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Abstract Background: Luspatercept, an erythroid maturation agent, has shown efficacy in improving anemia in both β-thalassemia and lower-risk myelodysplastic syndromes (MDS). In the BELIEVE trial, which led to its approval in transfusion-dependent β-thalassemia, thromboembolic events were notably higher in patients with risk factors such as splenectomy. More recently, the COMMANDS trial demonstrated superior transfusion independence with luspatercept over erythropoiesis-stimulating agents (ESAs) in ESA-naive, lower-risk MDS patients. However, limited data exist regarding comparative thrombotic risk in real-world MDS populations. We conducted a multicenter, real-world study to evaluate thrombotic event rates associated with luspatercept versus ESAs in MDS patients without prior venous thromboembolism (VTE). Methods: We queried the TriNetX Research Network, a federated real-time electronic health record (EHR) database covering over 100 million patients across major healthcare organizations. Adults (≥18 years) with a diagnosis of MDS (ICD-10-CM code D46) and no prior history of deep vein thrombosis (DVT) or pulmonary embolism (PE) were included. Patients were stratified based on treatment with luspatercept or ESAs (epoetin alfa or darbepoetin alfa). Propensity score matching (PSM) using a 1:1 nearest-neighbor algorithm without replacement was performed to balance demographics and clinical covariates. Primary outcomes included the incidence of DVT, PE, and composite VTE events within 12 months of therapy initiation. Results: A total of 6,448 patients with MDS and no prior VTE were identified: 5,698 received ESAs and 750 received luspatercept. The overall mean age was 72.5 ± 13.5 years, with 48.1% male. After PSM, 741 patients were included in each treatment arm. The matched cohort had a mean age of 76.7 ± 10.7 years, and 41.3% were female. In the ESA group, 58/741 (7.8%) developed DVT compared to 27/741 (3.6%) in the luspatercept group (Hazard Ratio [HR] 1.4; 95% CI, 0.9–2.3). PE occurred in 27 ESA-treated patients (3.6%) versus 13 luspatercept-treated patients (1.8%) (HR 1.3; 95% CI, 0.6–2.7; p=0.941). The overall composite VTE rate was 10.0% (74/741) in the ESA group and 4.9% (36/741) in the luspatercept group (HR 1.3; 95% CI, 0.9–2.0; p=0.732). Conclusion: In this large, multicenter real-world analysis, we observed a numerically lower incidence of thrombotic events with luspatercept compared to erythropoietin-based agents in patients with MDS, though differences did not reach statistical significance. These findings support the thrombotic safety profile of luspatercept observed in clinical trials and warrant further prospective validation.

Abstract Introduction: Autologous CD19 CART therapies have been utilized across a wide range of B cell driven autoimmune diseases (AD), including systemic lupus erythematous (SLE), idiopathic inflammatory myopathies (IIM), systemic sclerosis (SSc), & myasthenia gravis (MG). To date, a number of autologous CD19-CART therapies have delivered durable drug free responses in AD patients. However, the safety profile of autologous CD19-CART therapies across different AD has yet to be fully explored. This is especially true for CRS & ICANS. Here, we provide novel insight into the mechanism underlying the safety profile of resecabtagene autoleucel (rese-cel) an autologous CD19 41BBz CART therapy across four separate Phase I/II clinical trials in SLE, IIM, SSc, & MG. Objectives: The primary objective of each trial is safety & tolerability of rese-cel at Day 29. Key secondary objectives include changes in clinical scores & use of immunomodulatory agents. Key translational assessments include CART cell pharmacokinetics (PK), impact on peripheral B cell populations (pharmacodynamics), & serum cytokine levels. Methods: 19 Patients (data cutoff: 6/2/2025 SLE; 5/6/2025 IIM, SSc, and MG), with active disease refractory to standard of care have been treated across 4 Phase I/II clinical trials in SLE (8 patients; NCT06121297), IIM (8 patients; NCT06154252), SSc (2 patients; NCT06328777), & MG (1 patient; NCT06359041). All patients were treated with a single weight-based infusion of rese-cel at a dose of 1 x 106 cells/kg following lymphodepletion (flu 25 mg/m2/d on Days -5, -4, & -3, & cy 1,000 mg/m2/d on Day -3). All non-glucocorticoid immunomodulatory agents were stopped prior to lymphodepletion. Glucocorticoids were tapered post-infusion. Patients were not given prophylactic tocilizumab pre-infusion. Translational assessments were determined as follows: CART PK was evaluated by flow cytometry & dPCR; B-cell enumeration & phenotyping were evaluated by flow cytometry; & serum cytokines were evaluated via immunoassay. Results: Across all indications (19 patients), 7 episodes of CRS were observed (7/19). 