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BACKGROUND: Chronic aortic regurgitation (AR) is associated with significant cardiac remodeling, but the prevalence and prognostic impact of extravalvular cardiac damage remain unexplored. METHODS: Adults with moderate or greater chronic AR identified on echocardiogram between January 2008 and July 2024 were included. Exclusion criteria were acute AR, hypertrophic and infiltrative cardiomyopathies, prior cardiac surgery, and valve stenosis. Cardiac damage was classified into hierarchical stages: no cardiac damage (stage 0), left ventricular damage (stage 1), moderate or greater mitral regurgitation or left atrial enlargement or atrial fibrillation (stage 2), pulmonary hypertension or moderate or greater tricuspid regurgitation (stage 3), and significant right ventricular dysfunction (stage 4). The primary outcome was the association between cardiac damage stages and all-cause mortality under medical surveillance. RESULTS: Of 4026 patients (median age, 72 [61–80] years), 78% had moderate AR, 11% had moderate-severe, and 11% had severe AR. Cardiac damage was present in 87% of patients: 14% in stage 1, 53% in stage 2, 18% in stage 3, and 2% in stage 4. In a multivariable model, including age, sex, AR severity, and Charlson Comorbidity Index, cardiac damage stages were associated with mortality. Adjusted hazard ratios were 1.42 (95% CI, 1.04–1.96) for stage 1, 1.58 (95% CI, 1.21–2.06) for stage 2, 2.78 (95% CI, 2.10–3.67) for stage 3, and 5.34 (95% CI, 3.67–7.76) for stage 4. Adding cardiac damage staging to multivariable models improved predictive accuracy for mortality, increasing the concordance statistics from 0.73 (95% CI, 0.71–0.75) to 0.76 (95% CI, 0.74–0.77). CONCLUSIONS: Cardiac damage is present in nearly 90% of patients with moderate or greater AR and is associated with increased mortality, highlighting the need for a more comprehensive evaluation of cardiac structure and function beyond the aortic valve and left ventricle.

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.

Abstract Introduction: Cilta-cel is a BCMA-directed CAR T-cell therapy that has shown remarkable efficacy in patients with RRMM. As real-world (RW) experience with cilta-cel continues to expand, and with the recent FDA guidance reducing the recommended proximity to the CAR T center from four to two weeks post-infusion, there is growing interest in identifying patients at low risk for severe early complications who may be safely managed in the outpatient setting and potentially ‘discharged’ home earlier. Methods Data were collected from 769 patients with RRMM treated with cilta-cel at 15 institutions in the U.S. via the Multiple Myeloma Immunotherapy Consortium.Logistic regression was used to identify predictors of patients who could be managed in the outpatient setting (low-risk group). Based on expert consensus within the Consortium, low-risk patients were defined as: grade ≤1 CRS, no ICANS, and no IEC-HS. The remaining patients were categorized as high-risk. We evaluated baseline characteristics with missingness < 20% as predictors, including age, sex, race, and ethnicity, ECOG performance status (PS) at time of lymphodepletion (LD), extramedullary disease, bone marrow plasma cell (BMPC) percentage, high-risk cytogenetics, bridging therapy including response, penta-refractory status, number of prior lines of therapy, prior anti-BCMA therapy, baseline C-reactive protein (CRP), and baseline ferritin. The cohort was restricted to patients with complete data on all predictors (n=455) and split into a training and testing cohort (80/20 split, n=364/91). Bidirectional stepwise regression was used to build the predictive model using variables with significance of p<0.15 selected for entry. The best model was selected based on the AIC (Akaike Information Criterion) and a significance level of p<0.05. Results Among the 455 patients with complete data included in the final model, 290 (64%) were categorized as low-risk and 165 (36%) as high-risk. Compared to the low-risk group, high-risk patients were more likely to have an ECOG PS ≥2 at time of LD (20% vs 9%, p<0.001), high-risk cytogenetics (47% vs 35%, p=0.009), and penta-refractory disease status (34% vs 24%, p=0.031). High-risk patients also had a higher median BMPC percentage (15% vs 5%, p<0.001), and higher baseline pre-LD CRP and ferritin. Overall response rates were high, at 95% vs 90% (p=0.047) for the low vs high risk groups, with complete response or better achieved in 73% vs 66% of patients, respectively (p=0.14). With a median follow-up of approximately 11 months, median progression-free survival was not reached (95% CI: 27-NA) in the low-risk group and 18.2 months (95% CI: 13.1-NA) in the high-risk group. In terms of safety, non-ICANS neurotoxicity (NINT) occurred less frequently in the low-risk group (6.6% vs 13%, p=0.015). Specifically, Parkinsonism was observed in 1.7% vs 6.1% (p=0.013), and cranial nerve palsy in 4.5% vs 5.5% (p=0.7), respectively. Non-relapse mortality (NRM) was lower in the low-risk group (4.2%) compared to the high-risk group (14%; p < 0.001). The most common causes of NRM in the low- and high-risk groups were acute toxicities (0% vs 36%, including CRS, IEC-HS, and ICANS), delayed toxicities (0% vs 8%, including colitis, NINT, and Parkinsonism), infections (50% vs 48%), and