.87–0.90), accuracy of 89.2% and F1 of 0.80. In multiclass lymphoma subtype classification (total n=1,176 cases), the test set included 296 cases per fold. LymphoVision achieved a mean test AUC of 0.98 (range 0.97-0.99), mean test accuracy of 87.1% and mean F1 of 0.84. Class-wise recall was 92.0% for DLBCL (n=112), 88.2% for FL (n=72), 77.2% for MZL (n=29), 70.8% for MCL (n=35), 87.5% for CHL (n=24), and 95.8% for benign/reactive lymphoid conditions (n=24). Conclusion: LymphoVision is a lymphoma-specialized FM trained using self-supervision that achieves high diagnostic accuracy across multiple clinically meaningful tasks using weak supervision and standard H&E images, suggesting the encoder has learned fine-grained lymphoma morphology. Based on historical benchmarks from the 1997 International Lymphoma Study Group classification project, expert hematopathologists achieved diagnostic agreement rates of 55% to 84% using H&E morphology alone for the non-Hodgkin lymphoma (NHL) entities included in our multiclass task. LymphoVision approached or exceeded these benchmarks. These findings underscore the value of our approach using disease-specialized pretraining and intelligent patch sampling for data-efficient histopathology learning. LymphoVision has the potential to augment diagnostics, enable scalable AI-powered classification in real-world workflows, and serve as a foundation for prognostic and theragnostic applications. External validation and multimodal integration are ongoing.

Abstract Introduction: Leukemogenesis is driven by nucleophosmin 1 mutations(NPM1-m) or lysine methyltransferase 2A rearrangements(KMT2A-r) in ~35–40% of acute myeloid leukemia (AML) cases. Nearly half of AML patients will develop relapsed/refractory (R/R) disease within a year, with <20% expected response rate following venetoclax/azacitidine (Ven/Aza) and progressively poorer outcomes with each subsequent line of therapy. Ziftomenib–a potent, highly selective, oral, investigational menin inhibitor–has demonstrated clinical activity as both monotherapy and in combination for adults with R/R NPM1-m or KMT2A-r AML. KOMET-007 (NCT05735184) is an ongoing, open-label, ph1a/b study of ziftomenib in combination with standard chemotherapies in adults with newly diagnosed and R/R NPM1-m or KMT2A-r AML. Here we present updated safety and clinical activity in patients with R/R AML treated with the recommended ph2 dose (RP2D) of ziftomenib 600 mg in combination with Ven/Aza across ph1a/b. Methods: Adults (≥18y) with R/R NPM1-m or KMT2A-r AML enrolled independently into separate arms; patients in dose escalation (ph1a) and expansion (ph1b) were treated with oral ziftomenib 600 mg once daily (QD; continuously from C1D8 onward) plus standard doses of Ven/Aza. Primary endpoints: AEs, complete remission (CR; ELN 2022), dose limiting toxicities (DLT; ph1a only). Key secondary endpoints: composite CR (CRc; CR with full, partial or incomplete hematologic recovery), overall response, duration of response. Results: As of June 25, 2025, 80 patients (51 NPM1-m, 29 KMT2A-r) with R/R AML were enrolled (20 ph1a; 60 ph1b) and treated with ziftomenib 600 mg QD + Ven/Aza. Median age was 63y (range 19–85), 50% were female, 74% had ECOG PS 0–1; 22 (28%) had FLT3 co-mutations and 7 (9%) had IDH co-mutations. Median number of prior therapies was 1 (range 1–6); 18% (14/80) had prior stem cell transplant; 25 (49%) NPM1-m and 19 (66%) KMT2A-r patients had prior Ven exposure. 