6 of 7 patients experienced a Grade 1 CRS, & 1 patient had a Grade 2 CRS. 2 patients developed ICANS; 1 patient had a Grade 4 (previously presented at ACR Convergence 2024), & the other patient had a Grade 3. Both ICANS events were rapidly resolved without sequelae using standard therapy. These CRS and ICANS events differed across indications. In IIM, 4 of 8 patients experienced Grade 1 CRS and no patients experienced ICANs. In SLE, 2 patients experienced Grade 1 CRS and one developed Grade 4 ICANs. In SSC, 1 of 2 patients experienced Grade 2 CRS & the other experienced Grade 3 ICANS. In MG, no CRS or ICANS was observed. Rese-cel infusion products were ~ 66% transduced, with a mean CD4:CD8 ratio of 6. Post-infusion, peak CART expansion was observed on day 12 & the mean peak expansion was 89 cells/µL (SD +/- 214). B cells were rapidly depleted from peripheral blood post-infusion, with nadir occurring at 13 days & repopulation beginning at 62 days post-infusion on average. Re-emergent B cells were largely of the CD24+CD38+ transitional naïve phenotype. Commensurate with B cell depletion, serum BAFF induction was observed, with a mean fold induction of 16 & mean peak level of 56,404 pg/µL (SD: +/- 45,547). Serum cytokines associated with CRS & ICANS; IFNg, IL6, & IL8 reached peak elevation on days 10, 9, & 10 respectively post-infusion. The mean peak elevation for IFNg, IL6, & IL8 were 232 pg/ µL (SD: +/- 320), 44 pg/ µL (SD: +/- 60), & 80 pg/ µL (SD +/- 73), respectively. Conclusion: Rese-cel appears to be well tolerated in autoimmune patients with rates of CRS & ICANS of 37% & 11% across all autoimmune indications, respectively (SLE patients had a 25% CRS rate & 12.5% ICANS rate, IIM patients had a 50% CRS rate & 0% ICANS rate, SSC patients had a 50% CRS & 50% ICANS rate, & MG patients had a 0% CRS & ICANS rate). Notably, the frequency & severity of CRS appears to be low, with no CRS in 63% of patients (12/19) & most CRS events (6/7) being Grade 1. The lower frequency & severity of both CRS & ICANS events are likely correlated with the relatively modest induction of serum IFNg, IL6, & IL8 found in autoimmune patients post rese-cel weight-adjusted dose infusion. High BAFF levels reflect deep systemic B cell depletion. Together, these data support further support late-stage clinical development of rese-cel in autoimmune disease.

Abstract BackgroundWarm autoimmune hemolytic anemia (wAIHA) is clinically characterized by autoantibody-mediated (typically IgG) erythrocyte destruction at body temperature. While oral corticosteroids remain first-line therapy, rituximab is frequently used as a second-line agent, mostly supported with concomitant background medications, yet real-world evidence is limited and utilization is driven by published retrospective data and expert opinion. Real-world evidence characterizing its utilization patterns and outcomes is needed to inform clinical practice. AimsThis study aimed to: 1) describe treatment patterns among patients with newly diagnosed wAIHA, 2) evaluate rescue therapy use and healthcare resource utilization (HCRU) with current standard of care (SOC), 3) characterize patterns of rituximab use during the first year. MethodsNewly diagnosed wAIHA patients were identified from multiple US databases (MarketScan® Databases, IQVIA PharMetrics, Optum Clinformatics®, and Optum PanTher EHR). Patients with ≥1 wAIHA diagnosis code in any position (ICD-10-CM D59.11) from October 2020 to December 2023 and 12-month post-index follow-up were pooled together. Secondary wAIHA was defined with evidence of hematologic malignancy, solid tumors, immunodeficiencies, or autoimmune diseases in the 6 months prior to diagnosis. Patients on treatment were defined by use of oral corticosteroids (OCS), immunosuppressants (IST) (including azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, or tacrolimus) or rituximab. Initial therapy was defined as the first treatment occurring ≥ 30 days prior to diagnosis. Therapies were identified as combination when initialized within 21 days of each other. The regimen is considered active until all therapies are discontinued or a new agent is initiated. Rituximab regimens were classified as standard (4 weekly doses), alternative (2 doses given 2 weeks apart), single infusion, or extended (>4 infusions). Results Among 2,028 wAIHA patients (median age 62.0 years, 59% female), 55% had secondary wAIHA. Among patients on treatment (n=1,439), 64% received OCS monotherapy; rituximab