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Abstract Introduction: Primary central nervous system T-cell lymphoma (PCNSTL) is a rare form of PCNSL, comprising 2–8% of cases. Prognostic factors remain undefined, and no standard treatment protocol currently exists. Prior studies have been limited by small sample sizes, incomplete molecular profiling, and poor representation of novel treatment modalities. In this study, we aimed to identify clinicopathologic factors associated with patient (pt) outcomes and delineate the spectrum of treatment regimens used to inform future clinical practice. Methods A multicenter retrospective study was conducted across 15 North American academic institutions. Pts aged ≥18 years with biopsy-confirmed PCNSTL between 2009 and 2025 with no evidence of systemic disease were included. Cases with CNS relapse of systemic T-cell lymphoma were excluded. Baseline characteristics were analyzed using independent t-tests, Fisher's exact tests, or Pearson's chi-square tests. Primary endpoints were overall survival (OS) and progression-free survival (PFS), evaluated by Kaplan–Meier, log-rank tests, and Cox regression. Results: Forty-two pts met inclusion criteria. Median age was 57 (range 19–77), 69% were male, and 79% were white. Most (69%) had ECOG 0–1. No patients had HIV, hepatitis B or C, or a history of solid organ transplant. LDH was elevated at diagnosis in 38%, and 24% had B-symptoms. Mean absolute lymphocyte count at diagnosis was 1.82/µL. The most common histologic subtypes were PTCL-NOS (76%), followed by ALK-negative ALCL (12%) and γδ T-cell lymphoma (5%). All patients had parenchymal brain lesions with 57% having multifocal disease. Additionally, CSF involvement was seen in 21%, vitreoretinal involvement in 3%, and deep brain involvement in 34%. Next-generation sequencing was performed in seven pts (17%), with disease-associated variants identified in three cases. Among these, two pts had mutations in TP53, and one had a mutation in DNMT3A. Cytogenetics were obtained in 7 pts with only one exhibiting a complex karyotype. Only one pt was EBV positive by EBER-ISH. Overall, 79% received HD-MTX-based therapy. First-line treatments were mainly HD-MTX alone (38%), HD-MTX + temozolomide (17%), or vincristine + procarbazine (12%). No patients were treated on clinical trials. Median treatment duration was 78 days and median number of treatment cycles was 4 (range 1–9 cycles). One patient received radiation alone; 5% received radiation with systemic therapy. A steroid pre-phase was used in 60%, with 44% exhibiting a clinical response. Overall response rate to first-line treatment was 63% (13 CR, 12 PR). Imaging alone was used in determining response in all patients. Repeated biopsy was not performed. Twelve patients (29%) underwent consolidative autologous transplant, most commonly with thiotepa/carmustine (TT/BCNU, 69%) or BEAM conditioning (25%). Median duration of follow-up was 10.4 months. Sixty-two percent of pts progressed during the study period, with 7% experiencing extra-CNS relapse. Median PFS was 8.2 months. Improved PFS was associated with >3 cycles of therapy (p=0.03) and transplant with TT/BCNU (p=0.0004). At last follow-up, 43% were in remission and 52% were deceased, mostly due to disease progression (77%). Median OS was 17.6 months. One- and two-year OS rates were 58% and 42%, respectively. OS was associated with Nottingham/Barcelona score <2 (p=0.02), >3 treatment cycles (p=0.0008), response to first-line therapy (p=0.0007), and TT/BCNU-based transplant (p=0.0001). IELSG, Taipei, and MSKCC risk scores were not significantly associated with survival, though IELSG approached significance (p=0.09). Discussion: This study is among the largest cohorts of PCNSTL pts compiled to date. PCNSTL remains rare and heterogenous. Treatment across centers largely mirrors management of B-cell PCNSL with high utilization of HD-MTX regimens and TT/BCNU conditioning autologous transplant. Survival outcomes within our cohort are consistent with those previously reported within the literature. Receipt of >3 cycles of therapy, TT/BCNU conditioning and Nottingham/Barcelona scores were associated with longer survival within our cohort. Limitations of our study include its retrospective design and heterogeneity within pt disease characteristics, treatments utilized and disease assessment intervals. Further exploration into pathophysiology and optimal management of this unique entity is needed.