other unrelated causes (50% vs 8%). The best model to predict low-risk patients that could be managed in the outpatient settingincluded BMPC percentage and ECOG PS at LD. In the training cohort, patients with a higher pre-LD BMPC percentage and an ECOG PS ³2 were less likely to be in the low-risk group(OR per 1-unit change in BMPC percentage = 0.99, 95% CI=0.98-0.99, p<0.001 and OR for ECOG PS 2-4 = 0.38, 95% CI=0.20-0.72, p=0.003). The AUC for this model was 0.663 in the training cohort and 0.659 in the testing cohort. Conclusion In this large, multi-institutional cohort of patients with RRMM treated with cilta-cel, we identified clinical factors associated with lower risk for early severe toxicities, supporting outpatient administration and the potential for earlier discharge in selected patients, particularly those who are fit and have low disease burden. Our findings provide a practical framework to guide risk stratification and outpatient CAR T management strategies, particularly in light of evolving regulatory guidance and growing RW experience with cilta-cel.

Abstract Background: Autoimmune hemolytic anemia (AIHA) is a condition in which the immune system erroneously attacks and damages red blood cells. While the epidemiology of AIHA has been examined in various European and Asian nations (Hansen 2020; Kao 2025), there is limited data available from the United States (US). Using US insurance claims data, this research aimed to determine the prevalence and demographic characteristics of AIHA over a five-year span. Methods: Five databases were used: Merative MarketScan Commercial Claims and Encounters; Optum's de-identified Clinformatics® Data Mart Database; Closed and Open claims sourced through HealthVerity; Merative MarketScan Medicare Supplemental Database; Merative MarketScan Multi-State Medicaid. AIHA was defined by ICD-10 diagnosis codes D59.1x in a given calendar year and a second code within 365 days prior. Annual prevalence in years 2019 – 2023 was calculated among people with insurance enrollment for at least 6 months in the calendar year. Annual prevalence was stratified by age group, sex, and prescription fill for an AIHA-related treatment (systemic steroids, immunosuppressants [azathioprine, mycophenolate, cyclosporin, cyclophosphamide, danazol, bortezomib, rituximab], splenectomy) in the calendar year. Extrapolation of prevalence rates for commercial and government assistance insurance to the US population for 2023 was implemented by age and sex-standardization to the US Census population. For data sources that included both commercial and government assistance insurance, patients aged <65 years were analyzed as commercial insurance and aged ≥65 years as government assistance. Results: AIHA prevalence in 2023 across databases ranged from 2.7 to 4.3 per 100,000 for ages <18 years; 4.2 to 9.4 per 100,000 for ages 18 – 34 years; 8.2 to 11.8 per 100,000 for ages 35 – 49 years; 15.4 to 23.9 per 100,000 for ages 50 – 64 years; 26.6 to 37.0 per 100,000 for ages 65 – 74 years; and 30.6 to 61.2 per 100,000 for age 75 years and older. Across databases and over time, the proportion of AIHA patients that were female was 55% – 67%. Across all databases, in year 2023, half (44% - 55%) of patients received any AIHA-related treatment, out of which one third (26%-34%) received systemic steroids, less than one quarter (9% – 17%) received rituximab, and one third (25% – 31%) received a different immunosuppressant. Compared to patients with commercial insurance, Medicaid-insured patients had lower AIHA-related treatment utilization, whereas Medicare-insured patients had higher utilization. Within age group and sex and by insurance type, low and high estimates of prevalence were used to define a range of prevalence. After standardization to the 2023 US Census population, the estimated prevalence in 2023 ranged from 38,459 to 57,235 patients diagnosed with AIHA, corresponding to prevalence rates of 11.6 to 17.3 per 100,000. This marked an increase from 2019 US Census-standardized estimates of 32,777 to 48,482, with corresponding prevalence rates of 10.1 to 14.9 per 100,000. Discussion: AIHA prevalence was higher in older age groups, with a peak prevalence in ages 65 and older. Prevalence increased approximately 15% over a 5-year interval and was notably higher in patients with commercial health insurance compared to government insurance programs, which may in part be due to the older age of the Medicare population. Fewer than half of patients received an AIHA-related treatment in 2023, which could reflect heterogeneity in disease severity necessitating treatment, in addition to the relapse-remitting nature of AIHA whereby patients experience remission for periods of time. Additionally, insurance claims do not specify an indication for treatment nor a reason for discontinuation; some treatments could have been prescribed for an underlying condition contributing to AIHA. Finally, prevalence extrapolation assumes Americans without health insurance are diagnosed with AIHA at the same rate as those with insurance, which may slightly overestimate the total number of diagnosed patients.Conclusion: AIHA prevalence in this study was consistent with estimates from European countries and has been increasing in recent years, providing evidence of consistent disease epidemiology across several geographies.