71 patients (89%) had Gr ≥3 treatment-emergent AEs, most commonly (≥20% of patients) febrile neutropenia (31%), decreased platelet count (28%), decreased white blood cell count (26%) and decreased neutrophil count (23%). Gr ≥3 ziftomenib-related AEs occurred in 30 patients (38%), most commonly febrile neutropenia (9%) and anemia (8%). 6% of patients discontinued ziftomenib treatment due to AEs. Differentiation syndrome (DS) occurred in 1 (1%) NPM1-m patient (Gr 3), which lasted 1d and successfully resolved with protocol-specified DS mitigation. No ziftomenib-related QTc prolongation was reported with the combination, and no DLTs were observed in ph1a. 70 patients (43 NPM1-m; 27 KMT2A-r) were response-evaluable (≥1 response assessment or death). Median follow-up was 18.0 wks for NPM1-m and 16.4 wks for KMT2A-r. Overall response rates (ORRs) were 65% (28/43) for NPM1-m and 33% (9/27) for KMT2A-r. CRc rates were 49% (21/43) for NPM1-m and 22% (6/27) for KMT2A-r after median time to first CRc of 4.9 wks (range 2.7–15.6) and 5.5 wks (range 2.6–18.9), respectively; measurable residual disease (MRD)-negativity rates (local) among tested CRc responders were 50% (9/18) for NPM1-m and 60% (3/5) for KMT2A-r after median time to first MRD-negativity of 5.9 wks (range 2.9–15.6) and 8.1 wks (range 7.7–18.9), respectively. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 43d overall (43d for NPM1-m; 71d for KMT2A-r), and median time to platelet recovery (≥100×109/L) was 27d overall (27d for NPM1-m; 23d for KMT2A-r). As of the data cutoff, overall median duration of CRc was not estimable; median overall survival was not estimable for NPM1-m and 21.1 wks for KMT2A-r. In Ven-naive patients, CRc rates were 71% (15/21) for NPM1-m and 33% (3/9) for KMT2A-r; CR rates were 48% (10/21) and 11% (1/9); and ORRs were 81% (17/21) and 56% (5/9), respectively. The study is ongoing with 44% (19/43) of NPM1-m and 11% (3/27) of KMT2A-r patients still on treatment, with responses continuing to evolve.Updated data to be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg QD + Ven/Aza was well tolerated with robust clinical activity in patients with R/R NPM1-mor KMT2A-rAML. No ziftomenib-related QTc prolongation was reported. One case of DS (NPM1-m, Gr 3) successfully resolved with protocol-specified mitigation. These data support further investigation of ziftomenib-based combinations in R/R NPM1-mand KMT2A-rAML.

Abstract Introduction: Nucleophosmin 1 mutations (NPM1-m) drive leukemogenesis in approximately 30% of acute myeloid leukemia (AML) cases. Ziftomenib is a potent, highly selective, oral, investigational menin inhibitor that has demonstrated clinical activity as both monotherapy and in combination for adults with NPM1-m or lysine methyltransferase 2A-rearranged (KMT2A-r) AML. KOMET-007 (NCT05735184) is an ongoing, open-label, dose-escalation (phase 1a) and expansion (phase 1b) study of ziftomenib in combination with standard chemotherapies in NPM1-m or KMT2A-r AML. Here we present phase 1b safety and clinical activity in patients with newly diagnosed NPM1-m AML who received the recommended phase 2 dose (RP2D) of ziftomenib 600 mg in combination with venetoclax and azacitidine (Ven/Aza). Methods: Adults (≥18 years) with newly diagnosed NPM1-m AML who were not eligible for intensive chemotherapy were enrolled in phase 1b and received ziftomenib 600 mg once daily plus standard doses of Ven/Aza. Ziftomenib was orally administered once daily continuously from Cycle 1 Day 8 onward. Phase 1b primary endpoints were adverse events (AEs) and complete remission (CR) per ELN 2022. Secondary endpoints included composite CR (CRc; defined as CR with full, partial, or incomplete hematologic