Abstract Background:Erdheim-Chester Disease (ECD) is a rare, incurable histiocytic neoplasm. Since its recognition in 1930, our understanding of ECD's pathophysiology has evolved. The identification of its clonal nature after 2015 established ECD as a cancer, prompting increased disease awareness and treatment advances. Targeted therapies show promising responses, but changes in ECD mortality over time have not been extensively documented. Methods:A multi-institutional retrospective cohort study analyzed adults with ECD consecutively seen at Mayo Clinic MN, AZ, and FL and the University of Alabama at Birmingham between 2007 and 2024. Clinical and prognostic data were abstracted. Overall survival was estimated using the Kaplan-Meier method and compared to expected survival using U.S. Census data, based on age at diagnosis (by calendar year), date of diagnosis, and sex. Standardized mortality ratios (SMRs) were calculated by dividing the number of observed deaths in the study population by the expected number of deaths using U.S. population data. Risk of death was compared by date of diagnosis (pre- and post-2015) using Cox proportional hazards analysis. Statistical analysis was performed with R software. Results:A total of 159 ECD patients were included (median age 58 years [range 19-82], 65% male). Forty-nine patients were diagnosed between 1990-2014 and 110 between 2015-2024. Median follow-up for the entire cohort was 4.0 years (95% CI: 3.2-4.4). Median follow-up for those diagnosed between 1990-2014 was 10.4 years (CI: 3.2-16.8), compared to 3.5 years (CI: 3.0-4.2) for those diagnosed between 2015-2024. The 5-year overall survival rate was 80% (95% CI: 72-88). Patients with ECD had an increase in mortality over expected, with 28 deaths compared to an expected 11.2, an SMR of 2.5 (95% CI: 1.7-3.6, p<0.001). Of 17 patients with an identified cause of death, death was attributable to ECD in 11 (65%), secondary malignancy in 1 (7%), and unrelated causes in 5 (29%). Cause of death was unknown in 11 patients. Among deaths, 11 (39%) were treated with targeted therapy, 8 (29%) with chemotherapy, and 1 (4%) received both. One patient (4%) received steroids, 1 received immunomodulator and targeted therapy (4%), and 6 (21%) received no disease-directed therapy. Of the patients whose death was related to ECD, 10 (91%) had multisystem disease. For 49 patients diagnosed pre-2015, 14 deaths occurred during the follow-up, significantly higher than the expected 5.2 deaths based on U.S. population data (SMR of 2.7 [95% CI: 1.5-4.4, p=0.001]). Among those diagnosed between 2015 and 2024, 14 deaths occurred, compared to expected 6.1 (SMR of 2.3 [95% CI: 1.3-3.8, p=0.006]). In an age- and sex-adjusted Cox proportional hazards model, diagnosis after 2015 vs. diagnosis prior to 2015 yielded a hazard ratio of 0.59 (95% CI: 0.27-1.31, p=0.19). Conclusion:The mortality rate of ECD patients remains higher than the general population, despite advancements in disease recognition and development of targeted therapies. While our data suggest a possible trend toward improved survival among patients diagnosed after 2015, we did not find statistically significant evidence of decreased mortality compared to those diagnosed prior to 2015. Larger cohorts with longer follow-up periods are needed to draw definitive conclusions regarding mortality.

