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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.

Abstract Introduction: Bruton tyrosine kinase inhibitors (BTKis) have transformed the treatment landscape for CLL, offering significant improvement in patient outcomes. Despite the widespread adoption of BTKis and their proven clinical benefits, data on the treatment preferences and priorities of patients with CLL in Asia, particularly in Japan, are limited. Understanding patient preference is critical for optimizing clinical decision-making and tailoring treatment strategies for Japanese patients. A comprehensive quantitative analysis was conducted to evaluate patient preferences for covalent BTKi treatment attributes and trade-offs among these attributes. Methods: An online survey applying discrete choice experiment (DCE) methodology was administered between April 29 and June 30, 2025 to Japanese adults (≥18 years of year) diagnosed with CLL. The design of DCE attributes and levels was informed by literature review and clinical consultations. Treatment attributes included efficacy (i.e., progression-free survival [PFS]), safety (i.e., impacts of diarrhea, headache, atrial fibrillation, and hypertension on quality of life [QoL]), and convenience (i.e., formulation type including tablet or capsule, and dosing frequency including once daily or twice daily). A conditional logistic regression was applied to estimate preference weights, which were used to calculate the relative importance as well as willingness-to-tradeoff between BTKi treatment attributes. Results: The study included 50 patients (mean age: 62 years; 30% female; 38% employed full-time; 60% reported no comorbid conditions). More than half (60%) were diagnosed ≥5 years ago. Around one quarter (24%) were treatment naive, and 76% received ≥1 treatment (40% first-line, 26% second-line and 10% third-line or later). Most patients (82%) reported living with or near their caregiver. In terms of travel time to obtain CLL medication, 46% reported travel time of one hour, 40% traveled less than 30 minutes, and 14% traveled more than two hours. The majority of patients (66%) were using High-Cost Medical Expense Benefit, while an additional 10% were either currently applying or planning to apply. In general, patients preferred treatments with less impact of AEs on QoL, higher efficacy, and less dosing frequency (P<.05). The top three treatment attributes with the highest relative importance were the impact of atrial fibrillation (24.7%) and diarrhea (21.0%) on QoL, and PFS (15.8%), followed by impact of headache (15.7%) and hypertension (14.1%) on QoL, dosing frequency (7.8%), and formulation type (capsule or tablet) (0.9%). Patients were willing to trade off PFS for improved quality of life: accepting reductions of 3.1 years for less impact from atrial fibrillation, 2.7 years for diarrhea, 2.0 years for headache, and 1.8 years for hypertension (none or mild vs. significant impact). Additionally, they were willing to accept a reduction of 1.0 years of PFS to receive a treatment given once daily rather than twice daily.Conclusions: This is the first quantitative assessment of treatment preferences among Japanese patients with CLL using a DCE approach. Findings from this study provide valuable Japan-specific insights, highlighting that although efficacy is important, patients prioritize safety factors, such as the impact of atrial fibrillation and diarrhea on QoL. These findings support the integration of patient perspectives into treatment planning to enhance shared decision-making, personalize care, and promote better adherence to long-term therapies in CLL management.