and IST, alone or in combination with OCS were received by an additional 28% and 5% of patients, respectively. Overall, 80% of treated patients received OCS in some combination during initial therapy. Within 12 months following diagnosis, 1 in 4 patients required ≥ 1 blood transfusion, 1 in 8 required either erythropoiesis-stimulating agents (ESA) or intravenous immunoglobulin (IVIG). Within 12 months of diagnosis, 35% of patients required ≥ 1 hospitalization, average length of stay 3.8 days; AIHA was the principal diagnosis for 65% cases. Greater than 1/3 of patients (38%) had ≥ 1 emergency department visit. Almost all wAIHA patients (98%) had an all-cause outpatient visit with a median of 31 visits per patient. Among patients receiving rituximab in any line (n=613), median time from diagnosis to first administration was 59.0 days (interquartile range: 42.0-171.0). For the first course of rituximab, 62.2% of patients received a complete course (standard, alternative, or extended courses). Among patients with a completed course, 39.8% had >4 infusions without a 90-day gap between administrations with a median of 8 administrations within 12 months. Of the nearly 38% of patients that did not receive a complete course of rituximab, 33% received a single infusion. The use of rescue medications in the period prior to rituximab treatment was compared to the period after treatment (defined as 60 days to 12-months post final rituximab infusion). Use of blood transfusions was observed to increase from 9.0% to 32.8%, while the use of ESA and IVIG were stable at approximately 2% and 4%, respectively.Conclusion With current wAIHA SOC, US HCRU remains high, posing a financial burden in terms of the rate of outpatient and emergency department visits, and inpatient stays. Rituximab is an early line therapy post-diagnosis, typically in combination with OCS. No changes in rescue treatments, and an increase in blood transfusions after rituximab infusion suggest treatment gaps remain. Analysis reveals heterogeneity in rituximab dosing patterns including high deviation from standard dosing practices; this variance from published expert opinion along with common use of rescue therapies suggests continued need for standardized guidelines and development of targeted therapies in wAIHA.

Abstract Background: Hypomethylating agent (HMA) with venetoclax (VEN) is used in clinical practice for frontline management of patients with myelodysplastic syndrome (MDS) based on encouraging data from phase 1 clinical trial (Garcia JS et al. Blood 2025). While the randomized clinical trial (VERONA-NCT04401748) did not show a survival benefit of azacitidine-VEN, the study had important differences such as exclusion of therapy related MDS and being conducted in several non-academic US centers. To better understand the impact of this regimen and its effects in subgroups, we conducted a real-world analysis of frontline MDS patients treated mainly at academic medical centers with HMA-VEN and compared to HMA monotherapy. Methods: This is a multicenter retrospective study of 19 US academic medical centers. We included contemporary cohorts of adults (age≥18 years) with MDS (intermediate, high or very high risk by IPSS-R) who were treated outside of clinical trials with either upfront combination of HMA-VEN or HMA monotherapy. Data on patient-related, disease-related and treatment-related variables were collected through chart review. Descriptive statistics were used for baseline characteristics. Overall survival (OS) and event free survival (EFS: progression, leukemic transformation, death as events) analysis was conducted using Kaplan-Meier method. Determinants of outcomes were analyzed using multivariable regression models. All analyses were conducted at a significance level of p<0.05. Results: Among 1198 patients with intermediate, high or very-high risk MDS, 313 patients received upfront VEN in combination with HMA [HMA-VEN] and 885 patients received HMA monotherapy. Median age was 70 (63-76) years and majority of patients had MDS with excess blasts-1 (34% overall, HMA-VEN=26%, HMA=37%) or MDS with excess-blasts-2 (41% overall, HMA-VEN=60%, HMA=34%). Disease risk by IPSS-R was intermediate (29% overall, HMA-VEN=18%, HMA=33%), high (30% overall, HMA-VEN=31%, HMA=30%) or very-high risk (41% overall, HMA-VEN=51%, HMA=37%, p<0.001). Therapy related MDS (t-MDS) was seen in 27% of patients (HMA-VEN=33%, HMA=25%, p=0.004), 34% had TP53 mutation (HMA-VEN=40%, HMA=32%, p=0.005) and 33% underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (HMA-VEN=42%, HMA=30%, p<0.001). The most common mutations detected at baseline included TP53 (34%), ASXL1 (22%), DNMT3A (16%), RUNX1 (16%), TET2 (14%), SRSF2 (13%), and U2AF1 (11%). The response rate by IWG 2006 criteria was significantly higher with HMA-VEN than HMA monotherapy (overall 81% vs 39%, CR: 17% vs 9.6%; marrow CR: 56% vs 14%, p<0.001). In multivariable analysis accounting for upfront treatment, AHSCT, genomic mutations, baseline bone marrow blasts and t-MDS, patients treated with HMA-VEN in the upfront setting had significantly improved EFS (median EFS 10.7 vs. 7.8 mon, HR 0.83, 95%CI 0.72-0.96, p=0.01) and OS (median OS 22.4 vs. 18.1 mon, HR 0.79, 95%CI 0.64-0.97, p=0.02). In addition, TP53 mutation status (OS: HR 1.88, 95% CI 1.57-2.26, p<0.001, EFS: HR 1.43, 95% CI 1.23-1.65, p<0.001), subsequent AHSCT (OS: HR 0.34, 95% CI 0.27-0.41, p<0.001; EFS: HR 0.47, 95% CI 0.40-0.54, p<0.001), and therapy related MDS (OS: HR 1.20, 95% CI 1.00-1.44, p=0.04, EFS: HR 1.10, 95% CI 0.96-1.27, p=0.2) were significant predictors on multivariable analysis. When separately investigated in subgroups, an OS benefit of HMA-VEN over HMA was seen in patients undergoing subsequent AHSCT (median OS 40.6 vs. 30 mon, p=0.05), bone marrow blast 10-19% (median OS 25.1 vs. 17.4 mon, P=0.01), de novo MDS (median OS 30 vs. 20.1 mon, P=0.003) and absence of TP53 mutation (median OS 34.9 mon vs. 23.1 mon, p=0.004). The benefit of HMA-VEN over HMA was also seen across molecular mutations including presence of ASXL1 mutation (median OS 35.2 vs 20.9 mon, p=0.03). Conclusions: In this large multicenter retrospective analysis from US academic medical centers, we found that HMA-VEN therapy significantly improved OS in certain subsets of high risk MDS including patients with 10-19% blasts, denovo MDS, subsequent AHSCT and those without TP53 mutation. While our analysis is limited by its retrospective design, prospectively exploring subgroups of MDS patients who could benefit from HMA-VEN therapy is needed.

Abstract Background. Uproleselan (GMI-1271) is an antagonist of E-selectin, an adhesion molecule expressed on endothelial cells in the vascular niche of the bone marrow. Engagement of E-selectin by acute myeloid leukemia (AML) blasts, which express E-selectin ligand, activates cell survival pathways and promotes resistance to chemotherapy. In multiple preclinical AML tumor models, blockade of E-selectin with uproleselan enhanced the efficacy of chemotherapy. Methods. We conducted a phase (P) 2/3 study in which subjects age ≥ 60 years with untreated, FLT3 unmutated AML were randomized to receive conventional chemotherapy with or without uproleselan. Induction chemotherapy consisted of 7+3 (cytarabine + daunorubicin) +/- uproleselan with a second induction cycle with 5+2 +/- uproleselan administered for residual AML. Uproleselan 800 mg IV was administered as a single dose 24 hours before the first dose of chemotherapy and then every 12 hours until 48 hours after the completion of chemotherapy. Post-remission therapy consisted of up to 3 cycles intermediate-dose cytarabine 2 gm/m2 IV d1-5 +/- uproleselan. Allogeneic transplant was performed at the discretion of the treating physician. The primary endpoint was event-free survival (EFS) for P2 and overall survival (OS) for P3. Results. The study enrolled 267 patients between March 2019 and November 2021, with a median age of 66.9 years (IQR 63.8-69.9). 32% were classified as 2017 ELN intermediate risk, 41% as adverse risk, with 62 (29%) having complex karyotype / mutated TP53. The P2 analysis was to be performed when at least 191 events were observed. However, as the required events had not been observed > 5 years after study initiation and 3 years after completion of P2 enrollment, an independent statistician was consulted, and the analysis plan was amended to conduct the P2 EFS analysis in November 2024. With a median follow-up of 53.1 months, the EFS was not significantly different between the two arms (HR 0.90, 95% CI 0.70-1.23, P=0.58). As the study did not meet its P2 EFS endpoint, enrollment in the P3 was not initiated. There was no significant difference in OS between the 2 arms (HR 0.99, p=0.94) with a median OS in the uproleselan arm of 23.6 months (95% CI 15.1-35.4 mo) vs 19.8 months (14.6-36.3) for the control arm. The overall rate of CR/CRi after induction was 65% (CR: 60%) in the uproleselan arm versus 63% (CR: 55%) in the control. MRD results by either local or central assessment in patients achieving a CR/CRi were available for 129 patients with the MRDneg rate of 81 % (95% CI 69.5-89.9%) in the uproleselan arm vs 67% (54.3-78.4%) in the control arm (p=0.053), The 30-day mortality was 5.3% for uproleselan vs 8.1% in the control. Forty-eight (36%) patients