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

Abstract 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: Flow cytometry (FC) is widely utilized for the identification of measurable residual disease (MRD) in multiple myeloma (MM), providing an essential laboratory indicator for prognostic assessment and therapeutic management. Unfortunately, the high level of expertise required, long manual analysis time, and complexity of FC data files currently limit the offering of this testing to selected reference laboratories. Methods: We developed an artificial intelligence (AI) pipeline to automatically enhance unaltered FC files, minimizing the expertise and manual analysis time needed to detect MM MRD using the 2-tube Euroflow Consortium Panel (Cytognos). Raw FC files corresponding to 150 MRD-positive bone marrow samples (MRD < 5%, median = 0.0022%), and 39 MRD-negative samples were processed through our CCADDAS (Clustering and Classification of All events, Dimensionality reduction, Downsampling and Aberrancy Scaling) pipeline, deployed on a custom clinical-grade cloud environment (Biolegend). Automated processing steps included elimination of acquisition errors (FlowCut), state-of-the-art clustering (PARC), cluster-informed and density-based downsampling with preservation of low-event subsets, dimensionality reduction (UMAP), and cluster-based anomaly detection compared to negative controls (29 bone marrow aspirates). In addition, a deep neural network (DNN) trained on expert-defined subpopulations from negative controls was included for automatic gating of normal subsets (Tensorflow v2). AI-enhanced data files were analyzed using a general-purpose flow cytometry analysis software (Kaluza v 2.3, Beckman Coulter), and %MRD estimates were compared to reported results based on traditional expert analysis of original FC files. Results: Cluster-informed downsampling reduced the number of cells to be manually analyzed from 4.1 million to 196,761 cells per tube, on average (95% cellularity reduction); resulting in a smaller FC data file (from 203.2 MB to 20.5 MB; 90% data reduction). Importantly, low-level MRD events were adequately preserved after downsampling (median 88% and 77% retention, for 0.01-0.001% MRD and < 0.001% MRD, respectively). True number of events were accurately estimated on gated subsets using an “upsampling factor” parameter [observed # events x mean (upsampling factor)]. Gating of normal subsets was completely automated using a DNN classifier parameter. In 96% of positive cases, MRD was rapidly identified as immunoglobulin light chain-restricted plasma cells on a single pre-calculated UMAP plot (tube 2), after dual coloring for kappa and lambda. On the remainder 4% of positive cases, MRD was easily segregated from benign plasma cells using the AI-generated “aberrancy scale” parameter or other strategies. The use of AI-enhanced files reduced manual analysis time from 15.05 minutes (SD = 6.84) to 1.29 minutes (SD = 0.90) per case, on average (p < 0.0001) (91% reduction of manual analysis time). MM MRD was detected in all positive cases above limit of detection for our assay (≥0.0002%), with excellent quantitative correlation with conventional analysis on original FC files (linear regression slope = 0.9841, P < 0.0001). Conclusion: We introduce a largely unsupervised AI pipeline that transforms raw MM MRD FC data from the Euroflow Consortium panel into a markedly smaller, AI-annotated and software-agnostic FC file, including comparison to normal controls. This CCADDAS pipeline simplifies and accelerates detection of MM MRD in clinical diagnostics, reducing the number of cells analyzed by 95% and manual analysis time by 91%, without impacting test performance. Moreover, CCADDAS can be utilized for any laboratory-developed MM MRD assay, and its small-sized export is compatible with any clinical FC software, computing platform, and analysis strategy. Adoption of CCADDAS is likely to facilitate the implementation of MM MRD FC analysis by more clinical laboratories.