Abstract Introduction Despite significant advancements in therapeutic strategies, acute lymphoblastic leukemia (ALL) continues to present a challenge with variable survival outcomes across diverse patient populations. It is increasingly evident that factors beyond clinical variables such as age, sex, race, income, and geographic location, play a critical role in determining prognosis. This study evaluates the impact of these factors on overall survival (OS) in patients with ALL using the SEER dataset. Methods Data were extracted from the SEER database (2002–2022) for patients diagnosed with ALL. Cases with incomplete survival data or missing key demographic variables were excluded. Variables included in the analysis were age, sex, race, household income (low <$50,000, mid $50,000–$74,999, and high ≥$75,000 income tiers), and geographic location. We used Kaplan-Meier survival curves to estimate the median survival time and multivariable Cox proportional hazards model to identify independent predictors of mortality. Result A total of 4,943 patients met inclusion criteria. The cohort was 56.6% male and 43.4% female. The majority of patients were White (77.3%), followed by Asian or Pacific Islander (11.9%), Black (7.4%), American Indian/Alaska Native (2.3%), and Unknown (1.1%). Most patients were aged 10–19 years (27.4%), 60–69 (12.9%), 50–59 (12.7%), with 11.9% aged 20–29 years. The median overall survival (OS) was 67 months. On Kaplan-Meier analysis, OS declined with age, from 43.0 months (95% CI: 33.0–56.0) in patients aged 40–49 to 2.0 months (95% CI: 2.0–3.0) in those ≥80. Median OS was 80.0 months (95% CI: 64.0–112.0) in males vs 58.0 months (95% CI: 49.0–79.0) in females. Patients in high-income areas had a median OS of 76.0 months (95% CI: 65.0–100.0) compared to 48.0 months (95% CI: 36.0–81.0) in mid-income areas. Among racial groups, Black patients had the shortest OS (33.0 months, 95% CI: 27.0–49.0), though race was not significant in adjusted models. On multivariable Cox regression, older age remained the strongest predictor of mortality. HR 1.54 (95% CI: 1.28–1.84) for age 40–49 and HR 7.90 (95% CI: 6.60–9.45) for age ≥80 (p < 0.001 for all). Male sex (HR: 1.10; 95% CI: 1.02–1.20; p = 0.018) and low income (HR: 1.29; 95% CI: 0.90–1.84; p = 0.165) were associated with worse outcomes, while high income was associated with better outcomes (HR: 0.90; 95% CI: 0.82–1.00; p = 0.045). Race and metropolitan residence were not independently associated with OS in the adjusted model.Conclusion In this population-based analysis of patients with ALL, older age, male sex, and lower income were independently associated with worse overall survival. While descriptive differences in survival were observed by race and geographic region, these factors were not statistically significant after adjustment. The findings highlight the critical role of age and socioeconomic status as determinants of ALL outcomes and underscore the need for targeted interventions to address these persistent disparities in care.

Abstract Background Myelodysplastic syndromes (MDS) develop from the acquisition of somatic mutations over years or decades. While some mutations are random stochastic events, others derive from extrinsic agents that promote genomic instability, including environmental exposures. Agent Orange (AO) is a phenoxy herbicide used by the U.S. military as a defoliant during the Vietnam War (1962-71), often diluted with gasoline to promote aerosolization, contaminated with the carcinogen dioxin during the manufacturing process, and linked to various cancers. We studied AO as a risk factor for MDS. Methods The prospective National Heart, Lung, and Blood Institute National MDS Natural History Study includes patients (pts) with suspected or recently diagnosed MDS enrolled from 6/2016-6/2024. Bone marrow samples underwent central pathology review, resulting in diagnoses including MDS, MDS/myeloproliferative neoplasm overlap (MDS/MPN), or clonal cytopenia of undetermined significance (CCUS). Pts completed detailed assessment for AO exposure and other risk factors for MDS development. Associations between AO exposure, mutation prevalence, and key covariates (demographics, diagnosis, military service, clinical history, cytogenetics and smoking) were assessed using univariate tests of association, multivariable regression and Cox regression models for survival and progression. Results Among 2115 enrolled pts, 1191 (56%) had a myeloid malignancy or precursor condition and 130 (6.1%) reported AO exposure, the majority (96%) male. Compared to unexposed pts, AO exposed pts were more likely to derive from the 1945-54 birth cohort (p<.001), of age to serve in Vietnam, and to have an ultimate diagnosis of MDS or CCUS vs. a non-clonal diagnosis (57% vs. 44%, p=.046). AO exposure was more common among Blacks (12% vs 6%, p=.02), specifically