in the uproleselan arm and 55 (40%) in the control arm underwent alloHCT, including 37 (27%) and 29 (22%) in CR1, respectively (p = 0.34). In patients undergoing alloHCT in CR1, those randomized to uproleselan and allografted in CR1 had an HR 0.71 (95% CI 0.34-1.47; P=0.35) compared to the control arm. Expression of E-selectin ligand on AML blasts was performed by flow cytometry, with subjects having an E-selectin ligand expression above the median having a trend towards worse median OS 16.2 (95% CI 11.4-24.3) vs 32.2 (15.9-57.8) months, but was not affected by treatment arm. In both univariate and multivariate analyses, WBC at baseline, ELN genetic risk group, and TP53/complex karyotype were found to be associated with EFS. A subgroup analysis identified an improvement in EFS favoring uproleselan in patients with mutated ASXL1 (HR 0.25, 95% CI 0.08-0.78, p<0.017). Conclusions. Although the addition of uproleselan to intensive chemotherapy was associated with a higher rate of MRDneg CR/CRi in older adults with AML, uproleselan failed to improve EFS or OS and did not overcome the adverse outcomes associated with higher E-selectin expression on AML blasts. The median OS of 20-24 months with an overall 3-year OS of almost 40% for patients treated on this study exceeds previous CALGB / US Cooperative Group studies (median OS ~12 months, 3-year OS ~20%) and continues to support a role for intensive chemotherapy in the management of older adults with AML. Furthermore, this study suggests a potential benefit for uproleselan in patients harboring ASXL1 mutations, which may warrant further investigation. ClinicalTrials.gov Identifier: NCT03701308

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 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.

Abstract Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with multiply relapsed or refractory (r/r) large B-cell lymphoma (LBCL). Though response rates are relatively high, most patients (pts) eventually experience progression of disease (POD). We sought to investigate the treatment patterns and clinical outcomes following POD post-BsAb for r/r LBCL Pts, as this has not previously been described. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCL 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, progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan Meier method. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAb, of whom a total of 168 (53.8%) pts experienced POD [104 of 193 (53.8%) treated with prior epco and 64 of 119 (53.8%) treated with prior glofit]. Pts with POD had a median age at BsAb start of 67 years (interquartile range [IQR] 58-76), most were male (68.4%), and the most common histology was diffuse large B-cell lymphoma not otherwise specified (n=122 [71.8%]). Sixty-seven of 168 pts (39.9%) with POD after BsAb had experienced primary refractory disease defined as failure to achieve PR or CR to frontline therapy. A total of 102 (60.7%) pts with POD to BsAb had received chimeric antigen receptor (CAR) T-cell therapy prior to BsAbs, with 33.3% of these pts being refractory to CAR T and 30.4% progressing within 6 months of CAR T-cell infusion. The median time to progression following BsAb start was 48 days. Following POD, 70 pts received no further anti-lymphoma therapy. Among 98 pts receiving subsequent therapy, 85 initially received systemic therapy and 13 initially received local therapy with radiation (concurrently with systemic therapy in 8 pts). The most commonly-used next line of systemic therapies included: loncastuximab tesirine in 19 pts (ORR 16.7%, all PR); commercial CAR T in 11 pts (ORR 50% [CR 36.4%, PR 18.2%); tafasitamab with lenalidomide in 7 (no responses); and other chemotherapy in 46 pts (ORR 27.6% [CR 24.1%]). The median follow-up time from POD was 9.2 months among survivors (95% confidence interval [CI] 7.8-13.3). Among those who initiated subsequent-line therapy following BsAbs, the median progression-free survival (PFS2) was 1.9 months (95% CI 1.5-2.4) and median overall survival (OS) from initiation of subsequent-line therapy was 3.9 months (95% CI 2.4-5.5). The estimated 1-year OS following initiation of next therapy was 12%. Conclusions: We report the outcomes of largest cohort of pts with POD post-BsAbs in r/r LBCL. Progression events occurred early after initiation of single agent BsAbs, and almost half of pts who progressed did not receive subsequent therapy. For those who received standard subsequent-line therapy after POD, response rates and survival outcomes were poor. Pts with POD after BsAB should be strongly considered for clinical trials of novel therapeutics or combination therapies.