recovery), overall response, and duration of response. Local measurable residual disease (MRD) was assessed by next-generation sequencing, RT-qPCR, and multiparameter flow cytometry. Results: As of June 25, 2025, 39 patients with newly diagnosed NPM1-m AML were enrolled and treated with ziftomenib 600 mg once daily plus Ven/Aza in phase 1b. Median age was 75 years (range 53–93), 54% were female, 46% had ECOG PS 0–1; 12 (31%) had FLT3 co-mutations and 9 (23%) had IDH co-mutations. Median duration of follow-up was 16.3 weeks (range 1.6–41.1). Twenty-nine patients (74%) had grade ≥3 treatment-emergent AEs, most commonly (≥20% of patients) decreased neutrophil count (31%) and decreased platelet count (23%). Grade ≥3 ziftomenib-related AEs occurred in 14 patients (36%), most commonly decreased neutrophil count (15%) and decreased platelet count (13%). No ziftomenib treatment discontinuations occurred due to AEs. Differentiation syndrome occurred in 1 (3%) patient (grade 2), which successfully resolved with protocol-specified mitigation. One patient (3%) had investigator-assessed ziftomenib-associated QTc prolongation (grade 3); however, there were concomitant significant electrolyte abnormalities and event resolved with electrolyte repletion. At time of data cutoff, 31 NPM1-m patients were response-evaluable (≥1 response assessment or death). CRc rate was 84% (26/31) after a median time to first CRc of 3.5 weeks (range 2.4–9.4), with local MRD-negativity rates among tested CRc responders of 54% (13/24) after a median time to first MRD-negativity of 8.4 weeks (range 2.9–17.4). CR rate was 58% (18/31) and overall response rate was 94% (29/31), with responses and MRD-negativity rates continuing to evolve. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 36 days, and median time to platelet recovery (≥100×109/L) was 28 days. The median duration of response and median overall survival were not reached as of the data cutoff, at a median follow-up of 16.3 weeks. The study is ongoing, with 81% (25/31) of NPM1-m patients still on-study and 77% (24/31) still on ziftomenib treatment. Updated safety and clinical activity results will be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg once daily combined with Ven/Aza was well tolerated and demonstrated robust clinical activity in patients with newly diagnosed NPM1-m AML, including 84% CRc after a median of 3.5 weeks and 54% CRc MRD-negativity after a median of 8.4 weeks. Low rates of ziftomenib-related cytopenia and no additional myelosuppression were observed with this combination. One case each of differentiation syndrome (grade 2) and investigator-assessed QTc (grade 3) were successfully resolved. Taken together, these data support the RP2D determination and advancement of this ziftomenib-based combination in the KOMET-017 (NCT07007312) randomized phase 3 study in patients with newly diagnosed NPM1-m AML.

Abstract Background The benefit of high-dose chemotherapy and autologous stem cell transplantation (ASCT) as a consolidation strategy after initial chemotherapy in peripheral T-cell lymphoma (PTCL) is currently unclear, and a randomized trial (EA4232/PTCL-STAT) to answer this question is currently underway. Angioimmunoblastic T-cell lymphoma (AITL) is a rare, aggressive subtype of nodal PTCL with poor prognosis and unique features. Here, we report a large-scale, real-world evidence on the role of ASCT in frontline AITL management. Methods We analyzed a national cohort of 5,827 patients diagnosed with AITL between 2004 and 2020 from the National Cancer Database (NCDB). Baseline demographic, clinical, and