Abstract Introduction: CTCLs are rare, heterogeneous non-Hodgkin lymphomas (NHL) with significant regional variability in treatment patterns. Prospective studies characterizing CTCL management, particularly in racially and ethnically diverse populations, remains limited. The LEO-MER multi-center prospective cohort study (NCT02736357) is designed to address the persistent disparities in outcomes research by enrolling historically underrepresented groups of patients diagnosed with lymphoma across the United States (US). Here, we present a real-world analysis of CTCL patients that reflects US academic practice, evaluating treatment patterns, as well as prognostic factors influencing survival outcomes. Methods: Patients aged ≥18 years with newly diagnosed CTCL were prospectively enrolled in either the University of Iowa/Mayo Clinic MER cohort (2002-2015) or the expanded LEO cohort (2015-2020), which included 8 US academic centers. Standardized protocols were used to abstract clinical, pathologic, treatment, and outcome data from medical records. ANOVA/Kruskal-Wallis and Fisher's/chi-square tests were used to compare patient distribution across demographic and clinical characteristics based on data distribution and sample size. Overall survival (OS) was calculated from diagnosis to death or last follow-up. Survival analyses employed Kaplan-Meier estimation supplemented by Cox proportional hazards modeling. Results: The LEO-MER cohort enrolled 223 CTCL patients (91 MER and 132 LEO). Subtypes included mycosis fungoides (MF, n=155, 69.5%), Sézary syndrome (SS, n=22, 9.9%), primary cutaneous anaplastic large-cell lymphoma (n=17, 7.6%), subcutaneous panniculitis-like T-cell lymphoma (n=11, 4.9%), cutaneous CD4+ small/medium T-cell lymphoproliferative-disorder (n=9, 4%), and other rarer CTCL subtypes (n=9, 4%). Among the MF/SS cohort, median age was 64 years (Range: 18-89 years), 58.2% (n=103) were male and race/ethnicity distribution included White (n=123, 69.5%), Black (n=29; 16.4%) and others/unknown (n=25; 14.1%). Stage distribution included 62.7% with early-stage (ES) MF (IA-IIA, n=111), 37.2% with advanced-stage (AS) MF (IIB-IVB, n=66). To complete diagnostic workup, T-cell receptor (TCR) testing was performed in 52.6% of skin biopsies (n=92) and 62.5% of blood samples (n=110), with clonal detection rates of 75% (69/92) in skin and 51.8% (57/110) in blood. Paired TCR matching between skin and blood samples was performed in 31.6% (n=56) of cases, demonstrating 53.6% (30/56) concordance. Blood flow cytometry data were reported in 80.1% (89/111) and 84.4% (56/66) of ES and AS MF cases, with T-cell population being detected in 7.2% (8/111) and 62.1% (41/66) of ES and AS cases. Nodal biopsies were obtained in 23.4% (n=41) of patients and clonality assessment was reported in 18.6% (33/177) of these cases. The MF/SS cohort's lifetime treatment exposure data (n=160) revealed topical skin-directed therapies alone (n=49, 31.8%) as the most common approach followed by lifetime exposure to topical skin-directed and systemic therapies (n=45, 29.2%) followed by multimodal exposure of topical skin-directed, radiation and systemic treatments (n=30, 19.5%). Only 5.6% of patients were enrolled in a clinical trial. First-line (1L) systemic regimens were predominantly a) immunomodulatory agents (n=47, 29.3%); including oral retinoid (n=20), extracorporeal photopheresis (n=18), interferon (n=9) followed by b) chemotherapy (n=30, 18.7%) and c) targeted therapies (n=17, 10.6%) including Brentuximab Vedotin (n=6), Romidepsin (n=5), Mogamulizumab (n=3), Vorinostat (n=2) and Pralatrexate (n=1). Multivariable analysis predicting 1L systemic treatment initiation demonstrated a significant association with presence of N2/N3 stage (N2/N3 vs N0/N1: Odds Ratio (OR): 5.45) and elevated LDH (OR: 5.30). At median follow-up of 91.1 months (mon), median OS was 122.3 mon (95% confidence interval 67.2-159.2 mon). In subset analyses, Black race (p=0.001) and SS (p=0.0001) were associated with worse OS outcomes. Conclusion: We present initial data from our prospective LEO-MER cohort, a large US-based multicenter consortia. Our findings demonstrate variability in both diagnostic staging and treatment approaches for MF/SS patients. The cohort demonstrated worse outcomes with high-risk disease and Black race/ethnicity. These findings warrant further study on the impact of underlying social determinant factors, given the variability noted in this population.