Abstract Somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis) are known to alter the immune milieu and can result in autoimmune disorders including VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome. There are currently no curative strategies for CH-linked autoimmune disorders besides allogenic hematopoietic stem cell transplantation. Recent work has shown a high prevalence of autoimmune syndromes among patients with IDH1/2 mutant myeloid neoplasms (MN). We thus hypothesized that IDH1/2-mutant CH might drive a subset of autoimmune disorders. To further characterize a possible association between IDH-mutant CH and autoimmune disease, we used data from two observational cohort studies, the UK Biobank (N=454,218) and All of Us (N=414,830). We observed 264 individuals with IDH1/2-mutant CH. IDH1/2 CH was associated with autoimmune disease (OR=1.8, p=4e-3), and, when compared to other CH genes with at least 100 carriers, showed the strongest effect size. When comparing autoimmune subtypes, we observed significant associations with polymyalgia rheumatica (OR=4.0, p=1e-3) and giant cell arteritis (OR=8.1, p=1e-6). IDH1/2 CH carriers had elevated CRP levels compared to other CH-carriers (p=1e-2) and non-carriers (p=8e-3). IDH1/2 CH was associated with lower neutrophil counts and higher monocyte counts. While most (68%) had blood counts outside the normal range, only a minority (11%) had severe cytopenias that met criteria for CCUS. Since IDH1/2 CH is associated with both autoimmune disease and blood count abnormalities, we sought to define the frequency, clinical presentation, and outcomes of IDH1/2-associated autoimmune disease among individuals with bone marrow biopsy confirmed CCUS. We used data from three CCUS cohorts: first, a multi-institutional cohort of CCUS patients with systemic autoinflammatory disease (SAID) who were UBA1-negative, second, a hospital-based cohort at Mayo Clinic, and third, a cohort of IDH1 carriers enrolled on a phase II clinical trial of ivosidenib (NCT05030441). Within 193 SAID patients who were free of myeloid neoplasm at the time of recruitment, IDH1/2 pathogenic variants were the most observed CH driver, occurring in 2% of individuals. These individuals (N=4) all had recurrent fevers and dermatologic manifestations, requiring chronic glucocorticoid treatment with 75% having inflammatory arthritis requiring multiple Disease-Modifying Antirheumatic Drugs (range 1-7, median=5). Within the Mayo Clinic cohort, 275 patients with CCUS were serially ascertained. Among those 8 (2.9%) were IDH1-mutant of whom 50% had autoimmune disease (three with seronegative rheumatoid arthritis and one with Sweet syndrome). At last follow up (median 16 months), 2 (25%) of 8 patients had progressed to MN. Within our open-label decentralized trial of ivosidenib (IDH1 inhibitor) in CCUS, we enrolled 20 patients, of whom 5 (25%) had a diverse array of pre-existing autoimmune disorders, including two cases of seronegative rheumatoid arthritis and one case each of Sweet syndrome, polymyalgia rheumatica, and Sjögren's syndrome. Underlying the clinical presentation of all five cases was episodic joint pain, with half also experiencing episodic dermatologic manifestations. The majority (58%, 11/19) of the IDH1mt-CCUS patients had an elevated hsCRP (>=5; range 6.91–46.2) including all four with co-occurring autoimmune disorders (range 7.97–46.2). Out of the 20 enrolled patients, 17 received at least 8 weeks of therapy, of which 9 had elevated hsCRP at baseline. Most of these (7/9) had normalization of hsCRP (falling below 5 mg/L) while on treatment (median time to hsCRP normalization of 58 days). Among the four patients with autoimmune disease, all had subjective improvement in their autoimmune symptoms following treatment with ivosidenib. In conclusion, we show that IDH1/2 CH is associated with autoimmune disorders and is particularly enriched among IDH1/2 CH carriers with co-occurring cytopenias. IDH1/2-associated autoimmune disease can range from classic rheumatic conditions such as rheumatoid arthritis to more severe VEXAS like presentations. IDH inhibition demonstrates efficacy for improving inflammatory manifestations within an ongoing clinical trial. Together these results nominate IDH mutant CH as a driver of autoimmune diseases with therapeutic implications.