socioeconomic characteristics were assessed. Treatment modalities included chemotherapy alone, chemotherapy with ASCT, and no treatment. Overall survival (OS) was evaluated using Kaplan-Meier method and multivariable Cox proportional hazards regression. Propensity score matching (PSM) was performed to validate ASCT's treatment effect. Results Among patients with complete treatment information (n = 5,224), the median age at diagnosis was 68 years (range 20–90). Frontline treatments included chemotherapy alone (68.6%, n = 3,584), chemotherapy with ASCT (14.6%, n = 761), and no treatment (16.8%, n = 879). Compared with patients who did not receive ASCT, those who underwent ASCT were significantly younger (median 60.0 vs 68.0 years), more frequently treated at academic centers (81.5% vs 57.9%, p < 0.001), and more likely to reside in areas with higher educational attainment (p < 0.001). They exhibited lower Charlson-Deyo comorbidity scores (CDS), with a higher proportion having a score of 0 (82.8% vs 73.6%, p < 0.001), and were more likely to have advanced-stage disease (93.0% vs 86.9%, p < 0.001). Furthermore, a higher proportion of patients who received ASCT were diagnosed in more recent years (p < 0.001). Sex, race, and IPI score distribution showed no significant baseline differences. Median follow-up time was 81.1 months (95% CI: 77.4–84.9), and the median OS was 23.3 months (95% CI: 21.3–25.2) for the entire cohort. For patients receiving chemotherapy with ASCT, the median OS was 139.2 months (95% CI: 104.2–174.2). In comparison, chemotherapy alone yielded a median OS of 23.6 months (95% CI: 21.4–25.8), while patients who received no treatment had a median OS of 4.0 months (95% CI: 2.7–5.2); overall p < 0.001. Median OS also significantly improved with more recent diagnosis eras: 20.1 months for patients diagnosed in 2004–2009 (95% CI: 16.8–23.4), 23.9 months for those diagnosed in 2010–2015 (95% CI: 21.0–26.7), and 26.7 months for patients diagnosed in 2016–2020 (95% CI: 23.1–30.4) (p < 0.001). Analyses consistently demonstrated longer median OS in female patients (27.5 vs. 20.7 months in males, p <0.001), and in patients treated at academic centers (27.5 vs. 16.4 months at non-academic centers, p < 0.001). Median OS varied by race (White: 24.0 months vs. Black: 15.2 months vs. Others: 30.3 months; p = 0.017). Patients with higher household income and higher educational attainment experienced significantly improved survival (p = 0.005 and p = 0.017, respectively). Patients with early-stage disease, lower IPI scores, and lower CDS also showed significantly longer survival (p < 0.001 for all comparisons). Multivariate Cox regression showed that chemotherapy with ASCT significantly reduced mortality risk compared to chemotherapy alone (HR = 0.438, 95% CI: 0.364–0.527, p < 0.001). No treatment significantly increased mortality risk (HR = 1.941, 95% CI: 1.634–2.305, p < 0.001). PSM analysis further validated that chemotherapy with ASCT significantly lowered mortality risk compared to chemotherapy alone (HR = 0.608, 95% CI: 0.503–0.736, p < 0.001), after matching for age at diagnosis, sex, race, income, education level, academic center, stage, CDS, and diagnosis era. Conclusion This large-scale, real-world analysis suggests that chemotherapy followed by ASCT is associated with significantly improved overall survival in patients with AITL, supported by unadjusted Kaplan-Meier analysis, adjusted multivariate Cox regression, as well as PSM analysis. These data support ASCT as an important consolidation strategy for AITL in real-world practice.