Abstract Background: Acute myeloid leukemia (AML) with TP53 alteration (TP53alt), including deletion (TP53del) detected by cytogenetics (CG) (karyotype, FISH, or genomic microarray) and/or TP53 mutation (TP53mut) identified by next-generation sequencing, is associated with poor prognosis. However, a subset of patients may achieve long-term survival after allogeneic hematopoietic cell transplantation (allo-HCT). Patient-, disease-, and transplant-related variables may inform risk stratification and improve treatment decision-making in this high-risk population. We used the CIBMTR registry to investigate outcomes of patients with TP53alt AML undergoing allo-HCT. Methods: We included adult patients with 2017 ELN adverse-risk AML who underwent first allo-HCT between 2013–2019 and had available CG and molecular data. TP53del was centrally reviewed by expert cytogeneticist. Patients were stratified into three TP53alt groups: Group 1 (TP53mut+/ TP53del+), Group 2 (TP53mut −/ TP53del+), and Group 3 (TP53mut+/ TP53del −). The control group comprised patients with 2017 ELN adverse-risk AML negative for both TP53mut and TP53del. Patients from embargoed centers, lacking consent or comprehensive research data, or missing CG and molecular information were excluded. Results: Of 6,474 patients with adverse-risk AML, 703 patients with TP53alt met inclusion criteria: Group 1 (n=203), Group 2 (n=271), Group 3 (n=229). The control group included 2,763 patients. Median age was 58 years (44% ≥60); 44% were female; 16% had Karnofsky score <90, and 52% had HCT-CI ≥3. Secondary AML was more frequent in TP53alt groups (32%, 27%, 27%) versus control (21%) (p<.01). Complex and monosomal karyotypes were most common in Group 1 (61%), followed by Group 2 (54%), Group 3 (31%), and control (6%), p<.01. More patients in Groups 1 and 2 (28% each) underwent HCT in primary induction failure/relapse (PIF/Rel) versus Group 3 (19%) and control (19%), p<.01. Median time from diagnosis to transplant was 5 months (1-331). Donor type was matched related in 23%, matched or mismatched unrelated in 50%, haploidentical in 18%, and umbilical cord blood in 7%. Conditioning intensity was myeloablative (MA) in 51%; reduced-intensity (RIC) in 36% , and 13% non-MA (NMA). Post-transplant cyclophosphamide (PTCy) was used in 27%; and in vivo T-cell depletion (ATG or alemtuzumab) in 26%. After median follow-up of 66 months (3-130), 5-yr OS was 18% (Group 1), 18% (Group 2), 35% (Group 3) vs 46% in controls (p<0.001). 5-yr LFS was 14%, 15%, and 28%, respectively, vs 38% (p<0.001). 5-yr CIR was 69%, 66%, and 52% vs 43% (p<0.001). Transplant-related mortality (TRM) was similar across groups (1-year: 12–16%). On multivariate analysis, compared with controls, TP53del (with or without TP53mut) was independently associated with higher relapse risk: Group 1 HR 1.97, Group 2 HR 1.91, Group 3 HR 1.45 (all p<0.001). These findings translated into inferior OS (HR 1.94, 1.87, and 1.45, respectively, p<0.001). PIF/Rel and CR2+ were also associated with worse survival (HR 2.58 (p<0.001) and 1.18 (p<0.001, respectively). No significant difference was observed between MA and RIC for relapse, while non-myeloablative regimens (HR 1.65; p<0.001) were associated with higher CIR. In vivo T-cell depletion increased relapse risk (HR 1.22; p=0.004). TRM was not influenced by TP53alt status; it was impacted by age, KPS, time from diagnosis to HCT, and GVHD prophylaxis regiment (non-PTCy). Conclusions: This large, registry-based study with long term median follow-up showed that among patients with adverse-risk AML, TP53alt is a strong independent predictor of poor post-HCT outcomes in AML, particularly when TP53del is present. Patients with TP53del , with or without concurrent TP53mut, experienced the worst outcomes, followed by those with isolated TP53mut. Despite the limitations of registry data including lack of information on timing of TP53mut, variant allele frequency (VAF), number of mutations, or accurate information on measurable residual disease (MRD), these findings reinforce the adverse prognostic impact of TP53alt and support its inclusion in risk stratification frameworks. While some patients with TP53alt —particularly those with isolated mutations—may benefit from allo-HCT, relapse remains the dominant cause of failure. Future studies incorporating TP53 functional status, VAF, clonal architecture, specific CG, MRD, and novel transplant approaches are warranted.