Abstract Introduction Defining the epidemiology of myelodysplastic syndromes/neoplasms (MDS) and precursor conditions, such as clonal cytopenia of undetermined significance (CCUS), is challenging due to inconsistent reporting, complex diagnostics, and evolving criteria. The National MDS Natural History Study (NHS) overcomes these challenges through central pathology review, prospective follow-up, and a nationally representative cohort enrolled at the time of suspected MDS, enabling robust analysis across the myeloid disease spectrum. We analyzed clinical, genetic, and pathologic features in NHS participants by race, ethnicity, and sex to characterize disease variation across populations. Methods The NHS (NCT02775383) enrolled individuals undergoing evaluation for suspected MDS from June 2016–July 2024 at 102 US sites. Participants underwent bone marrow assessment with centralized, adjudicated histopathology review. Those meeting WHO 2016 criteria for MDS, MDS/myeloproliferative neoplasm (MPN), CCUS, idiopathic cytopenia/dysplasia of undetermined significance (ICUS/IDUS), or oligoblastic AML were followed longitudinally. Demographics, comorbidities, exposures, and clinical data were collected at baseline and every 6 months. Deep DNA sequencing was performed on baseline marrow, with pathogenic variants manually curated (53 genes). Statistical analyses assessed associations using chi-squared, Fisher's exact, Kruskal-Wallis, logistic regression, and Cox models. A p-value <0.05 was considered significant. Results Among 2,021 participants, 1,174 (58%) were diagnosed with MDS or precursor conditions. Median age was 74 years (yrs) and 66% were male. Most identified as Non-Hispanic White (NHW, 92%), with 4% Black and 4% Hispanic. The most common diagnoses were MDS (42%) and CCUS (37%). Pathogenic somatic mutations were identified in 84% (774/918) of MDS/CCUS, with TET2 (26% of 918), DNMT3A (21%), and ASXL1 (16%) most frequent. Median follow-up was 1.8yrs and consistent across race, ethnicity, and sex (p≥0.6). Black, compared to NHW, participants were younger (69 vs 74 yrs, p=0.006) and trended toward more females (47% vs 34%, p=0.09) and more MDS diagnoses (51% vs 41%, p=0.07). Black participants showed more advanced disease (e.g., lower hemoglobin, higher peripheral blood blasts, higher variant allele frequencies (VAFs) of pathogenic mutations), yet received less MDS-directed treatment (14% vs 41%, p=0.01). Black, compared to NHW, participants had more mutations in RUNX1, TP53, BCOR, and DNMT3A, but fewer in TET2 and ASXL1. Hispanic, compared to Non-Hispanic, participants had fewer known pathogenic mutations, leading to more ICUS (19% vs 5%, p=0.02). Females, compared to males, were younger at diagnosis (72 vs 75yrs, p<0.001), had more ICUS/IDUS (20% vs 10%, p<0.001), fewer pathogenic mutations, especially in splicing/chromatin modifier genes (U2AF1, SRSF2, ASXL1, ZRSR2), more DNMT3A mutations, and lower VAFs (0.27 vs 0.33, p<0.001). Median overall survival (OS) was 6.4yrs, and shorter in MDS (4.2yrs) than CCUS (not reached). Worse OS was associated with age (adjusted hazard ratio (aHR) 1.06), MDS (vs CCUS; aHR 1.89), higher-risk disease by IPSS-R/CCRS (aHR 2.15), and TP53 mutations (aHR 2.17) (all p<0.001). A trend toward improved OS in Black participants was attenuated after adjustment (aHR 0.79, p=0.6). Progression (e.g., worsening of disease, increase in transfusion dependency, death) occurred in 53% of participants. Worse progression-free survival (PFS) was associated with MDS diagnosis (aHR 2.59), higher-risk disease by IPSS-R/CCRS (aHR 2.17), and TP53 mutations (aHR 1.86) (all p<0.001). Despite more advanced disease and less MDS therapy, Black participants trended toward improved PFS (aHR 0.62, p=0.14), while age was borderline significant (aHR 1.01, p=0.05). Conclusions For the first time, we show that among individuals evaluated for suspected MDS at sites across the US, 58% had MDS or precursor conditions. Differences across demographics underscore the heterogeneity of MDS. Black participants presented with more advanced MDS, received less treatment, but trended toward improved outcomes, particularly PFS, even after adjustment, suggesting biological rather than access-to-care differences driving disparities. These findings highlight the complex interplay of sex, race, and genetics in shaping MDS outcomes and reinforce the need for diverse, large-scale studies to improve risk stratification and personalized care.