Abstract Background: For LS-DLBCL, clinical trials (FLYER, LYSA/GOELAMS 02-03, LYSA LNH09-1B, S1001) have shown that 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP4) without radiation (RT) leads to durable remissions in >90% of cases. However, only patients (pts) with non-bulky disease and/or international prognostic index (IPI) of 0 and complete metabolic response (CMR) on interim positron emission tomography (PET) scan, if performed, were eligible for RCHOP4 alone in these studies. Outcomes in trial-ineligible LS-DLBCL and the appropriate real-world candidates for RCHOP4 are still undefined. Methods: We conducted a multicenter retrospective study of adult pts with stage I/II DLBCL of any tumor bulk, IPI and with or without B-symptoms diagnosed after 2011 and treated with RCHOP4 +/- 2 cycles R from 21 U.S. centers. Pts with PMBCL, PTLD or receiving non-standard dose RCHOP for cycle (C) 1 or planned consolidative RT were excluded. The primary endpoint was PFS from C1 by Kaplan-Meier method, not counting indolent lymphoma relapse. Event free survival (EFS) was time to next therapy without progression (including unplanned RT for non-CR), progression or death. A competing risks analysis of non-relapse mortality (NRM) vs. DLBCL progression was performed. Results: The characteristics of the 428 pts were: median age 60 (18-88), 60% male, 11% Hispanic and 4% non-Hispanic Black, 62% stage I, 15% elevated LDH, 3% ECOG PS>1, 5% tumor bulk >7cm, 9% had B-symptoms and median Charlson Comorbidity Index (CCI) was 4 (2-12). IPI was 0, 1 and 2-3 in 42%, 46% and 12% and stage-modified IPI (smIPI) was 0, 1, 2 and 3-4 in 25%, 48%, 21% and 6% of pts. 66% had nodal (59% head/neck, 11% pelvic, 9% multiple above diaphragm, 7% abdominal) and 46% extranodal sites (37% head/neck, 20% gastric/intestinal, 9% spleen, 8% skin/soft tissue); 6% had transformed/concurrent FL/MZL or grade 3B FL, 33% (138/408) were non-GCB cell of origin (COO), 25% (90/357) double expressor (DEL) and 0.5% (2/379) double-hit. 13% had completely resected disease, 97% staging PET and 47% bone marrow biopsy. Median diagnosis to treatment interval was 30 days (IQR 20-43), 6% had dose reductions after C1, 77% had an interim PET (iPET) after C2 (33%) or C3 (67%), 15% received 2 additional cycles R and 4% CNS prophylaxis. CMR rates by iPET were 83% after C2 and 94% after C3, and 95% by end-of-treatment PET. iPET PMR was more likely if smIPI>2 or bulky disease. Median follow-up time was 2.7 years. There were 32 progression events: 14 occurred at the primary site and 17 at distant sites (1 unknown), and 12 occurred after 2 years. Another 11 pts received unplanned RT after RCHOP4 for non-CR. There were 24 deaths, 12 without prior progression. Cause of death was DLBCL in 7 and non-DLBCL in 17 cases (6 infection, 2 ILD, 2 heart failure, 2 second cancer, 1 seizure, 4 unknown). EFS, PFS and OS rates were 88%, 90% and 96% at 3 years. By univariable Cox regression, Black race, elevated LDH, smIPI>2, DEL, increasing CCI, multiple subdiaphragmatic nodal sites and iPET PMR were associated with worse PFS. Non-significant variables of note included COO, extranodal sites, complete resection, missing bone marrow biopsy, missing iPET and additional cycles R. By multivariable analysis (including age>60, stage, ECOG PS>1, elevated LDH, bulky disease, CCI, B-symptoms and DEL), ECOG PS>1 (HR 3.95 p=0.050), CCI (HR 1.29 p=0.003) and DEL (HR 2.02 p=0.069) were associated with worse PFS. Cumulative incidence of DLBCL progression and NRM were 8% and 2% at 3 years. Competing risk analysis by univariable models found that age>60, ECOG PS>1, smIPI>2, elevated LDH, CCI and bulky disease were associated with NRM, while DEL and B-symptoms were associated with DLBCL progression.Conclusion: Presented is the largest retrospective cohort of LS-DLBCL treated uniformly with RCHOP4 to date. Despite modest follow-up time and lack of an “intention-to-treat“ population, this study shows that abbreviated RCHOP4 leads to excellent outcomes in the real-world, albeit with continuous risk of late relapse. smIPI risk factors were associated with worse PFS, though this may in part be driven by risk of non-lymphoma death. As pts with advanced age, poor performance status or comorbidities may benefit from reduced treatment exposure, RCHOP4 should still be considered for these and other “trial-ineligible” pts, particularly if other high-risk features (iPET PMR, DEL or B-symptoms) are absent.