Abstract Background Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell production and contributes to the onset and severity of anemia, for which there is a large unmet need for safe and effective treatments. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. In studies involving healthy volunteers (Novikov, et al, J Clin Pharmacol 2024:64(8):953-962) and participants with MF (Gangat et al, Blood 2024;144(Suppl1):657), DISC-0974 dosing resulted in reduced serum hepcidin levels and increased serum iron, with a favorable safety profile. Clinically meaningful improvements in anemia were also observed: 50% of non–transfusion-dependent (nTD) participants achieved a mean hemoglobin increase of ≥1.5 g/dL for at least 12 weeks, while 80% of participants with low transfusion burden (TD low) and 40% of participants with high transfusion burden (TD high) achieved transfusion independence (TI) for ≥16 and ≥12 consecutive weeks, respectively. Aims This Phase 2, open-label, multiple-ascending dose study (NCT05320198) assesses efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) in participants with MF. Methods Participants were enrolled into 3 primary cohorts (n=30 per cohort), categorized by the units of red blood cells transfused in the 84 days prior to screening: nTD (hemoglobin <10 g/dL with 0 units), TD low (1-2 units), and TD high (3-12 units transfused). Additionally, an exploratory cohort of participants receiving concomitant treatment with momelotinib or pacritinib (n=10) was included. Eligible participants were ≥18 years of age with hemoglobin <10 g/dL or a transfusion requirement meeting World Health Organization diagnostic criteria for primary or secondary MF. A stable dose of concomitant hydroxyurea and/or Janus kinase (JAK) inhibitor (ruxolitinib and fedratinib for primary cohorts; momelotinib and pacritinib for exploratory cohort) was allowed. Major exclusion criteria included liver iron concentration ≥7 mg/g dry weight (TD high only) and nutritional, genetic, infectious, or autoimmune anemia. DISC-0974 was administered subcutaneously at a dose of 50 mg once monthly for a total of 6 doses. Dose escalation to 75 mg was required for inadequate or loss of response. Primary endpoints included evaluating hematologic response defined for TD low and TD high as TI during any 16- and 12-week consecutive period, respectively, and for nTD as a mean hemoglobin increase of ≥1.5 g/dL from baseline for at least 12 weeks. Secondary endpoints included PK/PD markers of iron regulation and safety assessments. Data were summarized using descriptive statistics. Results As of 01 July 2025, enrollment of the exploratory cohort of momelotinib was complete (n=10). Baseline hepcidin values in the exploratory cohort were similar (mean (SD) of 83.6 (62.8) ng/mL) to baseline hepcidin values from the DISC-0974 Phase 1b study (mean (SD) of 85.8 (71.0) ng/mL, n=35), and sustained hepcidin reduction was observed after DISC-0974 dosing. Early hematologic responses observed after 1 to 3 doses in the exploratory cohort were comparable to those reported in the Phase 1b study (Gangat et al, Blood 2024;144(Suppl1):657). Based on these initial data, the protocol was amended to allow concomitant momelotinib or pacritinib in all cohorts. Preliminary results, including baseline characteristics, PD, and hematologic responses across all cohorts, will be presented.