Abstract Background: Venetoclax (VEN)+obinutuzumab (VO) is an effective therapy for CLL/SLL requiring regular monitoring for tumor lysis syndrome (TLS) during VEN ramp-up. The CLL14 trial of VO reported no TLS during VEN ramp-up; however, there are limited real-world data on monitoring practices and TLS outcomes for different dose levels and monitoring timepoints. This study assessed VEN initiation prophylaxis and monitoring outcomes for patients (pts) with CLL/SLL starting VO in first line (1L) in an outpatient, real-world setting. Methods This interim analysis relied onretrospective observational data from 4 US sites of the CLL Collaborative Study of Real-World Evidence (CORE). Adult pts with CLL/SLL were eligible if they: (1) started VO per-label outside of a clinical trial in 1L, or immediately after exposure in 1L to agents with different mechanisms of action (i.e., BTKi, anti-CD20 only) of <30 days; (2) prior to VEN start, had either (i) low physician-determined tumor burden (TB) (i.e., all lymph nodes [LN] <5 cm and ALC <25 x 109/L), or (ii) medium physician-determined TB (i.e., any LN ≥5-<10 cm or ALC ≥25 x 109/L) with creatinine clearance ≥80 mL/min; (3) had no strong CYP3A inhibitors or prophylactic rasburicase from 3 days prior to VEN start until end of VEN ramp-up; and (4) had VEN ramp-up in an outpatient setting. TB-related labs/imaging was assessed from 2 months prior to obinutuzumab initiation (i.e., index date) until VEN start. VEN characteristics (i.e., dosing, duration), prophylaxis measures (i.e., antihyperuricemics and IV hydration), and TLS-related monitoring and management (i.e., lab results and interventions received) were collected per ramp-up week and TLS monitoring timepoint. Results Of 128 pts in CORE who initiated VO in any line, 72 pts met inclusion criteria (low TB: 57 [79.2%]; medium TB: 15 [20.8%]). Median (IQR) age was 62 (56.0, 68.5) years, 58.3% were male, and 81.9% had ECOG grade ≤1. Among pts tested, 7/68 (10.3%) had del(17p)/TP53 mutation and 43/66 (65.2%) had unmutated IGHV. Median (IQR) time from index to VEN start was 23.0 (22.0, 30.0) days. Most pts completed ramp-up (98.6% [71/72]) and followed a per-label regular dosing schedule (93.1% [67/72]). Prior to VEN ramp-up, all pts received prophylactic antihyperuricemics (allopurinol: 71 [98.6%]; febuxostat: 2 [2.8%]) and prophylactic hydration. In the 2 days prior to a dose escalation for at least 1 week of ramp-up, prophylactic IV hydration was reported for 27 (37.5%) pts based on physician determination. One pt stopped VEN after week 2 due to neutropenia (grade 3+). During ramp-up (median [IQR] of 9 [8, 12] blood tests per pt), no lab or clinical TLS was reported. Of 21 (29.2%) pts who received an intervention following a lab assessment, most had low TB at VEN start (16 [76.2%]). All interventions were either prophylactic or non-TLS-related. Following a lab assessment for at least 1 week of ramp-up, prophylactic IV or escalated oral hydration intervention was reported in 17/21 pts (81.0%) based on physician determination (e.g., to manage impaired baseline renal function in those with low TB, patient request, or institutional practice) (IV hydration: 15 pts; escalated oral hydration: 2 pts). By per-label monitoring timepoints, hydration intervention was given prophylactically following pre-dose lab tests for 7 pts (across weeks 1-5), 6-8 hours post-dose for 5 pts (weeks 1-2), and 24 hours post-dose for 10 pts (weeks 1-2). By per-label monitoring timepoints, other non-TLS-related interventions (i.e., blood transfusion for anemia, insulin for hyperglycemia, and potassium for non-TLS-related hypokalemia) were given following pre-dose lab tests for 2 pts (weeks 1-5) and 24 hours post-dose for 4 pts (weeks 1-2). Conclusion Consistent with the CLL14 trial, no TLS was reported in this real-world, interim analysis of pts with mostly low TB and good renal function at 1L VO initation. All interventions during VEN ramp-up were prophylactic or non-TLS-related, with prophylactic hydration commonly given based on physician preference. These results suggest that VO initiation is manageable in an outpatient setting. Consideration should be given for simplified monitoring requirements including potential removal of 6-8 hour post-dose lab in this population and be further explored in prospective studies. Data collection for this study is ongoing to further contextualize real-world VEN initiation prophylaxis and monitoring outcomes in a larger cohort.