Abstract Background Secondary central nervous system lymphoma (SCNSL) is a rare but significant complication, affecting approximately 2–10% of patients with diffuse large B-cell lymphoma (DLBCL), often leading to poor outcomes. The CNS-International Prognostic Index (CNS-IPI) remains a widely adopted tool for estimating CNS relapse risk; however, recent advances in molecular profiling and evolving treatment paradigms have challenged the adequacy of CNS-IPI alone in guiding risk assessment. This study evaluates the prognostic relevance of CNS-IPI in conjunction with molecular and clinical factors, specifically cell-of-origin (COO), gene expression, and frontline treatment regimens. The aim is to refine risk stratification and identify patients at highest risk for SCNSL. Method Building on our previous study, we analyzed data from patients with newly diagnosed DLBCL between 2002 and 2023, enrolled in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource. Patients with primary CNS lymphoma, CNS involvement at diagnosis, or who received CNS-directed therapy were excluded. COO was determined using the Hans algorithm and/or Nanostring profiling. Multivariate cause-specific Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for predictors of CNS relapse that were measured at the time of initial DLBCL diagnosis. Cumulative incidence with competing risks and cause-specific Cox models were used to analyze relapse risk. Result We included 2137 patients in our analysis, median age at diagnosis was 63 (IQR 53-72), with 41.6% (n=890) females. The albumin level was below normal in 32.5% (n=350), 64.0% (n=1367) had CNS-IPI of intermediate/high, 37.5% (n=586) had non-germinal center B-cell (GCB) COO, and 14.5% (n=309) were double expressor positive. At a median follow-up of 83 months (IQR 42 -143), 82 (3.8%) SCNSL relapses were observed; the 3 and 5 yrs cumulative incidence for SCNSL from time of DLBCL diagnosis were 3.7% (95% CI 3.0-4.7) and 3.8% (95% CI 3.1-4.8) respectively. In models accounting for death as a competing risk, the 5-year cumulative SCNSL incidence estimate for patients with a CNS-IPI low was 1.5% (95% CI 0.8-2.7), Intermediate was 4.9% (95% CI 3.7-6.4), and high was 6.1% (95% CI 3.8-9.6). The 5-year cumulative SCNSL incidence estimate for patients with non-GCB COO was 5.2% (95% CI 3.6-7.4) compared to 2.4% (95% CI 1.6-3.6; p=0.001) for GCB patients, and the 5-year cumulative SCNSL incidence for double expressor positive patients was 8.6% (95% 5.8-12.6) compared to 1.5% (95% CI 0.8-2.7; p<0.001) for double expressor negative patients. In a multivariable model (including CNS-IPI, COO, double expressor, treatment group, extranodal involvement, and albumin group), CNS-IPI intermediate (HR 2.85 [1.58-5.14]; p<0.001) and high (HR 4.31 [2.15-8.65]; p<0.001), non-GCB COO (HR 2.36 [1.37-4.06]; p=0.002], double expressor (HR 5.56 [2.88-10.73]; p<0.001), and below normal albumin (HR 1.89 [1.02-3.50]; p=0.042) were independently associated with increased risk of SCNSL. The majority of the SCNSL relapse occurred within the first 2 years after DLBCL diagnosis; 81.7% (n=67), with only 6.1% (n=5) occurring after 5 years. For patients who developed SCNSL, the median OS from the time of SCNSL diagnosis was 24 months (95% CI 17-34), with 5 years OS of 31% (95% CI 22-43). These findings are being validated using an external, international cohort, and final analysis will be presented at the time of presentation at ASH. Conclusion In this large, prospectively followed cohort with long-term follow-up data, SCNSL remains a rare but devastating complication of DLBCL, with a 5-year cumulative incidence of 3.8% and it is associated with very poor long-term survival. While CNS-IPI remains a strong predictor of SCNSL risk, our study identifies non-GCB COO and double expressor phenotype as independent, additive molecular risk factors. These findings suggest that current risk stratification tools may underestimate the risk of CNS relapse in molecularly defined high-risk subgroups. Considering the poor outcomes linked to SCNSL and the absence of a connection with frontline treatment types, future research should aim to enhance risk prediction models through molecular profiling and explore prophylactic strategies to reduce the likelihood of SCNSL.