Abstract Introduction With a median age of 60-70 years at diagnosis, many patients with MCL are ineligible for aggressive treatment. Bendamustine and rituximab (BR) is a standard therapy for older patients with MCL. Venetoclax (VEN) has shown pre-clinical evidence of synergy with chemotherapy. Thus, PrE0405 was designed to evaluate the addition of VEN to BR in previously untreated older patients with MCL. We have previously reported on response rate and short-term survival (Portell et al. ASH 2023). Here, we update survival and include minimal residual disease (MRD) at end of treatment (EOT). Methods Eligible patients included those that were previously untreated and diagnosed with MCL by presence of t(11;14) or cyclin D1 expression. Patients must have been ≥60 years of age at the start of therapy with a good performance status (ECOG 0-2). Adequate marrow and organ function was required, specifically a creatinine clearance ≥ 40 ml/min. Eligible subjects were treated with bendamustine 90mg/m2 D1-2 and rituximab 375mg/m2 IV D1 every 28 days for a planned 6 cycles of therapy. For patients ≥75 years, 70mg/m2 of bendamustine was allowed. VEN was given concurrently with BR. During Cycle 1, VEN was dose escalated weekly, as done in chronic lymphocytic leukemia, from 20mg to 200mg. For Cycle 2-6, VEN was administered as 400mg PO daily on days 1-10 only. Maintenance rituximab was encouraged but was per investigator discretion. Primary end point was PET-negative complete remission (CR) at EOT by Lugano Criteria and was confirmed by a negative bone marrow biopsy if involved at screening. MRD was assessed at EOT by next-generation sequencing (Clonoseq). Amended accrual goal was 33 patients with a planned 32 being eligible and treated. This provided an 81% statistical power to detect a 17% difference in CR rate (from 60% [E1411, Smith et al Blood 2024] to 77%) using an exact binomial test with a 1-sided alpha of 11.6%. Thus, BR-VEN would be considered promising if 23 or more subjects attained a CR. Results From 1/2020 to 3/2022, 33 subjects were enrolled, deemed eligible, and treated on study. Subjects were followed until 7/2024. Median age was 71 (range 61-80) and 76% (n=25) were male. All but 1 subject (97%, n=32) were White. MIPI was high in 67% (n=22), intermediate in 27% (n=9) and low in 6% (n=2). Ki67 was available in 25 (76%) subjects and was ≥30% in 14 (56%) and ≥50% in 7 (28%). Only one subject started bendamustine treatment at 70mg/m2; though 6 others had dose reductions during treatment. Thirty (90%) subjects completed all 6 cycles of therapy. Maintenance rituximab was administered in 19 (56%) of subjects and 9 completed all 12 recommended doses. Treatment was generally well tolerated. During BR-VEN, Grade ≥3 treatment-related adverse events (TRAE) occurring in >10% (i.e., 4 or more) of subjects were neutropenia (n=8, 24%), and thrombocytopenia (n=5, 15%). Other common TRAE of all grades were nausea/vomiting (n=19, 58%), diarrhea (n=10, 30%), and fatigue (n=19, 58%). At EOT with BR-VEN, overall response and CR rate was 97% (32 of 33) and 85% (28 of 33) respectively. The study met its primary endpoint of at least 23 subjects with a CR best response (p=0.002). EOT MRD sample (blood or marrow aspirate) was available for 28 subjects (85%). At EOT, MRD was undetectable for 100% (n=28) of evaluable subjects at a sensitivity of 10-4 and 10-5. At a sensitivity of 10-6, 64% (n=18) were undetectable, 4% (n=1) were detectable and 32% (n=9) were indeterminate. With a median follow up of 39.1 months, 3-year progression free survival (PFS) was 68.9 and 3-year overall survival (OS) was 70.0%. There were 11 total PFS events during follow up. Four subjects in remission died due to COVID-19, 1 died from influenza, one died from HSV encephalitis, and 2 others died from other causes. Two subjects died shortly after progression and 1 subject is alive following disease progression. As this study enrolled during the height of the COVID-19 pandemic, a sensitivity analysis was performed censoring the COVID-19 attributable deaths – PFS and OS at 3 years was 78.7% and 80.0%. Conclusions BR-VEN was generally well tolerated as induction therapy in older patients with MCL. It achieved a high CR rate of 85% with 100% MRD undetectable rate at 10-5 sensitivity in those evaluable. However, there were competing risks for survival in this older population as, of the 11 PFS events, only 3 events were due to progression; 8 were due to death without progression.