Abstract Introduction There is currently no standard-of-care for patients (pts) who cannot tolerate full dose anthracycline regimens in frontline large B-cell lymphoma (LBCL). R-miniCHOP is a commonly used regimen that provides curative intent treatment with manageable toxicity. Despite this, lymphoma and treatment-related mortality are the leading causes of death in these pts. Additionally, many pts may not be eligible to receive R-miniCHOP due to comorbidity or frailty. There are limited clinical trial and real-world data focused on this population. Methods Pts with LBCL age 18 years (yrs) and older were identified from the Lymphoma Epidemiology of Outcomes (LEO) cohort, a prospective study of newly diagnosed pts with non-Hodgkin lymphoma enrolled from 2015-2020 at 8 academic medical centers in the US. Pts with LBCL were included in this analysis if they had received R-miniCHOP or a regimen that did not include an anthracycline (nonAC). NonAC regimens included R-CVP, BR, rituximab, radiation and lenalidomide and rituximab. Pts completed the Vulnerable Elders Survey (VES-13) and were considered vulnerable if they had a score >3. Event-free survival (EFS) was defined as the time from start of treatment until progression/relapse, retreatment, or death due to any cause; EFS at 24 months (EFS24) was a secondary endpoint. Overall survival (OS) was defined as the time from start of treatment until death due to any cause. EFS and OS for R-miniCHOP and non-IC groups, as well as vulnerable and not vulnerable by VES-13 were estimated using Cox models. Results A total of 190 pts received R-miniCHOP (N=139) or nonAC (N=51). R-miniCHOP-treated pts were older (median 82 vs 72 yrs) and more commonly female (55% vs 35%). The majority in both groups (86% vs 78%) received their treatment at a LEO center and did not receive therapy on a clinical trial (89% vs 100%). Most pts receiving R-miniCHOP had high-intermediate (32%) or high (30%) international prognostic index (IPI) score, while both high-intermediate (22%) and high (20%) IPI were lower in the nonAC-treated pts. Cell of origin was determined by immunohistochemistry as available clinically, with GCB 42% vs 31%, non-GCB 32% vs 29%, and not done/unknown 26% vs 39% in R-miniCHOP vs nonAC pts. Double-hit status by FISH was known in 115 pts and was positive in 13% of R-miniCHOP pts and 10% of nonAC pts. The diagnosis-to-treatment interval (DTI) was ≤14 days in 30% of R-miniCHOP pts and 24% of nonAC pts. Of pts who had a VES-13 score (N=119), vulnerable status trended higher in the R-miniCHOP (66%) vs the non-IC group (50%; p=0.15). With a median follow-up of 50.5 months, the median EFS was 37.1 months and median OS was 50.0 months. R-miniCHOP, compared with non-IC, was associated with improved EFS (unadjusted HR=0.54, 95% CI 0.36-0.81; p=0.003) and OS (unadjusted HR=0.58, 95% CI 0.38-0.88; p=0.011). When adjusted for age, IPI, LBCL subtype (diffuse large B-cell lymphoma, not otherwise specified vs other), DTI and VES-13, R-miniCHOP was strongly associated with improved EFS (HR=0.26, 95% CI 0.14-0.50; p<0.001) and OS (adjusted HR=0.29, 95% CI 0.15-0.57; p<0.001). EFS24 rate was 56% in all pts and was superior in pts treated with R-miniCHOP vs non-IC (62.7% vs 34.1%; p=0.001). In the R-miniCHOP group, vulnerable status (adjusted for IPI) was associated with inferior OS (HR=2.22, 95% CI 1.09-4.50; p=0.028) and trended towards inferior EFS (HR=1.76, 95% CI 0.93-3.32; p=0.083). In a competing-risk cumulative-incidence analysis, lymphoma was the leading cause of death for pts receiving R-miniCHOP at 2 (0.16, 95% CI 0.11-0.24) and 5 (0.20, 95% CI 0.14-0.28) yrs, as well as for those receiving non-IC at 2 (0.35, 95% CI 0.24-0.53) and 5 (0.38, 95% CI 0.26-0.56) yrs. Treatment-related mortality was similar in both groups. In the R-miniCHOP group, the 2-yr (0.20 vs 0.03) and 5-yr (0.20 vs 0.11) lymphoma-related mortality was higher in pts who were vulnerable vs not by VES-13, while there were no differences for mortality due to therapy or other causes by vulnerable status. Conclusions These data support R-miniCHOP as a curative regimen in older and frail pts with the majority achieving EFS24. R-miniCHOP compared to non-IC use is strongly associated with improved EFS and OS when adjusted for disease and patient related variables. Within the R-miniCHOP group, vulnerable status is associated with inferior OS. Additional research efforts are needed to optimize outcomes for this group of pts.