Black males (21% vs 9%, p=.006). AO exposure was marginally associated with International Prognostic Scoring System (IPSS)-R poor-risk cytogenetics (p=.066) and lower baseline platelet count (p=.072). In multiple regression analyses, risk of AO exposure was significantly higher for the 1945-1954 birth cohort (OR [95% CI]=10.3 [4.4-30.6], p<.001), among those with military service (OR=24.1 [11.9-55.8], p<.0001), and for Blacks vs Whites (OR=2.6 [1.2-5.5], p=.017). The crude risk of AO exposure trended higher for patients with MDS compared to idiopathic cytopenia of undetermined significance (ICUS; OR=2.1 [0.9-6.0],p=.13), but not in multivariable analysis (OR=1.3 [0.5-4.4, p=.60]). AO exposure trended toward an association with younger age at MDS diagnosis (p=.06) and toward having a prior primary malignancy (49% vs. 41%, p=.09): Compared to non-AO exposed pts, AO exposed pts had higher rates of prior prostate cancer (16% vs. 8%), notable given its documented association with AO exposure. AO exposure was not associated with a history of or intensity of cigarette smoking (p=.67). After accounting for age, diagnosis, sex, and military service, AO exposure was significantly associated with increased numbers of pathogenic variants in 53 genes (OR=1.2 [1.0-1.4], p=.02) and with having Very Poor/Poor risk IPSS-R cytogenetics (OR=3.7 [1.2-11.1], p=.02). AO exposed and non-exposed pts had similar overall survival (HR=1.1 [0.8-1.7], p=.50), but those exposed to AO had a higher risk of disease progression in the first two years following diagnosis (HR =1.9 [1.2-2.8], p=.004). AO exposed pts appeared more likely to have del (5q) (15% vs. 8%) and del (20q) (13% vs. 5%) karyotypic abnormalities, and TP53 (7.7% vs. 4.5%), STAG2 (5.1% vs. 2.8%), and NRAS mutations (3.4% vs. 1.7%), although sample sizes were small. Focusing on gene pathways, AO exposed pts appeared more likely to have abnormalities in RAS signaling (10.3% vs. 5.7%), cell cycle (7.7% vs. 4.5%), and cohesion complex pathways (6.0% vs. 3.1%), but less likely to have abnormalities in cytokine receptor pathways (0% vs. 4.5%). ConclusionsIn our representative national cohort of pts with at least one cytopenia, and for the first time, we demonstrated that AO exposure is associated with younger age at MDS diagnosis, ultimate MDS diagnosis, genetic complexity of MDS, increased risk of disease progression, and with Black race, despite Black individuals comprising just 16% of men who served in the Vietnam War and being less likely to have MDS than white individuals. AO should formally be recognized as a risk factor for the development of MDS.

Abstract Background Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPN) characterized by myeloproliferation and an increased risk of thrombohemorrhagic complications, progression to myelofibrosis (MF), and reduced overall survival. Risk-adapted management of PV/ET favors treatment with cytoreductive therapy in high-risk patients. Hydroxyurea (HU) is the most frequently utilized first-line cytoreductive agent, however pegylated interferon alpha-2a (PEG) and the more recently approved, ropeginterferon alfa-2b (ropeg-IFN), have demonstrated a potential to induce molecular responses and improve event free survival (EFS) (Gisslinger Leukemia 2023). The Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 investigator-initiated clinical trials established the efficacy and safety of PEG in both treatment naïve (n=82) and HU intolerant/resistant (n=115) patients. MPN-RC 111/112 reported results up to 36 months with a median duration of treatment of about 24 months (Yacoub Blood 2019, Mascarenhas Blood 2022). This study aims to characterize the longer-term follow-up and outcomes of 111/112 trial patients treated at our center after the study terminated. Methods This is a single center retrospective review of 34 patients with high-risk ET or PV who were treated on the 111/112 trials with PEG and continued to be followed at Mount Sinai. IRB approval was obtained prior to data capture. Therapies initiated after PEG were examined, including duration of treatment, therapy-free intervals, and response to subsequent therapies. Clinical outcomes (during/after trial enrollment) included thrombotic/hemorrhagic events, progression to MF, leukemic transformation, hematopoietic stem cell transplantation (HSCT), and death. PEG related toxicity data included development of hypothyroidism, autoimmune disease, depression/mood disorder, liver dysfunction, and ocular toxicity. Results 34 patients were included in the analysis (16 ET and 18 PV) with median age of 73.5 years. 26 (14 PV and 12 ET) were enrolled on 111 from 2012 to 2015 and 8 (4 PV and 4 ET) were enrolled on 112 from 2011 to 2016. 