Abstract Introduction The International Prognostic Index (IPI) is widely used to stratify risk in large B-cell lymphoma (LBCL) across all ages, with age-adjusted (aa)IPI applied to younger patients. While there have been efforts to develop prognostic indices (PIs) tailored to older patients, few are adopted in clinical practice due to their complexity and reliance on functional assessments, which are not routinely collected in real-world registry datasets. Recently proposed SENIOR-IPI (Dubois, ASH 2024) was developed for older patients with LBCL receiving anthracycline (A)-based therapy. We assessed the performance of standard and novel PIs in patients aged 80+ years and externally validated the SENIOR-IPI. Methods We harmonized and pooled data of patients aged 80+ years with newly diagnosed LBCL from a national registry and two prospective cohorts: NiHiL (Czech Republic, enrolled 2010–2023), LEO (USA; n=222, 2015–2020), and MER (USA; n=77, 2010–2015), forming a cohort of 819 individuals. We included 536 individuals with complete data on IPI components and albumin, including 485 treated with chemotherapy and 397 with A-based regimens (primary cohort). Following PIs were evaluated: IPI, NCCN-IPI, (aa)IPI, and SENIOR-IPI (age per year, aaIPI components, LDH >3x ULN as extra point, and albumin, all weighted six-fold; extranodal involvement excluded due to lack of prognostic significance). Multivariable hazard ratios (HR) were estimated using Cox proportional hazards models; discriminative ability was assessed using C-index and calibration plots. The primary endpoint was overall survival (OS); event-free survival results were consistent (230/357 events were deaths) and are not reported here. Results Among the 397 A-treated patients (median age 82 years, range 80–99), ECOG performance status (PS) 2–4 was observed in 35% of patients, clinical stage III–IV in 67%, elevated LDH in 65% (8% with >3x ULN), >1 extranodal (EN) site in 32%, and albumin levels < 3.5 g/dL in 27%. In multivariable modeling, only age per year (HR=1.07, P<0.01), and clinical stage (HR=1.36, P=0.048) were independent predictors of OS, whereas ECOG PS (HR=1.27, P=0.12), trichotomized LDH by ULN (HR=1.23, P=0.08) and albumin (HR=1.17, P=0.35) were not significant. SENIOR-IPI had the highest discrimination (C-index 0.631) in A-treated patients, outperforming IPI (0.617), NCCN-IPI (0.591), and aaIPI (0.620), with consistent results across cohorts: NiHiL (0.633), LEO (0.619), and MER (0.621). SENIOR-IPI stratified patients into low- (L-Risk, 0–9 points, 28%), low-intermediate (L-Int, 10–19 points, 42%), high-intermediate (H-Int, 20–29 points, 23%), and high-risk (H-Risk, 30–40 points, 7%) categories, with OS medians of 6.3, 3.8, 2.4, and 1.4 years, respectively (P<0.01), and significant separation between L-Int and H-Int (HR=1.47, P=0.02). By comparison, IPI categorized patients as L-Risk (12%), L-Int (24%), H-Int (27%), and H-Risk (37%), with median OS of 8.7, 4.6, 4.8, and 1.9 years, resp. (P<0.01). aaIPI yielded following distributions: 13%, 29%, 37%, and 21%; and median OS: 8.7, 5.3, 3.4, and 1.5 years; P<0.01. NCCN-IPI stratified patients into three groups: L-Int (13%), H-Int (49%), and H-Risk (39%), with respective OS medians of 8.7, 4.1, and 2.5 years (P<0.01). All PIs showed modest overestimation of mortality (calibration slopes: SENIOR-IPI 1.36; IPI 1.24; aaIPI 1.30; NCCN-IPI 1.26; intercept: -0.97, -0.87, -0.92, -0.87, resp.). In the entire cohort (n=536), SENIOR-IPI showed highest C-index (0.651 vs IPI 0.622, aaIPI 0.631, NCCN-IPI 0.606), and stratified patients into L-Risk (26%, 2-year OS: 6.4 years), L-Int (40%, 3.2 years), H-Int (24%, 1.5 years), and H-Risk (10%, 0.6 years). Calibration slope was 1.18 (intercept -0.33). Among patients not receiving chemotherapy, SENIOR-IPI also performed best (C-index 0.759 vs IPI 0.738, aaIPI 0.757, NCCN-IPI 0.728). Conclusion SENIOR-IPI enables effective risk stratification of patients aged 80+ years with LBCL into four prognostically distinct groups, outperforming traditional indices (IPI, NCCN-IPI, aaIPI) in patients receiving A-based therapy, as well as in the entire cohort and in patients not receiving chemotherapy. While its discrimination is superior, modest miscalibration suggests that future recalibration may improve precision. These findings support SENIOR-IPI as a clinically relevant prognostic tool for the elderly LBCL patient population. Funding: NU21-03-00411, P50 CA97274, U01 CA195568.