Abstract Diffuse Large B Cell Lymphoma (DLBCL), the most common subtype of aggressive B-cell Non-Hodgkin Lymphoma (NHL), accounts for 30-40% of newly diagnosed NHL cases. Despite recent progress improving our understanding of molecular features of DLBCL, there is still a high relapse rate (~45%) among patients who undergo standard treatment (R-CHOP). Several groups have identified reproducible molecular clusters of DLBCL although, the biologic significance of many of the specific gene mutations within these clusters is poorly understood. DTX1 mutations are a feature of the BN2/C1 DLBCL classifiers and are among the mutations with unknown significance. BN2/C1 DLBCL are a mixture of ABC, GCB, and Unclassified cell of origin (COO) with a common signature being the presence of genetic alterations in genes known to regulate the NOTCH pathway; yet, these tumors lack transcriptional signatures of traditional NOTCH activation, suggesting a unique and undefined biology driven through non-canonical NOTCH pathway activation. DTX1 is an E3 ubiquitin ligase which directly binds the intracellular domain of the NOTCH receptor (NICD), targeting it for degradation, resulting in suppression of NOTCH pathway activity. We therefore hypothesize that DTX1 mutations lead to NOTCH pathway dysregulation and are a critical driver for a subset of BN2/C1 DLBCLs. Using whole exome sequencing (WES) data from 404 newly diagnosed DLBCL patients, we found 8% of patients with mutations in DTX1. Alterations in DTX1 were localized to the NICD binding domain, WWE1. In silico Alphafold modeling of DTX1 WWE1-interaction with NICD revealed that patient mutations clustered within predicted interacting surfaces with NICD. These findings lead to the hypothesis that mutations in the DTX1 WWE1 domain suppress its ability to bind to and degrade NICD, enhancing NOTCH pathway activation in DLBCL. To address this question, we first compared DTX1 protein expression by immunoblot in DTX1 WWE1 mutant (OCI-Ly3 and SUDHL2) and wildtype (WT) (OCI-Ly7, OCI-Ly19, SUDHL6, and U2932) DLBCL cell lines. We found higher expression of NICD1 (p=0.03) in OCI-Ly3 and NICD2 (p<0.0001) in SUDHL2 cell lines compared to WT. This increase was accompanied by an increase in NOTCH surface expression with higher NOTCH1 (p<0.0001) and NOTCH2 (p<0.0001) expression on OCI-Ly3 and SUDHL2 cells, respectively, compared to WT. To remove variability across cell lines we next used CRISPR to generate DTX1 knock out (KO) models using WT DTX1 DLBCL cell lines U2932 and OCI-Ly19. Analysis of NICD and NOTCH receptor protein expression confirmed our initial finding, showing an 8.5 and 4.8-fold increase of NICD1 and a 6 and 2.5-fold increase of NICD2 expression in the U2932 and OCI-Ly19 DTX1 KO cell lines, respectively, compared to empty vector (EV) controls. An increase in surface NOTCH1, and to a lesser extent NOTCH2, was seen in U2932 (p=0.01 and p=0.07, respectively) and OCI-Ly19 (p=0.001 and p=0.2, respectively) KO cells compared to EV controls. To identify pathways affected by DTX1 mutations, we next performed RNAseq on U2932 EV and KO cell lines. Of interest, we did not detect any significant changes in classical NOTCH driven genes (Hes1, Hey1, etc.), supporting prior studies on BN2/C1 tumors. However, we did identify potential non-canonical NOTCH-target genes that may contribute to lymphomagenesis. Gene expression in KO cells showed upregulation of genes involved in germinal center (GC) processes (AICDA, IRF4; p<0.001) and cellular growth and survival (IL6R, CCND2, STAT5B, BCL2; p<0.0001). Measurement of IL6R by flow cytometry and CyclinD2 by immunoblot further verified DTX1-mediated upregulation of IL6R (p<0.01) and CyclinD2 (p<0.01) for U2932 KO cells compared to EV control. We also observed downregulation of genes contributing