26 (81.3%) patients had mutations in JAK2, 3 (9.4%) in CALR, 1 (3.1%) in MPL, and 2 (6.3%) were triple-negative. At 12 months on trial, 12 (35.3%) patients achieved a complete response, 12 (35.3%) had a partial response, and 10 (29.4%) had no response to PEG. The median duration of follow up was 104.8 months after trial termination. 8 patients received no further therapy after the end of study, 12 received one subsequent therapy, and 14 received two or more subsequent therapies. 13 patients continued receiving commercial PEG or received it at some interval after study end and 2 patients were treated with ropeg-IFN. The median duration of PEG was 25.3 months on trial and 30.9 months when including those who continued on commercial PEG after trial termination. Median EFS was 140.4 months (95% CI 121.1 - Not estimated) including 5 (15%) patients with a thrombotic event, 1 (3%) with a hemorrhagic event, 8 (24%) progression to MF, 1 (3%) HSCT, 1 (3%) leukemic transformation, and 5 (15%) who died (2 second primary malignancies, 1 sepsis, 1 hemorrhage, 1 unknown). 25 of 34 patients developed toxicities potentially related to PEG therapy, including hypothyroidism (n=3), autoimmune disease (n=4), depression/mood disorder (n=10), liver dysfunction (n=13) and ocular toxicity (n=2). DiscussionPEG therapy is an effective therapy for ET and PV with the potential for durable responses. With a median follow up of more than 8 years, this single center retrospective analysis demonstrated a long EFS of greater than 11 years, accompanied by low rates of leukemic transformation and MPN-related death. There was no statistical difference in EFS based on response to PEG at 12 months on the initial 111/112 trials. The relatively short duration of PEG therapy may explain the rates of MPN-related events, including thrombosis and progression to MF. Future analyses should identify additional predictors of EFS, including duration of PEG treatment, best response to PEG at certain landmark intervals, and depth and/or duration of molecular response. This analysis also demonstrated high rates of PEG-related toxicities, although definitive causality was often difficult to determine. Additional clinical and molecular data will be available at the time of the meeting.

Abstract Introduction Multiple myeloma (MM) is clinically heterogeneous, and therapeutic response is profoundly influenced by the complex cytokine milieu of the bone marrow microenvironment. Unlike most cancers, MM staging incorporates non–tumor-burden markers such as serum albumin, β₂-microglobulin, and LDH, which are prognostically useful but biologically nonspecific. Although individual cytokines (e.g., IL-6, IL-17, TGF-β) have been linked to disease activity, a comprehensive, systems-level assessment comparing an exhaustive list of cytokines, chemokines, and growth factors across large patient cohorts is lacking. Here, we present evidence for an actionable cytokine panel, using gene expression–derived cytokine bioactivity as a surrogate measure. Methods CD138 enriched bone marrow plasma cell RNA-seq, Seq-FISH, and clinical data were obtained from the MMRF CoMMpass study. Data were TMM-normalized, log₂(x + 1) transformed, and mean-centered. Bioactivity scores for 64 cytokines, chemokines, and growth factors were inferred using CytoSig (National Cancer Institute). CytoSig leverages transcriptomic data from over 20,000 samples treated with individual molecules to model gene expression changes of cytokine regulators, targets, and response elements to provide z-scores. Reverse validation of bioactivity between samples scoring top and bottom quartiles of each cytokine was done using pathway analysis via Gene Set Enrichemnent analysis platform that verifies bioactivity across 7561 well-studied gene sets.(MSigDB C2 2025). Cytokines with upregulation of associated pathways were considered for downstream analyses (Criteria: Normalized enrichment score > 1). Genes were ranked by sign(logFC) × –log₁₀(p), identifying 44 significantly enriched pathways. Univariate Cox regression identified prognostic cytokines. To account for variable correlation and improve prediction, Elastic Net Cox regression (α = 0.5) was used, combining LASSO (L1) and Ridge (L2) penalties. For biological validation, pathway analysis was done between samples with high vs low serum C-Reactive Protein(CRP). Survival kinetics and clinical characteristics were analyzed for the derived model. Results A total of 767 NDMM patients were included (median age 63 years, range 27–93); median overall survival (OS) was 44.4 months (IQR 70.9). Revised International Staging System (R2-ISS) distribution was: Stage I 14.7%, II 24.0%, III 34.7%, and IV 6.4%. Based on the International Myeloma Society–International Myeloma Working Group (IMS–IMWG) definition, 32.2% of patients were classified as high-risk. Supervised analysis identified 30 univariate prognostic cytokines. Elastic Net retained BMP-7, IGF-1, IL-3, NRG1, IL-17A, IL-2, IL-21, and TGF-A (positive coefficients), and