Abstract Background: Chronic myelomonocytic leukemia (CMML) is a universally fatal adult myeloid neoplasm with a median survival of 32 months and no approved therapies that alter its natural history. Although most patients initially present asymptomatically, disease progression (DP) is inevitable and its biological triggers remain poorly understood. Anecdotes and small case series suggest that acute inflammatory events (AIE) may precipitate hyperleukocytosis and DP in some patients, but fragmented care in the U.S. has hindered large-scale retrospective analyses. To address this gap, we launched a prospective, multi-institutional observational study to systematically evaluate the relationship between AIEs and DP. Our aim is to identify modifiable, cell-extrinsic stressors that contribute to disease destabilization and inform strategies for prolonging the indolent phase of CMML. Methods: We enrolled patients with WHO-defined CMML in a clinically asymptomatic state, defined by: (1) MPN-SAF TSS <20, (2) no CMML-directed therapy, (3) no symptomatic splenomegaly, and (4) transfusion independence. Key exclusions included active malignancy, uncontrolled infection, or inability to attend monthly visits. Over 24 months, participants underwent monthly interviews to document AIEs, including flares of chronic illness e.g. gout, infections, surgery procedures, cardiovascular events, and trauma. AIE severity was graded by hospitalization status. Blood samples were collected at each visit, with bone marrow collected when clinically indicated. Cytokine profiling was performed using Olink Reveal assays, and genomic data were integrated to assess mutation-specific inflammatory patterns. DP was defined by worsening symptoms (MPN-SAF TSS ≥20 with ≥50% increase), new transfusion needs, therapy initiation, symptomatic splenomegaly, or transformation to CMML-2/AML. Descriptive statistics summarized baseline and AIE data. Progression-free (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression models. Results: A total of 102 patients were enrolled over 2 years, with a median follow-up of 1 year (range, 0.5–1.5). The median age was 72 years; 71 were male and 31 female. By FAB criteria, 38 had myeloproliferative-type CMML, and 8 met WHO 2022 criteria for CMML-2. CPSS-Mol risk distribution was: 49.0% low, 26.5% intermediate-1, 37.3% intermediate-2, and 3.99% high. A total of 260 AIE were recorded in 77 patients. The most common AIEs were surgical procedures (n=115 events in 53 patients), flares of chronic disease (n=99 in 38), and infections (n=87 in 47). DP occurred in 28 patients: 18 met symptom-defined criteria, 13 met disease-defined criteria, and 3 met both. Longitudinal labs showed significant post-AIE increases in WBC (6.29 → 7.73 ×10⁹/L, p = 0.02) and platelets (112 → 131 ×10⁹/L, p = 0.03), with no change in hemoglobin (p = 0.27). Progressors had significantly lower hemoglobin than non-progressors (11.6 vs. 12.7 g/dL, p = 0.037), with no differences in WBC or platelet counts (p > 0.5). Among those with DP, 25 of 28 had at least one AIE. AIE presence was significantly associated with DP (OR 3.76, p = 0.04). Flares of chronic disease conferred a threefold increased risk of DP (OR 3.37, p = 0.008) and remained an independent risk factor after adjusting for CPSS-Mol risk (OR 3.6, p = 0.009). Severe AIEs requiring hospitalization trended toward higher risk but were not statistically significant (OR 2.3, p = 0.09). Among the 44 patients with genomic data, all AIE-positive patients (29/29) harbored at least one epigenetic regulator mutations (TET2, DNMT3A, ASXL1, IDH1/2), compared to 12/15 AIE-negative patients (p = 0.034). Signaling mutations (JAK2, CBL, NRAS, KRAS) were also enriched in AIE-positive cases (11/29 vs. 1/15, p = 0.035). No significant differences were found in spliceosome or tumor suppressor mutations. No genomic features distinguished progressors from non-progressors, regardless of whether there was an AIE. Conclusion: In this interim analysis of a prospective multi-institutional CMML cohort, AIE were significantly associated with DP. Ongoing work is aimed at sequentially annotating genomic alterations and profiling secreted factors before and after AIEs. While this study continues to accrue and mature, these findings support inflammation as a modifiable driver to CMML biology and progression and lay the groundwork for future studies investigating inflammatory or supportive interventions to delay disease evolution.