to cell death (ex. BAX, CASP8, FAS; p<0.05) in KO cells compared to EV. Together, these novel findings support our hypothesis that DTX1 WWE1 mutations lead to dysregulation of the NOTCH pathway by driving overexpression of NICD and NOTCH, resulting in dysregulated expression of proteins involved in cell cycle, GC reaction, and apoptosis. We further provide new biologic insight into BN2/C1 DLBCL, ultimately highlighting a path toward novel therapeutic targets and the advancement of personalized medicine, as patients harboring these mutations may benefit from new therapies targeting inflammatory pathways, such as CELMoDs.

Abstract Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs). Their use is associated with relatively high response rates, with some patients experiencing prolonged remission. It is unclear whether continuous treatment beyond 12 months for pts in remission is beneficial, as continued immunosuppression may result in additional toxicity. We sought to report the outcomes of pts with prolonged remission and survival following BsAb administration. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCLs receiving commercially available epco or glofit between 2023 and 2025. Baseline characteristics and outcomes were extracted from medical records. Efficacy and survival outcomes were assessed by site investigators and included overall response rate (ORR), complete and partial response (CR, PR) rates. Pts who responded to BsAbs and had ≥365 days of follow-up from initiation of BsAb treatment were included in the analysis. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAbs (epco n=193, glofit n=119) with a median age of 66 years (interquartile range [IQR] 59-73) at BsAb start. Most were male (64.5%), had advanced stage disease (77.4%) and had ECOG performance status of ≤1 (93.3%) at BsAb start. Of 207 pts who had initiated treatment with BsAb ≥12 months prior to data cutoff, we identified 31 pts (15.0%) who had a response to BsAbs (19 epco, 12 glofit) and were alive without progression at 12-months post-BsAb initiation and included them in this landmark analysis. Of the cohort of 19 pts treated with epco, 6 discontinued due to reasons other than disease progression including CAR-T cell therapy (n=2), secondary malignancy (n=2), allogeneic transplant (n=1), or other reasons (n=1). Thirteen of 19 pts received ≥12 months of epco treatment, and, with a median follow-up of 16 months from the start of BsAb, 12 of 13 pts continued receiving epco beyond 12 months with one pt discontinuing after 12 months (observed for an additional 41 days prior to censoring). Of the cohort of 12 pts treated with glofit, 8 pts were observed after completing all planned therapy and 4 patients underwent allogeneic transplant. Among all 31 BsAb-treated patients alive and in remission at 12 months, at the time of data cutoff, 5 pts (12.9%) had progressed (2 previously treated with epco and 3 with glofit). Three of the 4 pts who underwent allogeneic transplant after prior glofit treatment experienced disease relapse. A total of 24 pts (77.4%) were alive at the time of last follow-up, with the causes of death being disease progression (n=1), secondary malignancy (n=1), infection (n=1), and unknown cause (n=4). Conclusions: In this large cohort of r/r LBCL pts treated with BsAbs monotherapy in the standard of care setting, a relatively small proportion of pts (15%) achieve the 12 month PFS landmark. In the absence of robust evidence for what constitutes best practice, different strategies are employed, including continuation of BsAb, observation as well as consolidation with allogeneic transplant or CAR T-cell therapy. Additional follow-up will be reported to help guide clinical decision making regarding the optimal management strategy for this high risk pt population.