IL-4, IL-18, BMP-4, palmitic acid, DHT, and BMP-2 (negative coefficients). In sensitivity analysis, after removing cytokines not passing GSEA validation, the cytokine score (CS) was established using BMP-7, IL-3, TGF-A, IL-17A, BMP-2, IL-18, BMP-4, and IL-4. High serum CRP–associated gene expression was linked to upregulation of IL-17 and BMP pathways and downregulation of IL-4 signaling. Patients with CS ≥ median had higher β2M (p < 0.001) and LDH (p = 0.005); creatinine (p = 0.07) and albumin (p = 0.6) were not significant. CS was higher in patients with del(17p), 1q21 gain, high-risk IGH, t(8;14), and del(1p), and lower in those with hyperdiploidy (all p < 0.01). CS achieved a C-index of 0.67. Median OS was 58.7 months in the high-CS group vs. 102.5 months in the low-CS group (p < 0.001). Adding continuous CS to a model with continuous β2M + continous albumin improved C-index from 0.65 to 0.72. ISS improved from 0.62 to 0.68; R2-ISS from 0.65 to 0.69. A multivariate model with β2M ≥ 5.5, del(1p) + 1q gain, t(4;14), deep del(1p), and del(17p) improved from 0.63 to 0.68 with CS. Discussion These findings require functional validation in patient samples through direct measurement of cytokine levels. BMP-7 remains understudied in MM. Elevated TGF-α, IL-3, and IL-17 promote angiogenesis, bone resorption, and immune dysfunction, while BMP-2 and BMP-4 act as tumor suppressors. IL-18 is being utilised to boost T-cell responses, and IL-4 is consistently reduced in MM. Conclusion This study provides evidence for a robust, clinically translatable cytokine, chemokine, and growth factor panel. IL-17, IL-4, and BMPs emerged as consistently regulated across all analyses. CS is associated with high-risk disease and inferior survival.

Abstract The CoMMpass study (NCT01454297) is a prospective, longitudinal observational trial involving 1,141 newly diagnosed, treatment-naïve multiple myeloma (NDMM) patients. Bone marrow aspirates from the study participants were collected, separated into CD138 negative and CD138 positive fractions for comprehensive molecular characterization of tumor (using bulk RNA sequencing and whole genome sequencing) and tumor immune microenvironment using 3' single-cell RNA sequencing (scRNA-seq). To support exploration of this rich multi-omic dataset, we developed CoMMpass Explorer (CE), an intuitive interactive platform that enables real-time analysis of clinical and genomic data from these study participants. CE provides four main views: Overall Summary for clinical feature distribution and Kaplan-Meier curves; Mutational Profile for visualizing and comparing somatic mutations; Tumor Profile for differential expression and gene set enrichment; and Immune Microenvironment for comparing cell type abundance and cell cycle dynamics between cohorts using scRNA-seq data. A central feature of CE is cohort building, where users can filter and stratify patients by clinical, genomic, and survival data elements to create custom cohorts for analysis. We validated CE by reproducing findings from two prior CoMMpass-based studies. In the first study by Simhal et al, we stratified patients using transcript-level expression by WEE1 into tertiles and confirmed that high WEE1 expression is associated with poorer progression-free survival across multiple genomic subgroups. In the second study by Manojlovic et al, we replicated mutation frequencies between African American and Caucasian patients by creating race-based cohorts. We further demonstrate CE's utility by identifying and comparing two NDMM cohorts of patients at baseline who have not received autologous stem cell transplant: cohort 1 includes patients that received up-front triplet therapy (N=342) and cohort 2 includes those who did not receive a triplet up-front (N=235). While survival differences between these two cohorts were not statistically significant (p>0.05), CE revealed elevated epithelial-mesenchymal transition (EMT) pathway activity in cohort 1. Immune profiling showed lower abundance of CD8+ T cells (p < 0.05) and NK cells (p = 0.01), but a higher abundance of B cells (p < 0.05) in cohort 1. Genomic data showed fewer EIF2AK3 mutations and higher transcript-level expression of EIF2AK3 in cohort 1. Notably, patients in cohort 1 with lower transcript-level expression of EIF2AK3 had better survival outcomescompared to patients in cohort 2. CE democratizes access to the CoMMpass multi-omic resource, allowing researchers to interrogate clinical and molecular heterogeneity with ease. By enabling hypothesis generation and replication of published results, CE serves as a valuable tool for identifying meaningful patterns in gene expression, mutation profiles, and immune contexture. It also highlights potential prognostic biomarkers, such as EIF2AK3 expression, that may inform treatment decisions in NDMM, especially in the context of triplet-based regimens.