Abstract Background: Post-transplant lymphoproliferative disorder (PTLD) occurs in up to 30% of high-risk solid organ transplant recipients and is strongly associated with the intensity and duration of immunosuppression. While Epstein-Barr virus (EBV)-positive monomorphic PTLD and diffuse large B-cell lymphoma (DLBCL) share overlapping morphologic features and expression of canonical B-cell markers, they exhibit distinct EBV transcriptional programs. Immunosuppressive regimens, essential for preventing graft rejection, impair EBV-specific cytotoxic T lymphocyte (CTL) responses, thereby promoting EBV-driven lymphomagenesis. We hypothesized that these differences in viral transcription and immune evasion reflect fundamentally distinct immune microenvironments and host responses in EBV-positive PTLD compared to DLBCL. Methods This prospective, non-interventional study has been conducted at Moffitt Cancer Center since 2019. To characterize tumor-specific T-cell responses in EBV-positive PTLD versus DLBCL, peripheral blood mononuclear cells (PBMCs) from enrolled patients were infected with EBV (ATCC VR-1492) to generate autologous, immortalized lymphoblastoid B-cell lines (LCLs). EBV antigen-specific immune responses were quantified using an IFN-γ ELISpot assay targeting EBNA1, LAMP1, LAMP2A, BARF1, and a CEF peptide pool as a control. To optimize cell viability and functional readout post-thaw, we implemented an overnight resting protocol for PBMCs, which demonstrated superior IFN-γ release compared to the conventional 1-hour rest. Results We present pilot data from 11 consecutive patients (55% male; median age 63.4 years), including 3 with PTLD (2 EBV-positive; 2 monomorphic) and 8 with EBV-negative DLBCL. A total of 12 evaluable PBMC samples were analyzed: 7 pre-treatment, 1 mid-treatment, and 4 post-treatment. Successful generation of autologous LCLs was predominantly achieved using pre-treatment samples, whereas samples collected after B-cell–targeted therapy (Rituximab ± CHOP) showed reduced transformation efficiency. Notably, early pre-treatment samples exhibited a relative enrichment of CD27⁺ memory B cells. Baseline flow cytometric profiling of B cells undergoing LCL transformation revealed low CD19 expression (range <1%–15%). Repeat immunophenotyping at 3 weeks identified residual T cells within cultures, suggesting ongoing B-cell clearance. In matched flow cytometry and ELISpot assays from 7 evaluable patients with pre-treatment samples, EBV-positive PTLD cases demonstrated pronounced overexpression of PD-1 and TIM-3, but not LAG-3, alongside markedly diminished T-cell responses to EBV antigens. This distinct immunophenotypic and functional signature suggests T-cell exhaustion or dysfunction, likely driven by prior immunosuppression, which may impair immune surveillance and facilitate EBV-driven lymphomagenesis. Conclusions Our findings reveal distinct immunologic profiles in EBV-positive monomorphic PTLD compared to EBV-negative DLBCL, characterized by immune exhaustion and impaired T-cell functionality. Specifically, overexpression of PD-1 and TIM-3—but not LAG-3—in EBV-positive PTLD correlated with diminished antigen-specific T-cell responses, as measured by ELISpot, underscoring the role of prior immunosuppression in shaping ineffective tumor-specific immunity. Successful generation of autologous LCLs was predominantly achieved from pre-treatment PBMCs, highlighting the impact of B-cell–depleting therapies (Rituximab ± CHOP) on downstream immune profiling feasibility. The persistence of residual T cells in long-term LCL cultures suggests ongoing B-cell clearance and may reflect previously unrecognized immune dynamics in PTLD. Collectively, these data provide novel insights into the immune landscape of EBV-driven PTLD and support the rationale for therapeutic strategies aimed at reversing T-cell exhaustion—such as immune checkpoint blockade or adoptive T-cell therapies—to restore anti-EBV immunity in transplant recipients.

Abstract Background Nodal peripheral T-cell lymphomas (nPTCLs) are a challenging group of non-Hodgkin lymphomas that frequently recur after or are refractory to first line (1L) treatment. Chemotherapy options in the relapsed or refractory (R/R) setting are limited. The incorporation of non-cytotoxic agents including antibody drug conjugates, immune checkpoint inhibitors, epigenetic modifiers, and phosphatidylinositol 3-kinase inhibitors offers new therapeutic potential and possibly better outcomes. We report on outcomes for patients (pts) with R/R nPTCL enrolled in the multi-center LEO-MER prospective cohort study (NCT02736357) who received second line (2L) therapy. Methods Six hundred and three adult pts with newly diagnosed nPTCL were prospectively enrolled in the University of Iowa/Mayo Clinic MER observational cohort (2002-2015) or the expanded LEO cohort (2015-2020). Secondary overall survival (sOS) was calculated from date of 2L treatment initiation to date of death or last follow-up. Secondary event-free survival (sEFS) was calculated from date of 2Ltreatment initiation to disease progression, initiation of 3rd line therapy, or death from any cause. sEFS and sOS were evaluated using Cox model and Kaplan-Meier estimator. Log-rank test was used to test the significance of difference between groups. Pts with concomitant B-cell lymphomas were excluded from this analysis. Results Thus far, 169 pts with nPTCL initiating 2L therapy were evaluated. Of these, 75 (44.4%) had PTCL-NOS, 63 (37.3%) had angioimmunoblastic T-cell lymphoma (AITL, inclusive of nodal T-follicular helper cell lymphoma), 20 (11.8%) had ALK-negative anaplastic large cell lymphoma (ALCL), and 11 (6.5%) had ALK-positive ALCL. At 2L treatment initiation, the median age was 64 with 86.1% of pts having advanced stage disease. Of the 108 pts with available international prognostic index (IPI) scoring, 46.3% had an IPI of ≥3. Thirty-four (20.1%) pts had received a consolidative autologous stem cell transplant (ASCT) in the 1L. A total of 86 pts (50.1%) had primary refractory disease (partial response, stable or progressive disease as best response to 1L therapy), 45 (26.6%) experienced early relapsing disease within 6 months of 1L therapy, and 38 (22.5%) had relapsed disease >6 months from 1L therapy. After a median follow-up of 7.1 years (yrs), median sOS was 1.52 yrs, and sEFS was 3.2 months (mos). There was no difference in sOS or sEFS regardless of timing of relapse. In keeping with other studies, ALK-positive ALCL pts had the best 5-year OS (70.1%) compared to other subgroups (ALK-negative ALCL 45.0%, AITL 30.4%; PTCL-NOS 21.3%). Lymphoma was the leading cause of death following 2L therapy, with a 2-year cumulative incidence of 49.2%. Eighty pts (47.3%) received only cytotoxic chemotherapy as second line (2L) therapy; ICE (41 (51.3%)) and gemcitabine-containing regimens were most common (14 (17.5%)). Seventy-five pts (44.4%) were treated with non-cytotoxic agents given as monotherapy or in combination with chemotherapy. The most common non-cytotoxic therapies were brentuximab vedotin (33 (44.0%)), romidepsin (17 (22.7%)) and immune checkpoint inhibitors (9 (12.0%)). Fourteen pts (8.3%) underwent palliative interventions involving radiation, steroids, or cyclosporine alone. Intent to proceed to transplant in the 2L was known in 158 pts (101 (63.9%) not intended, 57 (36.1% intended)). Following 2L treatment, 18 (10.7%) pts proceeded to consolidative ASCT and 10 (5.9%) to allogeneic transplant. Only 21 (12.9%) were treated on a clinical trial. Pts who received a non-cytotoxic agent had superior outcomes compared to pts receiving only chemotherapy; the median sOS was 30.4 mos (95% confidence interval [CI] 15.3, 53.52 mos) vs 11.7 mos ((95% CI 7.95,19.58); p=0.04; HR 0.67) and the median sEFS was 4.83 mos (95% CI 3.38, 10.09) vs 2.33 mos ((95% CI 1.71,3.02); p=0.02; HR=0.65). Conclusions We report here one of the largest prospective cohorts in R/R nPTCL. The LEO-MER cohort, despite its association with academic centers, shows poor outcomes regardless of refractory or relapsed disease, frequent inability to proceed to intended consolidative transplant, and low clinical trial participation in 2L, which corroborates findings from other registries (Jain 2025, Stuver 2019). Outcomes improved for pts treated with non-cytotoxic agents. Updated data including additional pts and subgroup analyses will be reported at the meeting.