Abstract Background: Haploidentical allogeneic stem cell transplantation (haplo-SCT) has been a transformative option for patients lacking matched donors. Post-transplant cyclophosphamide (PTCy) at 100 mg/kg total dose (50 mg/kg on Day +3 and +4) is a standard for graft-versus-host diseases (GvHD) prophylaxis. Efforts to decrease toxicity while maintaining efficacy have informed pursuits of dose de-escalation. However, data regarding the efficacy and safety of reduced-dose PTCy (<100 mg/kg) remain scattered and variably reported. Methods: We performed a systematic review registered on PROSPERO (CRD420250650291) and conducted per PRISMA guidelines. Six databases (Medline, Embase, Web of Science, Scopus, Cinahl, Cochrane) were searched initially up to May 2024. An updated search was conducted to include studies till June 2025. Eligible studies included prospective or retrospective cohorts or randomized trials evaluating low-dose PTCy in haplo-SCT recipients reporting on acute/chronic GvHD, overall survival (OS), relapse-free survival (RFS), immune reconstitution, or complications such as hemorrhagic cystitis or infections. Non-comparative studies, reviews, and abstracts were excluded. Data was extracted independently by two reviewers, and risk-of-bias (ROB) was assessed using ROBINS-I and Cochrane RoB-2 tools. Results: Thirty-three studies, including 31 observational studies and 2 randomized controlled trials (RCTs), encompassing over 2500 patients, met our eligibility criteria. Most studies originated from Asia, with smaller contributions from Europe, the United States, India and Latin America. Low-dose PTCy regimens ranged from 14.5 to 80 mg/kg, commonly administered as 50 mg/kg ×1 on day +3 or 40 mg/kg ×2 on days +3 and +4. Comparators included standard-dose PTCy (100 mg/kg), ATG-based prophylaxis, or other regimens. Median follow-up ranged from 4 months to over 5 years. Acute GvHD (grades II–IV) rates in low-dose PTCy arms ranged from 9% to 34%. Most observational data showed comparable or reduced incidence of aGvHD compared to controls. Chronic GvHD outcomes varied from 8-46% and showed no clear benefit of dose reduction in most studies.Two-year OS ranged widely from 47% to 100%, with some observational studies favoring low-dose PTCy but others showing no survival advantage. RFS was similarly variable. Hemorrhagic cystitis occurred in 3–33% of patients, with no clear dose-dependent pattern. Infections were inconsistently reported, but, when data were available, viral infections, including BK virus, CMV, and EBV reactivation, were common, with no consistent dose-dependent trend. Median time to immune reconstitution was slightly shorter in some cohorts, but clinical relevance remains uncertain. Two studies reported significantly reduced incidence of cardiac complications with lower PTCy exposure. One randomized controlled trial comparing 80 mg/kg PTCy + ATG with the Beijing Protocol reported significantly reduced aGvHD (11.5% vs. 39.3%, p=0.001) and better OS (75.4% vs. 54.1%, p = 0.021) and RFS ((72.7% vs. 55.0%, p = 0.044)) in the experimental arm. In contrast, the only other randomized study used ultra-low-dose PTCy (14.5 mg/kg ×2) vs. ATG and found no significant difference in acute GvHD (18.2% vs. 18.2%, p=0.996) or survival and was stopped early because of futility. Both RCTs showed comparable rates of cGvHD, toxicity, and immune reconstitution.Importantly, 87% of observational studies had a serious or critical ROB. Both RCTs had some concerns of bias due to inadequate allocation concealment and open-label design but were otherwise at low ROB. Conclusions: Low-dose PTCy for GvHD prophylaxis in haplo-SCT carries comparable or lower rates of acute GvHD, similar chronic GvHD incidence, and non-inferior survival outcomes in many studies. Marked heterogeneity in regimens, patient populations, high ROB, and selective reporting preclude definitive conclusions. Randomized trials must focus on identifying subgroups benefiting from de-escalated PTCy. Until then, low-dose PTCy remains a promising but investigational alternative in haploidentical transplantation.

Abstract Background: Mosunetuzumab (Mosun) is an off-the-shelf, CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells, including those that cause malignant disease. Mosun is FDA- and EMA-approved for relapsed/refractory follicular lymphoma (FL) after ≥2 prior lines of therapy as a fixed-duration intravenous treatment, and can be given in an outpatient setting without mandatory hospitalization. Initial Phase I/II data with Mosun monotherapy have shown notable efficacy and manageable safety in patients with previously untreated diffuse large B-cell lymphoma (DLBCL; NCT03677154; Olszewski et al. ASH 2022). The Phase II MorningSun study is the first to assess the efficacy and safety of subcutaneous (SC) Mosun monotherapy in elderly/unfit patients with previously untreated DLBCL; we report an interim analysis for this study. Methods: MorningSun (NCT05207670) is an open-label, multicenter, Phase II, basket study evaluating the safety, efficacy, and pharmacokinetics of Mosun SC monotherapy in patients with B-cell non-Hodgkin lymphoma. In the DLBCL cohort, eligible patients aged ≥80 years or aged 65–79 and considered ineligible for chemoimmunotherapy (CIT) were enrolled, primarily in US community sites. Hospitalization was not mandatory. Step-up doses of Mosun SC were administered on Day (D) 1 (5mg), D8 (45mg) and D15 (45mg) of Cycle 1, followed by 45mg on D1 of 21-day cycles, for up to 17 cycles or until unacceptable toxicity. The primary endpoint in this cohort was progression-free survival (PFS) rate at 24 months after first study treatment. Secondary endpoints included objective response rate (ORR), complete response (CR) rate, time to response (TTR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), and safety. An exploratory circulating tumor DNA analysis was performed using an AOA-NHL assay. Results: Overall,49 patients were enrolled, the majority at community sites (community, n=34; academic, n=15). Thirty-six patients had DLBCL, 6 had high-grade [Gr] B-cell lymphoma, 2 had T-cell/histiocyte-rich large B-cell lymphoma, and 1 had Gr 3B FL (histology missing/other lymphoma, n=4). Median age was 82.5 years (range: 71–101); 63.3% and 20.4% of patients had an ECOG performance status of 1 and 2, respectively; 40.8% had Ann Arbor stage IV disease; 51.0% had extranodal involvement; 18.4% had bulky disease; and 53.1% had an IPI score of 3–5. At the clinical cut-off date of February 10, 2025, 23 (46.9%) patients had discontinued treatment, mainly due to progressive disease (n=12, 24.5%) or an adverse event (AE; n=5, 10.2%); the median duration of follow-up was 12.5 months (range: 1.4–30.8) and the median number of cycles received was 14 (range: 1–17). The PFS rate at 12 months was 68.8% (95% confidence interval [CI]: 52.1–80.6) and OS rate at 12 months was 77.2% (95% CI: 61.1–87.3). The ORR and CR rates were 73.5% and 59.2%, respectively. Median TTR was 2.7 (range: 2.5–6.1) months. DOR and DOCR rates at 12 months were 84.6% (95% CI: 66.8–93.3) and 95.0% (95% CI: 69.5–99.3), respectively. The most common AE (any grade) was injection site reaction (n=25, 51.0%), which was mostly Gr 1 (n=24, 49.0%). Gr 3/4 AEs occurred in 65.3% (n=32) of patients, most commonly infections (16.3% [n=8]) and decreased neutrophil count (10.2% [n=5]); serious AEs occurred in 42.9% (n=21) of patients. Four patients experienced Gr 5 AEs (congestive cardiac failure, volvulus, unexplained death and intracranial hemorrhage, n=1 each); none were related to Mosun per investigator assessment. Infections occurred in 46.9% (n=23) of patients (Gr 1/2, 30.6% [n=15]; Gr 3, 16.3% [n=8]); no Gr 4/5 infections were observed. No immune effector cell-associated neurotoxicity syndrome events occurred. Cytokine release syndrome was reported in 12.2% (n=6) of patients, with 10.2% (n=5) Gr 1 and 2.0% (n=1) Gr 2 events, all of which resolved. In evaluable patients with a CR (n=16), 68.8% (n=11) of patients were minimal residual disease negative (p-value cut-off 0.005).Conclusions: There remains an unmet need for effective chemotherapy-free options in previously untreated elderly and CIT-ineligible patients with DLBCL. Interim data from MorningSun demonstrate that fixed-duration Mosun SC monotherapy is active in these patients, with promising efficacy and a manageable safety profile, with predominantly mild-to-moderate AEs, allowing for outpatient administration in the community practice setting.

Abstract Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C>T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P<0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P<0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.